Migraine and Other Headache Disorders

Migraine and Other Headache Disorders NEUROLOGICAL DISEASE AND THERAPY Advisory Board Gordon H. Baltuch, M.D., Ph.D. Department of Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania, U.S.A. Louis R. Caplan, M.D. Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A. Mark A. Stacy, M.D. Movement Disorder Center Duke University Medical Center Durham, North Carolina, U.S.A. Mark H. Tuszynski, M.D., Ph.D. Professor of Neurosciences Director, Center for Neural Repair University of California—San Diego La Jolla, California, U.S.A. 1. Handbook of Parkinson’s Disease, edited by William C. Koller 2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer’s Disease: Molecular Genetics and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimer’s Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinson’s Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos, and Elkan R. Gamzu 12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith 13. Handbook of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton 22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation, edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller 31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. Therapy of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer 37. Neurological Complications of Cancer, edited by Ronald G. Wiley 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. 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Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgether 51. The Autonomic Nervous System in Health and Disease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. Ingoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook 54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky 55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni 56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition, Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery, edited by Michael Schulder 59. Handbook of Parkinson’s Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 60. Clinical Neurovirology, edited by Avindra Nath and Joseph R. Berger 61. Neuromuscular Junction Disorders: Diagnosis and Treatment, Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by Kapil D. Sethi 63. Therapy of Parkinson’s Disease: Third Edition, Revised and Expanded, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 64. Epilepsy: Scientific Foundations of Clinical Practice, edited by Jong M. Rho, Raman Sankar, and José E. Cavazos 65. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders: Second Edition, edited by Roger Kurlan 66. Handbook of Cerebrovascular Diseases: Second Edition, Revised and Expanded, edited by Harold P. Adams, Jr. 67. Emerging Neurological Infections, edited by Christopher Power and Richard T. Johnson 68. Treatment of Pediatric Neurologic Disorders, edited by Harvey S. Singer, Eric H. Kossoff, Adam L. Hartman, and Thomas O. Crawford 69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications, edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber 70. Handbook of Essential Tremor and Other Tremor Disorders, edited by Kelly E. Lyons and Rajesh Pahwa 71. Handbook of Peripheral Neuropathy, edited by Mark B. Bromberg and A. Gordon Smith 72. Carotid Artery Stenosis: Current and Emerging Treatments, edited by Seemant Chaturvedi and Peter M. Rothwell 73. Gait Disorders: Evaluation and Management, edited by Jeffrey M. Hausdorff and Neil B. Alexander 74. Surgical Management of Movement Disorders (HBK), edited by Gordon H. Baltuch and Matthew B. Stern 75. Neurogenetics: Scientific and Clinical Advances, edited by David R. Lynch 76. Epilepsy Surgery: Principles and Controversies, edited by John W. Miller and Daniel L. Silbergeld 77. Clinician's Guide To Sleep Disorders, edited by Nathaniel F. Watson and Bradley Vaughn 78. Amyotrophic Lateral Sclerosis, edited by Hiroshi Mitsumoto, Serge Przedborski, and Paul H. Gordon 79. Duchenne Muscular Dystrophy: Advances in Therapeutics, edited by Jeffrey S. Chamberlain and Thomas A. Rando 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by Stuart D. Cook 81. Brain Embolism, edited by Louis R. Caplan and Warren J. Manning 82. Handbook of Secondary Dementias, edited by Roger Kurlan 83. Parkinson's Disease: Genetics and Pathogenesis, edited by Ted M. Dawson 84. Migraine, Russell Lane and Paul Davies 85. Migraine and Other Headache Disorders, edited by Richard B. Lipton and Marcelo E. Bigal Migraine and Other Headache Disorders Richard B. Lipton Albert Einstein College of Medicine New York, New York, U.S.A. Marcelo E. Bigal Albert Einstein College of Medicine New York, New York, U.S.A. New York London Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 © 2006 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3695-3 (Hardcover) International Standard Book Number-13: 978-0-8493-3695-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. 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Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Taylor & Francis Group is the Academic Division of Informa plc. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Preface With this first edition of Migraine and Other Headache Disorders, we celebrate the remarkable progress in the art and science of headache during the last decade. With 32 chapters by 54 leaders in the field, the book provides health care professionals with practical approaches to patient care and reviews the scientific foundations of headache. We emphasize migraine because of its high prevalence, enormous burden, and the increasing availability of effective management strategies. At the same time, we provide broad coverage of all the primary headache disorders. Finally, although not focusing on specific subtypes of secondary headaches, we discuss strategies for diagnosing and excluding the ominous causes of headache, based both on clinical evaluation and, when appropriate, the use of diagnostic testing. Our understanding of headache and the approach to treatment have been transformed by insights from many places. Based on the Second Edition of the International Classification of Headache Disorders, the book provides a series of diagnostic algorithms intended to simplify clinical practice. We also present up-to-date epidemiologic information on the primary headache disorders. Epidemiologic studies show that the overwhelming majority of headache sufferers who seek treatment in primary care settings have migraine. Diagnosis becomes more efficient when that fact is taken into account. Doctors should avoid oversimplifying the differential diagnosis of the primary headaches, however. Our understanding of migraine as a disorder has significantly evolved over the past decade, based on genetic, epidemiologic, and translational studies. Once considered an episodic pain problem, treating the pain seemed like a sensible strategy. In the past few years, many lines of evidence have suggested that migraine and other headache disorders are best understood as chronic disorders with episodic manifestations. Painful episodes are the most prominent manifestation of migraine. Nonetheless, between attacks, there is an enduring predisposition to headache that characterizes the migraine brain. Furthermore, migraine is not only a chronic disorder with episodic manifestations, it is sometimes a disorder that progresses in several ways. Progression may be clinical, as attacks increase in frequency until chronic or transformed migraine develops. This clinical progression is sometimes accompanied by the development of allodynia with sensitization as its presumed substrate. In addition, in some individuals, morphological progression takes the form of deep white matter lesion or posterior circulation strokes that increase with migraine attack frequency, probably reflecting neuroplastic changes in the brain. Herein we highlight the emerging data on progression and on the modifiable risk factors for migraine progression. Progress in treatment has also taken several forms. Since 1990, ten new acute treatments with a multiplicity of formulations and two preventive drugs have been iii iv Preface approved. Many studies show that acute treatments work best if given early in the attack. Combining acute treatments may improve treatment response in some individuals. In addition, recent epidemiologic data shows that, based on frequency and disability criteria, preventive treatment should be offered or considered in about 40% of migraine sufferers. The same studies show that only 12% currently receive preventive therapy. Preventive treatment decreases attack frequency and severity and possibly prevents migraine progression. The use of specific acute agents that act on the neural pathways of migraine pain, such as the triptans, dramatically improve patient outcomes. Migraine and Other Headache Disorders highlights the treatment approaches developed at some of the best headache clinics in the world. It also reflects many of the strategies adopted at The Montefiore Headache Center. The Montefiore Headache Center was the first headache specialty care center in the world, founded in 1945 by Dr. Arnold Friedman, and it is where we are both proud to be. We are extremely grateful to our mentors. Among them, Dr. Lipton wants to thank Dr. Seymour Solomon, who directed The Montefiore Headache Center for a quarter of a century, for being a wonderful mentor and teacher. He’d also like to thank his mentors and collaborators in research, particularly Drs. Philip Holzman, W. Allen Hauser, and Walter F. Stewart. Dr. Bigal wants to acknowledge Drs. Speciali and Bordini, from Brazil, and the teams at The New England Center for Headache (Rapoport, Sheftell, and Tepper) and at Montefiore (Lipton and Solomon) for their help and direction. We also want to thank the authors of the chapters in this book for their excellent work. Finally, we owe special thanks to our families, particularly our wives (Amy ´ Natkins Lipton and Janaına Maciel Bigal) and children (Lianna Lipton, Justin ´ Lipton, Luısa Bigal, and Hanna Bigal) for supporting us through evenings and weekends spent writing and editing as we prepared this book. Finally, to our readers, we hope this book furthers your efforts to improve the lives of headache sufferers. These common and disabling disorders are tremendously gratifying to treat. In a field where cures are rare, we can nonetheless help patients by empowering them with tools that relieve pain, restore their ability to function, and, perhaps, prevent disease progression. Richard B. Lipton Marcelo E. Bigal . . . . Lipton Introduction . . . 14 Headache Attributed to Nonvascular Intracranial Disorders . . 16 Headache Attributed to Psychiatric Disorders . . . 14 Headache Attributed to Head and/or Neck Trauma . 1 Classification of the Primary Headaches . . . Sinuses. . . 32 Conclusions . or Other Facial or Cranial Structures . 31 Probable Migraine—An Important Migraine Subtype . 23 The Burden of Migraine . . . . 23 The Epidemiology of Migraine . . . . Nose. . 5 Secondary Headaches . . .Contents Preface . . . . . . . . Lipton and Marcelo E. . 1 An Overview of the ICHD-2 . . . iii Contributors . . . . 14 Headache Attributed to Cranial or Cervical Vascular Disorders . Headache—Classification . . . . . . 33 References . . 1 Marcelo E. . 34 v . . . . . . . . . . . Neck. . . . . . . . . . . 15 Headache Attributed to Infection . . . . . . . 15 Headache Attributed to a Substance or Its Withdrawal . Bigal and Richard B. 16 Cranial Neuralgias and Central Causes of Facial Pain . . xv 1. . . . . 15 Headache Attributed to Disorders of Homeostasis . . . . . . 16 References . . . . . . . . . The Epidemiology and Impact of Migraine . . . . Eyes. 16 Controversies in the Classification of Primary Chronic Daily Headaches of Long Duration . . . . . . Teeth. . 17 2. . . . . . . . . . . Ears. . . . . 15 Headache or Facial Pain Attributed to Disorders of Cranium. . . Mouth. . . Bigal Introduction . 23 Richard B. . . . . . . . . . . . Scher Introduction . . . . 82 Familial Hemiplegic Migraine (FHM) . . . . . . . . . . . . . . Progressive Headache: Epidemiology. . . . . 38 Demographic Factors Associated with Chronic Daily Headache . . . . . . . Low and Kathleen Ries Merikangas Introduction . Comorbidity of Migraine . . . . . . . 65 . . 72 Occipital Cortex Excitability . . P. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 References . . . . . . . . . . . . 67 Neurophysiological Mechanisms . . . . . . . 72 Molecular Mechanisms . . . . . . . . . . . . . . . 75 Conclusions . . Pathophysiology of Migraine . 45 Nancy C. Goadsby Introduction . . . . . . . . . 81 Peter J. . . . . . . . . Pain Sensitivity: Intracranial and Extracranial Structures Todd D. . . 61 6. . . Pathophysiology of Aura . 42 4. . . . . Natural History. . . . . . . . . . . . . . . 83 Headache—Anatomy . 38 Other Factors Associated with Chronic Daily Headache Prevalence or Incidence . . .vi Contents 3. . . . . . . 84 . 67 M. . 74 Genetics . 83 Headache Physiology—Peripheral Connections . . . 54 5. Reuter Introduction . 53 References . . . . . . . . . . . . . . . . Sanchez del Rio and U. . . . . . . . . . . 42 References . . 45 Evidence for Migraine Comorbidity . . . . and Risk Factors . . . . . 82 Migraine Aura . . . . . . . 45 Methodology of Comorbidity Studies . . . . 77 7. . 46 Conclusion . . . 37 Classification . . . . . Rozen Anatomy of Head Pain . . . . 37 Ann I. . 39 Conclusion . . . . . 81 Genetics of Migraine . . . 81 Migraine—Explaining the Clinical Features . . 61 References . . . 67 Imaging Studies . . . . . . . 37 Chronic Daily Headache Epidemiology and Natural History . . . J. . . 104 Time Course of Sensitization in Migraine . Joost Haan. . . Terwindt. . . Frants. . .Contents vii Headache Physiology—Central Connections . . . . 133 Evaluation of the Acute Severe New-Onset Headache (‘‘First or Worst Headaches’’) . 106 The Effect of Allodynia on Treatment Outcome . . 89 References . . . 103 Human Studies of Allodynia in Migraine . . . . . 118 Sporadic Hemiplegic Migraine . . Evans and R. . . . . . . . 107 Conclusion . 131 General Indications for Neuroimaging for Headaches . . . . . . . . . 99 William B. 124 10. . 132 Neuroimaging for Migraine . Esther E. . . . 90 8. 120 Cluster Headache . 140 References . 100 Sensitization of the Dorsal Horn . . . . . 100 Rat Model of Migraine Headache and Allodynia . . . 138 New Daily Headaches . . . . M. Kaate R. Ferrari Introduction—Genetic Studies on Headache . . . . . 88 What Is Migraine? . . . 131 Randolph W. 107 Allodynia in Headache Disorders Other Than Migraine . Allodynia and Sensitization in Migraine . . . . . . . Arn M. Kors. . . . . . . 123 Tension-Type Headache . . and Michael L. Genetics of Migraine and Other Primary Headaches . . Oshinsky Introduction . . 108 References . . . . . 123 Concluding Remarks . . Identification or Exclusion of Secondary Headaches . . . Young. . Avi Ashkenazi. van den Maagdenberg. . J. 102 Human Studies of Allodynia in Pain Disorders Other Than Migraine . 135 Headaches Over the Age of 50 Years . . . . . . . Allan Purdy Introduction . . . . . . . . 123 References . . . . . 114 The Clinical Spectrum of the ATP1A2 Gene . . . . . . . . . . 113 The Clinical Spectrum of the CACNA1A Gene Mutations . 141 . 99 Sensory Processing by the Nervous System . 86 Central Modulation of Trigeminal Pain . 113 Gisela M. . . . . . . . . . . . . . . 106 The Effect of Treatment on Allodynia . . Vanmolkot. . . Rune R. . . . 132 Neuroimaging for Headaches with a Normal Neurological Examination . . . . . . . . . 120 Genetic Susceptibility in Migraine . 108 9. . . . . . and Michel D. . . . . . 203 Vincenzo Guidetti. . . . . 199 15. . 181 Menstrually Related Migraine . . . . Migraine with Aura . . . . . . . . . . 189 Migraine with Typical Aura . . . . . . . . . Bigal and Richard B. . . 199 References . . 198 Differential Diagnoses . . . . . . . . . . . . . . . Marcelo E. . . . . . . . . . . . 165 Appendix: The PRIME-MD Questionnaire . . . . . . . . . . 189 Malene Kirchmann Eriksen and Jes Olesen Introduction . 145 Conclusions . 184 14. . . . . . . . . . 204 RAP and Abdominal Migraine . . Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach . . . . . . 177 The Convergence Hypothesis . . . . Azzurra Alesini. . . . . 197 Basilar-Type Migraine . . . . . . . . . . . . Lipton and Marcelo E. Federica Galli. . . . . . 156 Assessing Migraine-Related Disability . Childhood Periodic Syndromes . . . Assessing Ongoing Treatment . . . 155 Screening for Migraine . and Federico Dazzi Introduction . . . . . . 184 References . .viii Contents 11. . 145 Richard B. . . . . 173 Fred Sheftell and Roger Cady Introduction—Migraine Without Aura: An Underdiagnosed and Undertreated Disorder . . . . . . . . . . . . 152 References . . . . . . . . 145 Approaching a Patient with Headache . . 165 References . . . 189 Classification . . . . . . . 203 Cyclical Vomiting . . . . . Diagnostic and Severity Tools for Migraine . . . . . . . . . . . . . Bigal Introduction . . . . 167 13. . . . 206 BPV of Childhood . . 163 Conclusion . . . 182 Conclusion . . . 183 Illustrative Case History . . . 173 The ICHD-2 Criteria for Migraine Without Aura . . 155 159 163 . . 174 Migraine in Clinical Practice . . . . . . . . . Assessing Psychological Comorbidity . . . . . Lipton Introduction . . . . 192 Familial and Sporadic Hemiplegic Migraine . . . . . . . . . . . . . . . . . . . . 207 . . 152 12. Migraine Without Aura . . . . . . Contents ix Benign Paroxysmal Torticollis . . . Migraine-Associated Seizures (‘‘Migralepsy’’). . . 209 Conclusion . . . . or ‘‘Monocular. . 213 Clinical Features . . . 210 16. . . and Migrainous Infarction . . . . . . . . . Status Migrainosus. 223 Prolonged Aura . . . Persistent Aura. 209 References . . . . 261 Kenneth A. . 257 References . . . Curtis Delplanche. . . . 227 Migralepsy . . . . 219 References . . Rothrock Introduction . . . . . . . . . . . . . . . . 228 Migraine and Stroke . . . . and John F. . . . . . Individualized Treatment Plan . 241 Establishing the Diagnosis . . . . . . . 252 Educating Patients . . 223 Status Migrainosus . . . . . . . . . 261 . . . . . Rapoport Introduction . . Principles of Headache Management . . . . . . . . . . . . 258 Further Reading (Patient Education Resources) . . Holroyd Introduction . 232 References . . 261 Behavioral Interventions . . . . . . . . . . . . . . . 223 Jessica Crowder. . . . 218 Differential Diagnosis . . . . . . . . 236 18. . . . 256 Conclusion . . . . . . . . 252 Establishing Realistic Expectations . 217 Pathophysiology .’’ Migraine . . . . . 242 Assessing Disability . 258 Appendix 1 . . . . . . . . . . . . . 241 Marc S. . . . 255 Developing an Appropriate. 254 Encouraging Patients to Become Active in Their Own Care . . 220 17. . . . . . Retinal. . . 260 19. 208 Alternating Hemiplegia of Childhood . . 218 Management . . . . . . Husid and Alan M. . 256 Why Headache Treatment Fails . . Grosberg and Seymour Solomon Introduction . 213 Brian M. . Behavioral and Educational Approaches to the Management of Migraine: Clinical and Public Health Applications . . . . 213 Diagnostic Criteria . . . . . . 215 Epidemiology and Prognosis . . . . 254 Headache Calendars . . . . . . 289 Ergotamine . . . 363 Riboflavin . 367 Butterbur (Petasites hybridus) . . . . . . . . . . Preventive Treatment for Migraine . . . . . . . . . 277 Combinations of NSAIDs and Triptans . . 289 Hans-Christoph Diener and Volker Limmroth Introduction . . . . 264 Integrating Drug and Behavioral Treatments . Oral Triptans . . . . 304 References . . . . . 270 References . . . . . 274 Medications for the Treatment of Nausea . . . . . . . . . . . . . . 267 Conclusion . . . . 311 Mechanism of Action of Preventive Medications . . . . 363 Jean Schoenen and Delphine Magis Introduction . . 292 Conclusions . . . . . . . 347 23. . . . Specific Acute Migraine Treatment: Ergotamine and Triptans . 273 Simple Analgesics . 279 OPIOIDS . . . . . 369 Magnesium . . . . . . . . . . . . . . . 315 Setting Treatment Priorities . . . . . . 345 References . . 283 21. 363 Coenzyme Q10 . . . . . 282 References . . 273 Abouch Krymchantowski and Stewart J. . 366 Thioctic Acid (a-Lipoic Acid) . Specific Treatments . . . . . . . . . . . . . 279 Nonspecific vs. . 367 Feverfew (Tanacetum parthenium) . . . . 278 Neuroleptics in the Treatment of Pain . 311 Stephen D. . . . . . . 313 Specific Migraine-Preventive Agents .x Contents Treatment Delivery . . . . . . . . . . . . . Tepper Introduction . . 263 Efficacy . . . . . . 270 20. . . . . . . . Silberstein Introduction—Why and When to Use Migraine-Preventive Medications . . 280 Conclusions . . 265 Education for Self-Management . . . . . . . . . Herbal Medicines and Vitamins . Nonspecific Migraine Acute Treatment . 304 22. . . . . 290 Triptans . . . 266 Community Applications . . . . 289 Ergotamine vs. . 370 . . . . . . . . . . 423 Status Migrainosus/Intractable Pain . . . . . Friedman Introduction . . . . Lipton Introduction . . 376 Preventive Therapy . . . . . . . . . . . Progression Forms of Migraine . 442 28. . . . . . 413 How to Approach a Patient with Acute Headache in the ED . . . . . . . 417 Specific Situations . . . . . . 449 . . . . . . . . . . 425 References . . . Treatment of Migraine in Children and Adolescents . . . 409 26. . . . . 432 Prospects for Preventing Headache Progression . . . . . . . 393 Frederick G. . . . . 431 Epidemiology of the CDHS . . . . 375 Paul Winner Introduction . . . . . . . . 375 Acute Treatment . 448 Drugs Targeting the ORL-1 Receptors . . . . . . . . . . 432 Transformed Migraine . .Contents xi Conclusions . 422 Disposition . . . . . . . . Freitag Introduction . . . . . . . . . . . 446 Adenosine Receptors . . . Inpatient Management and Invasive Treatment Strategies for Migraine and Chronic Daily Headaches . . . . . . . . . . . . . . 371 24. 381 Conclusions . . 388 References . . 431 Marcelo E. . 405 Conclusion . . 393 Invasive Treatment of Migraine and Chronic Daily Headaches . 370 References . . . . 414 Treatment . 445 Todd Schwedt and David Dodick Introduction . . . Bigal and Richard B. 389 25. . . . . . . 426 27. . . . . . 413 Merle Diamond and Benjamin W. . . . . . . . . . . . . . . . . . . . . . . . . The Future of Migraine Therapies . . . . . . . . . 408 References . Migraine in the Emergency Department . . . . . . . . . . . . . . 445 Trigeminal Receptor Targets . . 441 References . 393 Inpatient Treatment . . . 448 Vanilloid Receptors . . xii Contents Glutamate Receptors . . . . 449 CGRP Receptor Antagonists . . . . 450 NOS Inhibitors . . . . 450 Pharmacogenomics . . . . 451 Summary . . . . 452 References . . . . 453 29. Tension-Type Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Rigmor Jensen Introduction . . . . 457 The Epidemiology of TTH . . . . 458 The Clinical Presentation of TTH . . . . 460 Physical Examination in Subjects with TTH . . . . 462 Psychological Aspects of TTH . . . . 463 Pathophysiology . . . . 463 Treatment . . . . 464 References . . . . 465 30. Trigeminal Autonomic Cephalgias . . . . . . . . . . . . . . . . . . . . . . . 471 David Dodick Introduction . . . . 471 Pathophysiology . . . . 471 Cluster Headache . . . . 473 Paroxysmal Hemicranias . . . . 484 SUNCT Syndrome . . . . 486 References . . . . 487 31. Other Primary Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Lawrence C. Newman, Susan W. Broner, and Christine L. Lay Introduction . . . . 495 Primary Stabbing Headache (ICHD-2 Code 4.1) . . . . 495 Primary Cough Headache (ICHD-2 Code 4.2) . . . . 496 Primary Exertional Headache (ICHD-2 Code 4.3) . . . . 497 Primary Headaches Associated with Sexual Activity (ICHD-2 Code 4.4) . . . . 498 The Hypnic Headache Syndrome (ICHD-2 Code 4.5) . . . . 499 Primary Thunderclap Headache (ICHD-2 Code 4.6) . . . . 500 Hemicrania Continua (ICHD-2 Code 4.7) . . . . 501 New Daily-Persistent Headache (ICHD-2 Code 4.8) . . . . 503 Conclusion . . . . 505 References . . . . 505 32. When the Treatment of Headache Fails . . . . . . . . . . . . . . . . . . . 509 Richard B. Lipton and Marcelo E. Bigal Introduction . . . . 509 Reason 1: The Diagnosis Is Incomplete or Incorrect . . . . 509 Contents xiii Reason 2: Important Exacerbating Factors May Have Been Missed . . . . 514 Reason 3: Pharmacotherapy May Be Inadequate . . . . 515 Reason 4: Nonpharmacologic Treatment May Be Inadequate . . . . 517 Reason 5: Other Reasons for Treatment Failure . . . . 517 Conclusions . . . . 518 References . . . . 518 Index . . . . 523 Contributors Azzurra Alesini Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Avi Ashkenazi Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Marcelo E. Bigal Department of Neurology, Albert Einstein College of Medicine, The Montefiore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A. Susan W. Broner The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Roger Cady Headache Care Center, Primary Care Network, Springfield, Missouri, U.S.A. Jessica Crowder Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. Federico Dazzi Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Curtis Delplanche Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. M. Sanchez del Rio Department of Neurology, Headache Program, Hospital Ruber International, Madrid, Spain Merle Diamond Diamond Headache Clinic and Rosalyn Finch School of Medicine, Chicago, Illinois, U.S.A. Hans-Christoph Diener Essen, Germany David Dodick Department of Neurology, University of Duisburg-Essen, Mayo Clinic College of Medicine, Scottsdale, Arizona, U.S.A. xv xvi Contributors Malene Kirchmann Eriksen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark Randolph W. Evans Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, Department of Neurology, The Methodist Hospital, and Baylor College of Medicine, Houston, Texas, U.S.A. Michel D. Ferrari Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Rune R. Frants Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Frederick G. Freitag Diamond Headache Clinic, Chicago and Department of Family Medicine, Chicago College of Osteopathic Medicine, Downers Grove and Department of Family Medicine, Rosalind Franklin University of Medicine and Science/Chicago Medical School, North Chicago, Illinois, U.S.A. Benjamin W. Friedman Department of Emergency Medicine, Albert Einstein College of Medicine, The Montefiore Headache Center, New York, New York, U.S.A. Federica Galli Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Peter J. Goadsby Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K. Brian M. Grosberg Department of Neurology, The Montefiore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A. Vincenzo Guidetti Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Joost Haan Department of Neurology, Leiden University Medical Center, Leiden, and Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands Kenneth A. Holroyd Ohio, U.S.A. Psychology Department, Ohio University, Athens, Marc S. Husid Department of Neurology, Walton Headache Center, Medical College of Georgia, Augusta, Georgia, U.S.A. Rigmor Jensen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark Esther E. Kors Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Contributors xvii Abouch Krymchantowski Outpatient Headache Unit, Instituto de Neurologia, and Deolindo Couto, Headache Center of Rio, Rio de Janeiro, Brazil Christine L. Lay The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Volker Limmroth Department of Neurology, Cologne City Hospitals, University of Cologne, Cologne, Germany Richard B. Lipton Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Montefiore Headache Center, New York, New York, U.S.A. Nancy C. P. Low Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, U.S.A. Delphine Magis Departments of Neuroanatomy and Neurology, Headache ` ` Research Unit, University of Liege, Liege, Belgium Kathleen Ries Merikangas Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, U.S.A. Lawrence C. Newman The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Jes Olesen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark Michael L. Oshinsky Department of Neurology and Preclinical Research, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. R. Allan Purdy Division of Neurology, Dalhousie University, and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada Alan M. Rapoport The New England Center for Headache, Stamford, Connecticut, and Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A. ´ U. Reuter Department of Neurology, Charite, Universitatsmedizin Berlin, ¨ Berlin, Germany John F. Rothrock Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. Todd D. Rozen Department of Neurology, Michigan Head Pain and Neurological Institute, Ann Arbor, Michigan, U.S.A. xviii Contributors Ann I. Scher Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A. Jean Schoenen Departments of Neuroanatomy and Neurology, Headache ` ` Research Unit, University of Liege, Liege, Belgium Todd Schwedt Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Fred Sheftell The New England Center for Headache, Stamford, Connecticut, U.S.A. Stephen D. Silberstein Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Seymour Solomon Department of Neurology, The Montefiore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A. Stewart J. Tepper The New England Center for Headache, Stamford, and Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Gisela M. Terwindt Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Arn M. J. M. van den Maagdenberg Department of Neurology and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Kaate R. J. Vanmolkot Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Paul Winner Palm Beach Headache Center, and Nova Southeastern University, Fort Lauderdale, Florida, U.S.A. William B. Young Department of Neurology and Inpatient Program, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. 1 Headache—Classification Marcelo E. Bigal Department of Neurology, Albert Einstein College of Medicine, The Montefiore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A. Richard B. Lipton Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Montefiore Headache Center, New York, New York, U.S.A. INTRODUCTION Headache is one of the most common symptoms in mankind (1,2). Given the range of disorders that present with headache, a systematic approach to headache classification and diagnosis is essential both for good clinical management and for useful research. The first edition of the International Classification of Headache Disorders (ICHD-1) (3) was the accepted standard for headache diagnosis, from its publication (1988) to the release of the ICHD-2 (2004) (4). It established uniform terminology and consistent operational diagnostic criteria for the entire range of headache disorders. It was translated into 22 languages, providing the basis for clinical trial guidelines for primary headaches (5). Although the basic structure and most of the original categories are preserved in the ICHD-2, relative to the ICHD-1, there are many changes that will influence headache care and research. These changes include a restructuring of the criteria for migraine, new subclassification of tension-type headache (TTH), introduction of the concept of trigeminal autonomic cephalalgias (TACs), and addition of several previously unclassified types of primary headache. In this chapter, we present an overview of the ICHD-2, highlighting the primary headache disorders and their diagnostic criteria. This chapter is complemented by Chapter 11, where we offer an algorithmic approach to primary headache diagnosis based on attack frequency and duration, using the ICHD-2. Details on diagnosis and treatment of primary headache disorders are discussed in specific chapters. AN OVERVIEW OF THE ICHD-2 Like its predecessor, the ICHD-2 separates headaches into primary and secondary disorders (Table 1). The criteria for primary headaches are clinical and descriptive 1 2 Table 1 The ICHD-2 Classification: An Overview Bigal and Lipton 1. Migraine 1.1. Migraine without aura 1.2. Migraine with aura 1.3. Childhood periodic syndromes that are commonly precursors of migraine 1.4. Retinal migraine 1.5. Complications of migraine 1.6. Probable migraine 2. TTH 2.1. Infrequent episodic TTH 2.2. Frequent episodic TTH 2.3. Chronic TTH 2.4. Probable TTH 3. CH and other trigeminal autonomic cephalalgias 3.1. CH 3.2. Paroxysmal hemicrania 3.3. SUNCT 3.4. Probable trigeminal autonomic cephalalgia 4. Other primary headaches 4.1. Primary stabbing headache 4.2. Primary cough headache 4.3. Primary exertional headache 4.4. Primary headache associated with sexual activity 4.5. Hypnic headache 4.6. Primary thunderclap headache 4.7. Hemicrania continua 4.8. NDPH 5. Headache attributed to head and/or neck trauma 5.1. Acute post-traumatic headache 5.2. Chronic post-traumatic headache 5.3. Acute headache attributed to whiplash injury 5.4. Chronic headache attributed to whiplash injury 5.5. Headache attributed to traumatic intracranial hematoma 5.6. Headache attributed to other head and/or neck traumata 5.7. Postcraniotomy headache 6. Headache attributed to cranial or cervical vascular disorders 6.1. Headache attributed to ischemic stroke and transient ischemic attack 6.2. Headache attributed to nontraumatic intracranial hemorrhage 6.3. Headache attributed to unruptured vascular malformations 6.4. Headache attributed to arteritis 6.5. Carotid or vertebral artery pain 6.6. Headache attributed to CVT 6.7. Headache attributed to other intracranial vascular disorders 7. Headache attributed to nonvascular intracranial disorder 7.1. Headache attributed to high cerebrospinal fluid pressure 7.2. Headache attributed to low cerebrospinal fluid pressure 7.3. Headache attributed to noninfectious inflammatory disease 7.4. Headache attributed to intracranial neoplasm 7.5. Headache attributed to intrathecal injection 7.6. Headache attributed to epileptic seizure 7.7. Headache attributed to CM1 (Continued) Headache—Classification Table 1 The ICHD-2 Classification: An Overview (Continued ) 3 7.8. Syndrome of transient HaNDL 7.9. Headache attributed to other nonvascular intracranial disorders 8. Headache attributed to a substance or its withdrawal 8.1. Headache induced by acute substance use or exposure 8.2. MOH 8.3. Headache as an adverse event attributed to chronic medication 8.4. Headache attributed to substance withdrawal 9. Headache attributed to infection 9.1. Headache attributed to intracranial infection 9.2. Headache attributed to systemic infection 9.3. Headache attributed to HIV/AIDS 9.4. Chronic postinfection headache 10. Headache attributed to disorder of homoeostasis 10.1. Headache attributed to hypoxia and/or hypercapnia 10.2. Dialysis headache 10.3. Headache attributed to arterial hypertension 10.4. Headache attributed to hypothyroidism 10.5. Headache attributed to fasting 10.6. Cardiac cephalalgia 10.7. Headache attributed to other disorders of homoeostasis 11. Headache or facial pain attributed to disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures 11.1. Headache attributed to disorder of cranial bone 11.2. Headache attributed to disorder of neck 11.3. Headache attributed to disorder of eyes 11.4. Headache attributed to disorder of ears 11.5. Headache attributed to rhinosinusitis 11.6. Headache attributed to disorders of teeth, jaws, or related structures 11.7. Headache or facial pain attributed to TMJ disorder 11.8. Headache attributed to other disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structures 12. Headache attributed to psychiatric disorder 12.1. Headache attributed to somatization disorder 12.2. Headache attributed to psychotic disorder 13. Cranial neuralgias and central causes of facial pain 13.1. Trigeminal neuralgia 13.2. Glossopharyngeal neuralgia 13.3. Nervus intermedius neuralgia 13.4. Superior laryngeal neuralgia 13.5. Nasociliary neuralgia 13.6. Supraorbital neuralgia 13.7. Other terminal branch neuralgias 13.8. Occipital neuralgia 13.9. Neck–tongue syndrome 13.10. External compression headache 13.11. Cold stimulus headache 13.12. Constant pain caused by compression, irritation, or distortion of cranial nerves or upper cervical roots by structural lesions 13.13. Optic neuritis 13.14. Ocular diabetic neuropathy (Continued) 4 Table 1 The ICHD-2 Classification: An Overview (Continued ) Bigal and Lipton 13.15. Head or facial pain attributable to herpes zoster 13.16. Tolosa–Hunt syndrome 13.17. Ophthalmoplegic ‘‘migraine’’ 13.18. Central causes of facial pain 13.19. Other cranial neuralgias or other centrally mediated facial pains 14. Other headaches, cranial neuralgias, and central or primary facial pain Abbreviations: TTH, tension-type headache; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; NDPH, new daily-persistent headache; CVT, cerebral venous thrombosis; CM1, Chiari malformation type I; HaNDL, headache and neurological deficits with cerebrospinal fluid lymphocytosis; MOH, medication-overuse headache; TMJ, temporomandibular joint; ICHD, International Classification of Headache Disorders; CH, cluster headache. and, with a few exceptions [i.e., familial hemiplegic migraine (FHM)], are based on headache features, not etiology. In contrast, secondary headaches are attributed to underlying disorders. The four categories of primary headaches are (i) migraine; (ii) TTH; (iii) cluster headache (CH) and other TACs; and (iv) other primary headaches. There are nine categories of secondary headache (against eight in the ICHD-1). Finally, there is a 14th category that includes headache not classifiable elsewhere (Table 1). Key operational rules for the classification are summarized below, quoted or paraphrased from the ICHD-2 (4): 1. The classification is hierarchical, allowing diagnoses with varying degrees of specificity, using up to four digits for coding at subordinate levels. The first digit specifies the major diagnostic type, e.g., migraine (1.) The second digit indicates a subtype within the category, e.g., migraine with aura (1.2.). Subsequent digits permit more specific diagnosis for some subtypes of headache, e.g., FHM. 2. Patients should receive a diagnosis for each headache type or subtype they currently have (that is, have experienced within the last year). For example, the same patient may have medication-overuse headache (8.2.), migraine without aura (1.1.), and frequent episodic TTH (2.2.). Multiple diagnostic codes should be listed in their order of importance to the patient. This means that if a patient has four attacks of migraine without aura (1.1.) and eight attacks of frequent episodic TTH (2.2.) per month, but describes the migraine as being more incapacitating, the migraine diagnosis should be listed first. 3. For headaches that meet all but one of a set of diagnostic criteria, without fulfilling those of another headache disorder, there are ‘‘probable’’ subcategories, for example, probable migraine (1.6.) and probable CH (3.4.1.). 4. The diagnosis of any primary headache requires the exclusion, on clinical grounds or using subsidiary investigation, of any other disorder that might be the cause of the headache (i.e., of a secondary headache disorder). 5. Secondary headache diagnoses are applied when the patient develops a new type of headache for the first time in close temporal relation to onset of another disorder known to cause headache. Diagnosis of secondary headache in a patient with a preexisting primary headache can be challenging. Onset of a secondary headache is more likely when (i) there is a very close temporal relation to onset of the potentially causative disorder; (ii) exacerbation of the headache is marked, or differs in pattern from the preexisting 5. Complications of migraine 1.6.6. Sporadic hemiplegic migraine 1.5. Typical aura without headache 1. CLASSIFICATION OF THE PRIMARY HEADACHES The ICHD-2 divides the primary headaches into four major categories. Basilar-type migraine 1. FHM 1.1. Frequency and severity may be specified parenthetically. which are discussed in sequence below. Table 2 The ICHD-2 Classification of Migraine 1. or return to the earlier pattern.2.2 Status migrainosus 1. .2.4.6.’’ now considered a cranial neuralgia.3.2.2.2. Typical aura with nonmigraine headache 1. and CM (1. the ICHD-2 does not specifically code frequency or severity.Headache—Classification 5 disorder. Cyclical vomiting 1. Benign paroxysmal vertigo of childhood 1.1.1. Although some headache types include frequency in their diagnostic criteria [i.5 Migraine-triggered seizures 1. International Headache Society Classification. Migraine without aura 1. 6. ICHD. Probable migraine 1.3.2.3.2.) has been added.5. or (iv) there is improvement or disappearance of headache. but there is a restructuring of the criteria for migraine with aura.2.5.3 Persistent aura without infarction 1.1..e. familial hemiplegic migraine. has been moved to item 13 (Cranial Neuralgias and Central Causes of Facial Pain) (Table 2). Ophthalmoplegic ‘‘migraine.5. This is unchanged from the ICHD-1. after relief from the potentially causative disorder. Probable migraine without aura 1.3. Migraine Migraine is subclassified into six major categories. Typical aura with migraine headache 1. chronic migraine (CM) and chronic TTH].2.4. Migraine with aura 1.2. Retinal migraine 1.5.) and migraine with aura (1.3. chronic migraine.1 CM 1. (iii) other evidence is strong that the potentially causative disorder can cause headache of the type experienced.1.3. at the discretion of the examiner.2. Probable migraine with aura Abbreviations: FHM.6.).1.5. Childhood periodic syndromes that are commonly precursors of migraine 1. Abdominal migraine 1. the two most important of which are migraine without aura (1. CM.5.4 Migrainous infarction 1. an adult pattern of unilateral pain often emerges in late adolescence or early adult life. Nausea and/or vomiting 2. walking or climbing stairs) D. At least five attacksa fulfilling B–D B. i History and physical and neurological examinations do not suggest one of the disorders listed in groups 5–12. b If the patient falls asleep during migraine and wakes up without it. pressure pain. but it is ruled out by appropriate investigations. a Migraine Without Aura Migraine without aura is a clinical syndrome characterized by headache features and associated symptoms (Table 3).6 Table 3 ICHD-2 Criteria for Migraine Without Aura Bigal and Lipton Migraine without aura Diagnostic criteria A. c In children. Not attributed to another disorderi Differentiating between migraine without aura and episodic tension-type headache may be difficult. a patient with unilateral. Therefore.e. only one of two possible associated symptom combinations is required. but with photophobia and phonophobia. code 1. photophobia and phonophobia may be inferred from behavior. throbbing pain may meet the criteria.1. if the pain is moderate and aggravated by physical activity. f Migraine headache is usually frontotemporal. . each type should be diagnosed. but migraine attacks do not occur for the first time in close temporal relation to the disorder. but so does a patient with bilateral.1. occurrence of at least one of the following: 1. and 1. Photophobia and phonophobiah E. history and/or physical and/or neurological examinations do suggest such disorder. chronic migraine.f 2. During headache. Occipital headache in children. Individuals who otherwise meet the criteria for migraine without aura but have fewer than five attacks should be coded 1. It is important to emphasize that:  Criteria for migraine without aura can be met by various combinations of features. and no single feature is required.  Similarly. Unilateral locatione. Pulsating qualityg 3. Aggravation by or causing avoidance of routine physical activity (i. International Headache Society Classification. Moderate or severe pain intensity 4. Abbreviation: ICHD. Patients with nausea but not photophobia or phonophobia fill the requirements as do patients without nausea or vomit. is rare and calls for diagnostic caution. duration of the attack is until the time of awakening. Headache has at least two of the following characteristics: 1.) d If attack frequency is 15 days/mo or more and if there is no medication overuse. g Pulsating means throbbing or varying with the heartbeat at rest or with movement. or such disorder is present. at least five attacks are required.c and occurring more than 15 days/mod (untreated or unsuccessfully treated) C.. (The evidence for untreated durations less than two hours in children should be corroborated by prospective diary studies.  Because two of four pain features are required. Headache attacks lasting 4–72 hoursb. many cases are attributable to structural lesions.5. whether unilateral or bilateral. According to the ICHD-2. e Migraine headache is often bilateral in young children. if a patient fulfills criteria for more than one type of migraine.6. h In young children. attacks may last 1 to 72 hours. and in young children. Fully reversible visual and/or sensory and/or speech symptoms but no motor weakness C.  In children. Typical aura symptoms develop over five minutes or more and last no more than 60 minutes. Headache that meets criteria B–D for migraine without aura (1. attacks may last 1 to 72 hours. the ICHD-2 establishes coding 1. and lines) and/or negative features (i. symptoms of brain stem dysfunction.) have been revised substantially.e.. Recently. At least two of the following three: 1.2. Reports have associated apparently Table 4 ICHD-2 Diagnosis of Typical Aura Diagnostic criteria A.e. but motor weakness. Each symptom lasts 5 min or more and 60 min or less D. photopsia or phosphenes. numbness) 2.2. At least one symptom develops gradually over 5 min or more and/or different symptoms occur in succession 3. which scintillates.1 CM [see also ‘‘Controversies in the Classification of Primary Chronic Daily Headaches of Long Duration’’].) begins during the aura or follows aura within 60 min E. Not attributed to another disorder Abbreviation: ICHD. The typical aura of migraine is characterized by focal neurological features that usually precede migrainous headache. the duration of the attack is timed until the time of awakening. . At least two attacks fulfilling criteria B–E B. and changes in level of consciousness. Scotoma.. loss of vision) and/or unilateral sensory symptoms including positive features (i. Dysphasia may be part of typical aura.1. International Headache Society Classification.). Such cases are coded Typical aura with nonmigraine headache (1. Visual distortions such as metamorphopsia.1.5. micropsia. If the patient falls asleep during migraine and wakes up without it.)..Headache—Classification 7  Attacks usually last from 4 to 72 hours if untreated. ragged edge.. The distribution is often cheiro-oral (face and hand). headache not fulfilling the criteria of 1. Migraine with Aura and Its Subtypes The criteria for migraine with aura (1. flickering lights. all of which may occur (10). Sensory symptoms occur in about one-third of patients who have migraine with aura (8–10). and visual aura is overwhelmingly the most common (7). pins and needles) and/or negative features (i.e. typical migraine aura has been noted to occur with nonmigrainous headache (i. often having a hemianopic distribution and expanding in the shape of a crescent with a bright. signal particular subtypes of migraine with aura (hemiplegic and basilar-type) that are not characterized by typical aura. If attack frequency is 15 days/mo or more in a subject not overusing acute medications. photophobia and phonophobia may be inferred from behavior. Homonymous visual symptoms including positive features (i. Typical visual aura is homonymous. and macropsia are more common in children (7–9).2. Typical sensory aura consists of numbness (negative symptom) and tingling or paresthesia (positive symptoms).7). spots.e.. and other visual manifestations may occur. but may accompany it or occur in the absence of the headache (Table 4) (6.e. 4. Vomiting occurs at least four times in an hour. each comprising multiple episodes of severe vertigo resolving spontaneously in minutes to hours (23). FHM (1. Typical aura occurring in the absence of any headache is coded typical aura without headache (1. Physical examination and investigations exclude other causes of these symptoms. replacing ‘‘basilar migraine. nausea. The onset of weakness may be abrupt.8 Bigal and Lipton typical aura with CH. which last one hour to five days in children free of symptoms interictally. Cerebellar ataxia may occur in 20% of FHM sufferers. Because 60% of patients with FHM have basilar-type symptoms. additionally. hemianopia) are predominant. chronic paroxysmal hemicrania (CPH). ataxia.1. nausea.) plus Typical aura with nonmigraine headache (1. CH (3. and no signs of gastrointestinal disease can be found. basilar-type migraine should be diagnosed only when weakness is absent.. may require investigation.2.e. a disorder most often reported by middle-aged men (12).2. and the electroencephalogram is also normal. Neurological examination and audiometric and vestibular functions are all normal between attacks. At least two of the following symptoms are present during the episode: anorexia. Cyclical vomiting (1. or when the aura is of atypical duration (13). at least one first-degree relative has had similar attacks (also meeting these criteria).) occurs in up to 2. dull or ‘‘just sore’’ quality. vomiting. These cases are classified according to both disorders [e. Abdominal migraine (1.2. and/or pallor. Basilar-type migraine (1.2.1. Differentiating this benign disorder from transient ischemic attack (TIA).3. and moderate or severe intensity. double vision. visual symptoms simultaneously in both temporal and nasal fields of both eyes. the disorder is classified as sporadic hemiplegic migraine (1. is involved.) is the first migraine syndrome to be linked to a specific set of genetic polymorphisms (14–18).2. Diagnosis requires at least two of the following aura symptoms. a disorder new to the revised classification (19).3. when negative features (i. all fully reversible: dysarthria. and sometimes vomiting (22).) is a disorder characterized by recurrent (at least five) attacks.). Benign paroxysmal vertigo (1. The abdominal pain has all of the following characteristics: midline location.6.)]. . or its territory. especially when it first occurs after age 40.’’ The change is intended to remove the implication that the basilar artery. Childhood Periodic Syndromes That Are Commonly Precursors of Migraine A number of more or less well-described disorders are classified under this heading (20–23). with recurrent attacks of abdominal pain associated with anorexia.2.2.) migraine without aura. The headache meets the criteria for (1.3.3. The distinguishing feature of basilar-type migraine is a symptom profile that suggests posterior fossa involvement (19). a medical emergency. Herein. vertigo. In patients otherwise meeting these criteria but who have no family history of this disorder.11). but usually lasts less than one hour. decreased hearing.). decreased level of consciousness. and hemicrania continua (HC) (10.) is a new term. periumbilical or poorly localized.5% of schoolchildren (21). aura includes some degree of motor weakness (hemiparesis) and may be prolonged for more than 60 minutes (up to 24 hours). tinnitus. A person with FHM may develop migraine with aura when adult and migraine without aura later in life.g.1.3. The hallmark of this disorder is recurrent and stereotyped episodes of intense but otherwise unexplained nausea and vomiting. and simultaneously bilateral paresthesias.) afflicts up to 12% of schoolchildren.5.. ) can be diagnosed with confidence until the overused medication has been withdrawn. When medication overuse is present (acute antimigraine drugs and/or opioids.4.2. Grosberg and Solomon present a detailed review of retinal migraine.) require that a seizure fulfilling the diagnostic criteria for any type of epileptic attack occurs during or within one hour after a migraine aura. Persistent aura without infarction (1.1. in the absence of medication overuse. Migraine and epilepsy are comorbid disorders (29). and neuroimaging confirms ischemic infarction.1.) is an uncommon occurrence.) nor medication-overuse headache (8.) is diagnosed when aura symptoms.5. This disorder should be coded as Migrainous infarction (1.6. which must be excluded (28). including TIA.5.). the codes to be assigned are that of the antecedent migraine (usually migraine without aura. Complications of Migraine The ICHD-2 lists five complications of migraine: CM (1. Neither CM (1.4. Drs.) plus probable medication-overuse headache (8. All cases evolve from episodic migraine.5.5. which is now being introduced into the ICHD-2 (27). A recent study suggests that many patients with ‘‘retinal migraine’’ experience retinal infarction of migrainous origin (25).) refers to an attack of migraine with a headache phase lasting more than 72 hours (26). 1. Meanwhile. optic neuropathy. or simple analgesics on 15 days/mo or more). must be ruled out by appropriate investigation (24).).7.5. and retinal detachment. If a single criterion is missing (and the full . the neurological deficit develops during the course of an apparently typical attack of migraine with aura and exactly mimics the aura of previous attacks. it is a likely cause of chronic headache. persist for more than one week.5. One or more otherwise typical aura symptoms persist beyond one hour.5. Nondebilitating attacks lasting for more than 72 hours are coded as probable migraine without aura (1. Recurrent attacks (at least two) of fully reversible scintillations. are accompanied or followed within one hour by migrainous headache (fulfilling criteria for 1.) plus probable CM (1. these criteria distinguish this disorder from other causes of stroke. or blindness. Probable Migraine Between 10% and 45% of patients with features of migraine fail to meet all criteria for migraine (or any of its subtypes) (30).3. Status migrainosus (1. Strictly applied. not if the former is present. scotomata. improvement within two months is expected if the latter diagnosis is correct (and is necessary to confirm it). hence its classification as a complication of migraine. The criteria for migraine-triggered seizure (1. It is an unusual but well-documented complication of migraine. Headaches are common in the postictal period.2. combination analgesics taken on 10 days/mos or more.) (see section ‘‘Controversies in the Classification of Primary Chronic Daily Headaches of Long Duration’’) when headache is both present and meets criteria for migraine (almost invariably migraine without aura) on 15 days/mo or more for three months or more.).5. but epilepsy can be triggered by migraine (migralepsy).1. otherwise typical of past attacks. The pain is severe (a diagnostic criterion) and debilitating. Other causes of monocular visual loss. Investigation shows no evidence of infarction.1. Migrainous infarction (1.1. and most from migraine without aura.2.5. affecting one eye only.Headache—Classification 9 Retinal Migraine This disorder is rare.).6. In Chapter 16. and in fact have.6. Such patients often meet criteria for. Pressing/tightening (nonpulsating) quality 2. A recently recognized disorder that phenotypically resembles chronic TTH. Tension-Type Headache TTH is the most common type of primary headache. The ICHD-2 distinguishes three subtypes: Infrequent episodic TTH (2.2. but is nosologically distinct from it (as far as is known). but does not prohibit activities) 3. or one but not the other may be present E. Frequent episodic TTH (2. perhaps without recognizable episodes). In contrast to migraine. nonpulsating quality.X Not associated with increased pericranial tenderness Note: X means the correspondent digit of infrequent episodic (i).) (headache on 15 or more days/mo. The diagnostic criteria for TTH are presented in Table 5. Fulfills criteria for 2. with one-year period prevalences ranging from 31% to 74% (32. Chronic TTH invariably evolves from episodic TTH but.).1. At least two of the following pain characteristics: 1. At least 10 episodes fulfilling criteria B–E. Number of days with such headache less than 1 day/mo (episodic infrequent). Mild or moderate intensity (may inhibit. No nausea or vomiting (anorexia may occur) b. Associated with pericranial tenderness Diagnostic criteria: A.10 Bigal and Lipton set of criteria for another disorder are not met).). Fulfills criteria for 2. the applicable code is probable migraine (1. Abbreviation: ICHD. does not evolve from an episodic headache but is present daily and is Table 5 ICHD-2 Classification of Tension-Type Headache Diagnostic criteria A. episodic TTH (less than 15 attacks per month) and chronic TTH (15 or more attacks per month). frequent episodic (ii). or chronic (iii). The pain is not accompanied by nausea.) (headache episodes on 1–14 days/mo).2.X. medication-overuse headache (8. like CM.or phonophobia does not exclude the diagnosis. The ICHD-1 distinguished two subtypes. International Headache Society Classification. Both of the following: a. cannot be diagnosed in patients overusing acute medication. Increased tenderness on pericranial manual palpation 2.X.2. or 15 or more (chronic) B. Not associated with pericranial tenderness Diagnostic criteria A. and just one of photo. Photophobia and phonophobia are absent. Not attributed to another disorder 2. . and lack of aggravation by routine physical activity. and Chronic TTH (2. Epidemiologic studies demonstrate that probable migraine is common and associated with temporary disability and reduction in the health-related quality of life (31).3.) (headache episodes on less than 1 day/mo).1. the main pain features of TTH are bilateral location.33). mild-to-moderate intensity. although withdrawal of the medication is required to confirm this diagnosis. from 1 to 14 (episodic frequent). Bilateral location 4. Headache lasting from 30 min to 7 days C. No aggravation by walking stairs or similar routine physical activity D.X B. 8. Severe or very severe unilateral orbital. Headache is associated with a sense of restlessness or agitation D. and autonomic signs are usually obvious. excruciating unilateral head pain accompanied by autonomic dysfunction (34). Chronic CH can evolve from episodic CH. or both 6.). knife-like. the diagnosis should be probable TTH (2. Forehead and facial sweating 5. Eyelid edema 4. Conjunctival injection. In chronic CH (3. exhibiting often marked agitation and restlessness.1. and/or temporal pain lasting 15–180 min untreated for more than half of the period (or time if chronic) C. ptosis. At least five attacks fulfilling B–D B. Miosis. they should receive both diagnoses. supraorbital. and received the denomination of cluster-tic syndrome have been described (36). attacks recur for more than one year without remission. This disorder manifests as intermittent. .) occur in cluster periods lasting from seven days to one year separated by attack-free intervals of one month or more.Headache—Classification 11 unremitting from onset or within three days of onset. CH is classified into two subtypes (Table 6).1. According to the ICHD-2. International Headache Society Classification.). When a headache fulfills all but one of the criteria for TTH and does not fulfill the criteria for migraine without aura.). Not attributed to another disorder Abbreviation: ICHD. patients find it difficult to lie still. short-lasting. drilling. Attacks of Episodic CH (3. piercing. or stabbing. Table 6 ICHD-2 Classification of Cluster Headache Diagnostic criteria A. After an attack. During this pain. and may revert to episodic CH (35).4. rhinorrhoea. or both 3.2. It usually peaks in 10 to 15 minutes but remains excruciatingly intense for an average of one hour within a duration range of 15 to 180 minutes. Headache is accompanied by at least one of the following symptoms or signs that have to be present on the side of the pain: 1. The ICHD-2 includes several disorders not in the previous edition. or both 2. Nasal congestion. This condition is separately classified as new daily-persistent headache (4. Cluster Headache The diagnostic criteria for CH have not substantially changed. CH and Other TACs The addition of the term TACs to the classification reflects the observation that CH is one of a group of primary headache disorders characterized by trigeminal activation coupled with autonomic activation.1. or with remissions lasting less than one month. or develop de novo. Approximately 85% of CH patients have the episodic subtype. lacrimation. Patients who have both CH as well as trigeminal neuralgia. Frequency of attacks: from one every other day to eight per day for more than half of the period if chronic E. The pain of CH is described variously as sharp. boring. the patient remains exhausted for some time. in contrast to the pulsating pain of migraine. Diagnostic neuroimaging. supraorbital. Other features such as autonomic signs are lacking (40. such as hypnic headache. straining.).2. The ICHD-2 includes episodic paroxysmal hemicrania (3. and (iii) absolute response to therapeutic doses of indomethacin (37–39). Some patients with both CPH and trigeminal neuralgia have been described (CPH-tic syndrome). . HC. Like CH. these disorders are distinguished by the presence or absence of attack-free intervals lasting one month or more. Headache attacks believed to be a subtype of TAC but fulfilling all but one of the diagnostic criteria for it are diagnosed as probable TCA. Some headaches. severe.1.12 Bigal and Lipton Paroxysmal Hemicrania As a group. is mandatory to differentiate secondary and primary forms of cough headache. with moderately severe pain peaking in intensity within three seconds and prominent tearing (40). Primary Cough Headache This headache is brought on suddenly by coughing. primary thunderclap headache.41). Pain is exclusively or predominantly in the distribution of the first division of the trigeminal nerve (orbit. The diagnostic criteria require at least 20 high-frequency attacks (3–200 per day) of unilateral orbital. or temporal pain. (ii) symptoms of parasympathetic activation ipsilateral to the pain (as in CH).1.).) and is a very rare primary headache. The attacks are characteristically dramatic.2. and strictly unilateral orbital. which need to be carefully evaluated by imaging or other appropriate tests. Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing The short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome (3. and parietal area). especially.) and CPH (3.2. they should receive both diagnoses. supraorbital. in the absence of any underlying disorder such as cerebral aneurysm or. with special attention to the posterior fossa and base of the skull. temple. Arnold–Chiari malformation (42). lasting 5 to 240 seconds and accompanied by ipsilateral conjunctival injection and lacrimation. The ICHD-1 included CPH only. or Valsalva maneuver. the paroxysmal hemicranias have three main features: (i) at least 20 frequent (more than five per day) attacks of short-lasting (2–30 minutes). Other Primary Headaches This group of miscellaneous primary headache disorders includes some mimics of potentially serious secondary headaches.3. and new daily-persistent headache were not included in the ICHD-1. Primary Stabbing Headache Episodic localized stabs of head pain occurring spontaneously in the absence of any structural cause (formerly referred to as ‘‘jabs and jolts’’) are diagnosed as primary stabbing headache (4. It lasts for up to a few seconds and recurs at irregular intervals with a frequency ranging from one to many per day. and not otherwise. or temporal stabbing or pulsating pain. ).). Two subtypes are classified: preorgasmic headache (4. Primary exertional headache is pulsating and lasts from 5 minutes to 48 hours. and not otherwise. and cannot be made if this manner of onset is not clearly . and orgasmic headache (4. It does not occur outside sleep (47). After the first occurrence of any exertional headache of sudden onset. Primary Thunderclap Headache Severe headache of abrupt onset.). explosive and severe. a dull ache in the head and neck.6.4.4. is classified as primary thunderclap headache (4. with exacerbations of severe pain. in many cases on more nights than not.2. Diagnosis of the latter requires exclusion of subarachnoid hemorrhage and arterial dissection. although this code is not applied to thunderclap headache meeting the criteria for 4. This diagnosis can be established only after excluding subarachnoid hemorrhage.) and headache associated with sexual activity (4. or 4. is that it is present daily and is unremitting from or very soon (less than three days) after onset. Primary Headache Associated with Sexual Activity Headache precipitated by sexual activity usually begins as a dull bilateral ache as sexual excitement increases and suddenly becomes intense at orgasm (46). Pain is moderate. very different from the unilateral orbital or periorbital knife-like intense pain of CH. 4. Hemicrania Continua This daily and continuous strictly unilateral headache is defined by its absolute response to therapeutic doses of indomethacin. which awakens the patient at a constant time each night.2. Intensity peaks in less than one minute.Headache—Classification 13 Primary Exertional Headache This disorder is triggered by physical exercise. otherwise resembles chronic TTH (2.1.4.).4. Some bilateral or alternating-side cases have been reported (51).50). Diagnosis is not confirmed until it has been present for more than three months. and occurring with orgasm. Hypnic Headache This primary headache disorder of the elderly is characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain. which according to the ICHD-2 but not accepted by all.3.2. There is no history of evolution from episodic headache. and is distinguished from primary cough headache (4. Pain lasts from 1 hour to 10 days and may recur within the first week after onset but not regularly over subsequent weeks or months (48). which mimics the pain of a ruptured cerebral aneurysm.3.). Hypnic headache is usually bilateral (though unilaterality does not exclude the diagnosis) and mild to moderate. and autonomic symptoms accompany these exacerbations although less prominently than in CH and CPH (49. Autonomic features are absent. appropriate investigations must exclude subarachnoid hemorrhage and arterial dissection (43–45). New Daily-Persistent Headache The essence of this headache. Chronic post-traumatic headache does not disappear three months after the trauma. and unaffected by routine physical activity. Nor can it be made in the presence of medication overuse. (iv) arteritis (including giant cell arteritis). postendarterectomy headache. (iii) unruptured vascular malformations. (vi) cerebral venous thrombosis. phonophobia. although the diagnostic criteria require only any two of these features. including CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). lactic acidosis. NDPH is typically bilateral. of mild to moderate intensity. HEADACHE ATTRIBUTED TO CRANIAL OR CERVICAL VASCULAR DISORDERS This category encompasses a large group of headaches that fulfill the following criteria: symptoms and/or signs of a vascular disorder. SECONDARY HEADACHES Discussing the classification of the secondary headaches in depth is beyond the scope of this chapter. 3. MELAS (mitochondrial encephalopathy. or mild nausea. and stroke-like episodes). Headache is greatly reduced or disappears within three months (this may be shorter for some disorders) after successful treatment or spontaneous remission of the causative disorder. HEADACHE ATTRIBUTED TO HEAD AND/OR NECK TRAUMA This category includes headaches that occur for the first time in close temporal relation to a known trauma (52). appropriate investigations indicating the vascular disorder. Headache occurs in close temporal relation to the secondary disorder. We will briefly discuss their classification. The ICHD-2 also classifies under this group those headaches secondary to intracranial hematoma and postcraniotomy. and the headache developing in close relationship with the vascular disorder. (53–59). the headache should be classified as acute post-traumatic headache. . (ii) nontraumatic intracranial hemorrhage. and (vii) other intracranial vascular disorders. etc. and/ or there is other evidence of a causal relationship. etc. pressing or tightening in quality. The secondary disorder known to be able to cause headache has been demonstrated. Otherwise.). There are exceptions to this general rule. (v) carotid or vertebral artery pain (including arterial dissection. 2. In brief.14 Bigal and Lipton recalled by the patient. If there is remission within three months after the trauma. the classification of all secondary headaches follows the same format: 1. This group includes headaches related to (i) ischemic stroke and TIAs. The same rule applies to acute and chronic post–whiplash injury headache. chronic post-traumatic headache is the diagnosis. There may be any but not more than one of photophobia. they are coded to this group.66).64) (i) nitric oxide donor substances. (vii) Chiari malformation type I (CM1). (iv) headache attributed to hypothyroidism. (v) headache attributed to fasting. In others. (iii) carbon monoxide. . (vii) cocaine. This group also includes headaches related to HIV/AIDS and chronic postinfectious headaches (67). HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS This group of headaches was formerly referred as headaches associated with metabolic or systemic diseases. the use of the ‘‘probable’’ term exemplifies the difficulty of causal attribution (see section ‘‘Controversies in the classification of primary chronic daily headaches of long duration’’). (iii) arterial hypertension. and (viii) syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (60–62). and sleep apnea). headache may be the most prominent symptom and an initial warning symptom. cardiac cephalgia. HEADACHE ATTRIBUTED TO A SUBSTANCE OR ITS WITHDRAWAL When new headaches occur in close temporal relation to substance use or withdrawal. In addition. and (ix) other acute substance use. The ICHD-2 classifies in this group those headaches following acute exposure to (63. (vi). (v) headache related to intrathecal injections. chronic medication overuse is a risk factor for the development of CDH (65. (iv) intracranial neoplasm. and (vii) headache attributed to other disturbances of homeostasis (68. a diagnosis of probable CM and probable medication-overuse headache should be assigned. such as ischemic or hemorrhagic stroke. (viii) cannabis. (vi) postseizure headache. (vi) monosodium glutamate. headache may be unrecognized because of focal signs and/or disorders of consciousness. HEADACHE ATTRIBUTED TO NONVASCULAR INTRACRANIAL DISORDERS This category includes an extensive and heterogeneous group of disorders (7). if a subject has a frequent headache associated with medication overuse and meets otherwise the criteria for CM. They are: (i) high cerebrospinal fluid pressure.69). Definite diagnosis of medication-overuse headache requires that headaches remit or improve when the overused medication is withdrawn. HEADACHE ATTRIBUTED TO INFECTION This is a very straightforward group where headaches secondary to intracranial and extracranial (systemic) infections are classified. (ii) low cerebrospinal fluid pressure. (iv) alcohol. They include the following headaches: (i) headache attributed to hypoxia and/or hypercapnia (high altitude. diving. (ii) dialysis.Headache—Classification 15 In many of these conditions. such as subarachnoid hemorrhage and giant cell arteritis. (ii) phosphodiesterase inhibitors. (iii) noninfectious inflammatory diseases. Prior to withdrawal. (v) food components and additives. Using the ICHD-2. or by trigger factors C. including (72. International Headache Society Classification. (viii) occipital neuralgia. NECK. (vi) supraorbital neuralgia. superficial.16 Bigal and Lipton HEADACHE OR FACIAL PAIN ATTRIBUTED TO DISORDERS OF CRANIUM.73) (i) trigeminal neuralgia. the prototype of a cranial neuralgia. or distortion of cranial nerves or upper cervical roots by structural lesions. (xv) herpes zoster. Attacks are stereotyped in the individual patient E. and the facial structures. NOSE. EARS. (iii) nervus intermedius neuralgia. stabbing. the last chapter of the ICHD-2 codes the cranial neuralgias and facial pain. migraine) and a psychiatric disorder (e. (ix) neck–tongue syndrome. . are summarized in Table 7. irritation. the neck. Not attributed to another disorder Abbreviation: ICHD. Paroxysmal attacks affecting one or more divisions of the trigeminal nerve lasting from a fraction of a second to two minutes B. The pain has at least one of the following characteristics: intense.. There is no clinically evident neurological deficit D. (xiv) ocular diabetic neuropathy.g. SINUSES. OR OTHER FACIAL OR CRANIAL STRUCTURES This is a very heteronegenous group classifying headache and facial pain due to disease of the cranium. CONTROVERSIES IN THE CLASSIFICATION OF PRIMARY CHRONIC DAILY HEADACHES OF LONG DURATION Primary CDH is defined as a group of primary headaches that occur more than 15 days a month (or 180 days a year) with a duration of four or more hours per day Table 7 ICHD-2 Classification of Trigeminal Neuralgia A. (xii) constant pain caused by compression. EYES. (xi) cold stimulus headache. Criteria for trigeminal neuralgia. depression) occur together in the same person (71). This should be distinguished from psychiatric comorbidities where a headache disorder (e. sharp. precipitated from trigger areas.. HEADACHE ATTRIBUTED TO PSYCHIATRIC DISORDERS This group provides a link to classify those extremely rare headaches that are causally attributable to a psychiatric disorder. Cranial neuralgias are not classified under this chapter. (xvii) ophthalmoplegic migraine. (ii) glossopharyngeal neuralgia. The headache may be attributed to a somatization disorder or to a psychotic disorder. (x) external compression headache. and (xviii) central causes of facial pain. MOUTH. CRANIAL NEURALGIAS AND CENTRAL CAUSES OF FACIAL PAIN Finally. (vii) other terminal branch neuralgias. (xiii) optic neuritis. TEETH. (xvi) Tolosa–Hunt syndrome. The ICHD-2 includes criteria for cervicogenic headache (70).g. (v) nasociliary neuralgia (Charlin). (iv) superior laryngeal neuralgia. Headache—Classification 17 (see Chapter 27 for the clinical features. Stewart WF.. ed. REFERENCES 1. Cephalalgia 1988. 3. The system subclassifies these main diagnoses as ‘‘with medication overuse’’ or ‘‘without medication overuse. Lipton RB. a primary CDH develops in a person with previous history of headaches. which. 2. diagnosis. Migraine and headache: a meta-analytic approach. cranial neuralgias and facial pain. and (iv) HC. In: Crombie IK. The S-L classification allows the diagnosis of NDPH in patients with migraine or episodic TTH if these disorders do not increase in frequency to give rise to NDPH. which only requires absence of history of evolution from migraine or episodic TTH. Rasmussen BK. Controversies exist regarding the differences between CM and TM and the best way to classify NDPH. It is the new onset of this primary daily headache that is the most important feature. The IHS criteria consider NDPH in those cases where the headaches resemble TTHs (in other words. Scher AI. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders. NDPH is characterized by the relatively abrupt onset of an unremitting primary CDH. with some attacks of full migraine superimposed. Seattle: IASP Press. 15(1):45–68. Of these proposals. however. 1999:159–170. Epidemiology of Pain. and TM is a headache syndrome not included in the ICHD-2. Patients with TM typically have a past history of migraine. Epidemiology of headache. or (iii) concurrent superimposed attacks of migraine that fulfill the IHS criteria. but this is no longer appropriate. a few proposals for the classification of these patients have emerged. This issue is fully discussed in Chapter 27. (ii) chronic TTH. (ii) a period of escalating headache frequency. Studies reported difficulties using the ICHD-1 to classify CDH sufferers (74. associated symptoms become less severe and frequent. and treatment of CDH). Second. A revision of the criteria for CM is currently being considered by the International Headache Society Classification Committee. the clinical features of the pain are not considered in making the diagnosis. The S-L criteria divide the CDH into four main diagnoses: (i) transformed migraine (TM). The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles chronic TTH. CDH is addressed neither in the ICHD-1 nor in the ICHD-2. a patient without a previous headache syndrome develops a chronic headache that does not remit. Subjects report a process of transformation (chronification) over months or years.e. CM has a specific definition in the ICHD-2.75). (iii) new daily-persistent headache. TM and CM have been used synonymously in the past. According to the S-L criteria. i. As a consequence. .’’ As a syndrome. 8(suppl 7):1–96. As of the writing criteria for CM would require 15 or more days of headache per month and at least 8 days of migraine. provides criteria for the CDH subtypes. The S–L criteria classify TM in two situations: First. and as headache increases in frequency. one of the three following links with migraine are satisfied: (i) a prior history of migraine. usually migraine without aura. the Silberstein and Lipton (S-L) criteria have been most widely used (76). NDPH with migrainous features or coexisting new-onset migraine does not meet the criteria for this diagnosis according to the ICHD-2) (77–80). Cephalalgia 1995. Olsen TS. 15:43–60. Epilepsy and migraine. Migraine aura and prodrome. 23. Lipton RB. 87:543–552. Lipton RB. Olesen J. 24(suppl 1):9–160.18 Bigal and Lipton 4. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Migraine with prolonged aura. 4(suppl 2):S13–S24. Panayiotopoulos CP. a prospective recording of symptoms. Arch Dis Child 1995. Rozen TD. In: Olesen J. In: Hockaday JM. Block G. eds. Guidelines for controlled trials of drugs in migraine: second edition. 19. Migraine in Childhood. 73:359–362. 14. 28. Post-traumatic chronic paroxysmal hemicrania (CPH) with aura.. et al. 40:52–53. Zagami AS. 1:33–39. Retinal Migraine Current pain and headache reports. A reappraisal and long-term follow-up study. Tfelt-Hansen P. Ophoff RA. et al. Cephalalgia 1981. et al. 17:12–21. Peres MF. 22:246–248. Stenirri S. Brain Dev 2001. 8. Welch KMA. and headache during migraine attacks. Brain 1996. 6. Migrainous stroke. Abu-Arafeh I. Laverda AM. Siow HC. Nat Genet 2003. Cephalalgia 2000. Headaches in the elderly. Classic migraine. Benign paroxysmal vertigo of childhood. Classification of primary headaches. Lauritzen M. Lipton RB. Kraft M. Brain Res Bull 2001. Timing and topography of cerebral blood flow. Silberstein SD. Rothrock JF. 13. 63(3):427–435. 5. 8:87–97. 11. Olesen J. Swenson MR. Fleisher DR. Drigo P. 45:63–67. 25. 23:94–101. 1988:35–53. Neurology 2001. Troost T. 23:38–41. Haploinsufficiency of ATP1A2 encoding the Na/K pump a2 subunit associated with familial hemiplegic migraine type 2. Genetics of migraine. 29. Causative and therapeutic aspects. Headache 2000. Grosberg BM. 21. 134:533–535. Carrera P. Philadelphia: Lippincott Willians & Wilkins. 45:175–182. 15. Vergouwe MN. Haan J. The Headaches. Steiner TJ. et al. Russel MB. Headache Classification Subcommittee of the International Headache Society. Cohen J. Acta Neurol Scand 1986. Russel G. Hemicrania continua with aura. Pfeffer D. . 10. Cell 1996. Cyclic vomiting syndrome and migraine. 72:413–417. 2000:511–516. Young WB. Terwindt GM. A nosographic analysis of the migraine aura in a general population. J Pain Symptom Manage 1993. 1999:303–308. 2005. Neurol Clin 1997. Matharu MJ. Boston: Butterworths. Headache 1983. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. et al. Tfelt-Hansen P. Bigal ME. et al. Olivarius B. Tfelt-Hansen P. Ferrari MD. Silvestri L. advance online publication. 20(9):765–786. Newman LC. 28:791–798. Neurology. Familial hemiplegic migraine. Bigal ME. Terwindt GM. 9. et al. Marconi R. Jensen K. Olesen J. 2004. Ophthalmoplegic migraine and retinal migraine. Benign Childhood Partial Seizures and Related Epileptic Syndromes. 7. 119:355–361. Special forms: variants of migraine in childhood. Ferrari M. 27. Basilar migraine: a review. Ann Neurol 1990. ed. Cephalalgia 2004. Familial hemiplegic migraine: a ion channel disorder. 24. aura. 17. Olesen J. Friberg L. Carli G. Esperanca P. Hansen H. ed. 20. Status migrainosus. The International Classification of Headache Disorders: 2nd edition. 56:273–275. Goadsby PJ. Hosking G. Lipton RB. Dahlof C. Cephalalgia 2002. Bento MS. 56:239–241. Silberstein SD. Staehelin-Jensen T. 12. J Pediatr 1999. Arch Neurol 1988. Semin Neurol 1995. Epilepsy Behav 2003. Silberstein SD. Couch JR. 18. 16. Diamond S. Walicke P. 22. De Fusco M. 26. London: John Libbey & Company Ltd. In: Panayiotopoulos CP. A population-based analysis of the criteria of the International Headache Society. Sjaastad O. 4:1085–1092. Huston J. Evidence for a new (?) treatable headache entity. 32. 14:9–21. J Child Neurol 1993. Olesen J. Headache 1993. al-Sabbab H. Vaga study of headache epidemiology. 39:1226–1230. SUNCT syndrome and other short-lasting headaches with autonomic features. J Head Trauma Rehabil 1999. 48. Neurology 1986. Arq Neuropsiquiatr 2000. 33. et al. 46. Lowenkopf T. Brain 1997. Dodick DW. Brown RD. Epidemiology of tension-type headache. 39. Headaches related to sexual activity. Spierings EL. 31:20–26. 16:93–96.Headache—Classification 19 30. Sjaastad O. 36. Diagnosis and treatment of cluster headache. Campbell IK. The hypnic (‘‘alarm clock’’) headache syndrome. Lipton RB. Idiopathic stabbing headaches lasting a few seconds. Berciano J. 14:105–108. 8:235–236. Nonaneurysmal thunderclap headache with diffuse. Vazquez-Barquero A. Spierings EL. Simon D. 11:129–134. 20:787–803. 19: 118–123. 31. Cephalalgia 1991. A spectrum of exertional headaches. Headache in acute cerebrovascular disease. Cephalalgia 2003. Lafatta J. Headache 2001. Dodick DW. The one-year period prevalence of strict migraine and probable migraine within a health-plan population. Monzillo PH. 38. 46:1520–1524. . 49. Packard RC. J Neurol Neurosurg Psychiat 1976. 41. Diagnosis of migraine: empirical analysis of a large clinical sample of atypical migraine (IHS 1. Rozen TD. Lipton RB. 52. A review of paroxysmal hemicranias. Lipton RB. Cephalalgia 1998. Cephalalgia 2000. Idiopathic stabbing headache (jabs and jolts syndrome). Green MW. Cephalalgia 2001. 4:65–70. Hemicrania continua: another headache absolutely responsive to indomethacin. Antonaci F. Dangond F. Oterino A. 44. Bordini C. Iglesias F. Med Clin North Am 1991. 18:152–156. Ribeiro S. Bigal ME. Bigal ME. 36:1445–1450. 53. Extracephalic jabs/idiopathic stabs. 279(5):381–383. Patel N. Chronic paroxysmal hemicrania in a young child: possible relation to ipsilateral occipital infarction. including new cases. 33:257–258. Pascual J. 37. Bajwa ZH. Rains JC. Rasmussen BK. multifocal. Schrader H. Cephalalgia 2002. Jensen R. Langenberg D. Dale I. Pettersen H. Dodick DW. ‘‘Hemicrania continua’’: a clinical review. JAMA 1998. Neurology 1997. Headache 1974. 40. Cephalalgia 1999. Broeske D. 43. 22(6):432–438. Sjaastad O. 50. 21:584–595. Kolodner K. 45. 23(1):50–54. Lipton RB. Goadsby PJ. Cluster headache. 75:579–594. Cephalalgia 1996. Cough. Goadsby PJ. 51. 47. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. 42. exertional. Ruiz J. Stovner LJ. Lipton RB. Sheftell FD. Leotta C. Sanvito WL. Hier DB. Neurology 2004:247–251. Cephalalgia 1984. Gorelick PB. Espejo J. 35. and sexual headaches: an analysis of 72 benign and symptomatic cases. Leckie RS. Tepper SJ. Cardiac cephalgia: a treatable form of exertional headache. Pareja JA. Bakketeig LS. 49:813–816. Mosek AC. Cluster-tic syndrome: report of five new cases. Britton JW. 120:193–209. Newman LC. Lipchik GL. Penzien DB. Epidemiology and pathogenesis of posttraumatic headache. segmental and reversible vasospasm. Cantos E. Rapoport AM. 34. Stewart WF. Kudrow L. de Isla C. Sjaastad O. Caplan LR. Schwartz BS. Lance JW. Headache 1991. Greenberg MA. Lenn NJ.7) patients and proposed revision of the IHS criteria. Silberstein SD. Neurology 1996. 58(2B):518–521. Da Costa AR. 120:1105–1113. 55. 1. Terrence CF. Gebrewold A. Altura BT. et al. Mathew NT. Lipton RB. 18:455–462. 47(4):871–875. Russell MB. 2000:929–938. Neurology 1991. In: Major Problems in Neurology. Headache associated with chronic use of substances. Stolt-Nielsen A. Cephalalgia 1998. 104:972–999. Gomez-Arada F. 114:155–180. Jensen TS. 60:595–601. The IHS criteria revisited. Funct Neurol 2002. Cephalalgia 2003. 17(1):35–36. 72. Headache associated with dialysis. Cephalalgia 1994. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 1988. Sliwinski M. Welch KMA. Bellmyer LR. Rushton JG. 14:443–446. 65. Clinical spectrum of CADASIL: a study of 7 families. In: Olesen J. Bigal ME. 64. 38:201–205. Bassi P. 58. 9:59–61. Neurology 1996. Ramadan NM. Marti-Masso FJ. Cerebral Venous Thrombosis. Altura BM. The International Headache Society (IHS) headache classification as applied to a headache clinic population. Rapoport AM. 75. Analgesic rebound headache. Tfelt-Hansen P. Pain 1989. Olesen J. Chabriat H. Tietjen GE. 74. Canadillas F. 77. Cappa KG. Lipton RB. et al. 56. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Bordini CA. Lancet 1995. A study of 217 cases. Swanson JW. Headache related to increased intracranial pressure and intracranial hypotension. Tfelt-Hansen P. 1993:721–727. J Mental Sci 2000. 59. London: Saunders 1997:Vol. The Headaches. Cephalalgia 1989. Speciali JG. Wall M. Migraine and intra-cerebral hemorrhage. Ross Russell R. Miller RH. Bandera R. 70. Prevalence and outcome under thyroid hormone therapy. Stevens JC. Fabrizi P. 61. 35:163–165. Moreau T.20 Bigal and Lipton 54. The Headache. Brain 1991. Arch Neurol 1981. eds. Guidetti V. Fredriksen TA. Schuaib A. Curr Opinion Neurol 1996. et al. Alcohol induced spasm of cerebral blood vessels. 9:214–218. Cervicogenic headache: the importance of sticking to the criteria. Tepper SJ. 73. Loiero M. Levine SR. eds. Hing T. Brain 1997. Glossopharyngeal (vagoglossopharyngeal) neuralgia. Idiopathic intracranial hypertension: a prospective study of 50 patients. Sheftell FD. 66. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Nielsen TM. Tfelt-Hansen P. Neurology 1981. Rapoport AM. Bigal ME. Thomsen LL. Cephalalgia 2002. Acta Neurol Scand 1991. Basic characteristics. 84:277–281. Scintillating scotomata associated with internal carotid artery dissection: report of three cases. Sjaastad O. Warning signs in subarachnoid hemorrhage: a cooperative study. Welch KMA. Versen HK.. Antoniazzi AL. The headache of temporal arteritis. 60. Iba-Zizen MT. Neurology 2003. 69. Mangoni. Trigeminal neuralgia and other facial neuralgias. Headache 1988a. 38:17–24. Galli F. 22:432–438. 41: 1084–1087. Tfelt-Hansen P. Sanin LC. Vahedi K. 67. 76. Diener HC. New York: Raven press Ltd. Silberstein SD. Philadelphia: Lippincott Williams & Wilkins. Togoni G. In: Olesen J. 31:1257–1262. Welch KMA. Whisnant JP. . Bousser MG. A migrainous syndrome with cerebrospinal fluid pleocytosis. Bartleson JD. Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. Ostergaard E. 23:146–149. 71. Ramadan NM. Headache in hypothyroidism. Intravenous nitroglycerin as an experimental model of vascular headache. 346:934–939. 62. 68. et al. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Metz L. 28:662–665. 2nd ed. Solomon S. 63. J Am Geriatr Soc 1987. 18:687–689. 57. George D. Ali S. Olesen J. Relation to age and sex in a general population. Matharu MS. 21:82–83. 93:175–183. Neurology 1990. Goadsby PJ. Jensen R. Solomon S. Newman LC. Lipton RB. . The hypnic headache syndrome: a benign headache disorder of the elderly. 80. 79. Quantitative surface EMG of pericranial muscles. 40(12):1904–1905.Headache—Classification 21 78. Boes CJ. SUNCT syndrome or trigeminal neuralgia with lacrimation. Fuglsang-Frederiksen A. Cephalalgia 2001. Electroenceph Clin Neurophysiol 1994. . Connecticut. U. and The Montefiore Headache Center. It also helps to identify individuals at higher risk to progress to chronic daily headache (see Chapter 27). We close by linking the epidemiological data to treatment strategies directed to reducing the burden of migraine and preventing disease progression. New York.S. Marcelo E. The Montefiore Headache Center. as well as the patterns for health care use. In this chapter we review the epidemiology and risk factors for migraine in population studies. New York.A. Primary headache disorders have no apparent underlying cause (1. Lipton Departments of Neurology. Of the primary headache disorders. INTRODUCTION Headache disorders are divided into two major categories. as well as risk factors for disease progression. The most important forms of migraine are migraine with and without aura as well as a condition termed ‘‘probable migraine’’ (PM) (1). New York. THE EPIDEMIOLOGY OF MIGRAINE Efforts to improve the diagnosis and treatment of migraine should begin with epidemiologic data. tension-type headache is the most common in population studies (3). Epidemiological data can be used to identify the groups at highest risk for migraine. New York. or a stroke. which helps to describe the prevalence and burden of migraine and its scope and distribution. We discuss the burden and the costs of migraine. Finally. 23 . Albert Einstein College of Medicine. and The New England Center for Headache. The epidemiology of the other primary headaches is described in the respective chapters. including those in need of medical care among migraine sufferers.A. a brain tumor. Secondary disorders have an identifiable underlying cause such as an infection. Bigal Department of Neurology. epidemiologic data may provide clues to preventive strategies or disease mechanisms. Epidemiology and Population Health.2 The Epidemiology and Impact of Migraine Richard B. but migraine is most common among patients who seek medical care for headache (4).S. U. Albert Einstein College of Medicine.2). Stamford. Using the reported age of migraine onset from a prevalence study. From this data.0 per 1000 person-years in males and 22. incidence rates were low at the extremes of age and higher for ages 10 to 49. Stewart et al. The Incidence of Migraine The incidence of migraine has been investigated in a limited number of studies. by age and sex. supporting the findings reported above (9). Incidence refers to the rate of onset of new cases of a disease in a given population over a defined period. 1). In this study. Prevalence is defined as the proportion of a given population. 7. A study performed in a random sample of young adults (21–30 years) found that the incidence of migraine was 5. . we can conclude that migraine begins earlier in males than in females and that migraine with aura begins earlier than migraine without aura. because medical diagnosis may occur long after the age of onset. In males. incidence also peaked later than in other studies. migraine without aura peaked between ages 14 and 17 (18. In women. Prevalence is determined by the average incidence and average duration of disease (6). in females. New cases of migraine were uncommon in men in their 20s.4 (4. (7) found that. migraine with aura peaked incidence several years earlier.9/1000 person-years). a study using a linked medical records system showed a lower incidence (probably because many people with migraine do not consult doctors or receive a medical diagnosis) (8).1/1000 person-years).9 in men).0 in females (8).8 in women and 1.24 Lipton and Bigal Epidemiological studies focus on the incidence and prevalence of disease in defined populations (5). around five years of age at 6. In this study. Figure 1 Incidence of migraine. with a striking peak at the age of 20 to 29. which has a disease over a defined period. the average annual incidence rate per 1000 person-years was 3.6/1000 person-years. the incidence of migraine with aura peaked between ages 12 and 13 (14. Source: From Ref. However. the peak for migraine without aura was 10/1000 person-years between 10 and 11 years (Fig. 0–7. 12. At age 5. 37% to 51. Herein.and population-based studies (18–24). Thus. Overall. evaluated a random sample of 1868 teen-aged girls (aged 11–18) (507 reported headache).5% have headache and by age 7.6). For both boys and girls. 10. found that age and geography accounted for much of the variation in prevalence (14). when examined using various cross-sectional studies.11–13). as investigated in a number of school. These dramatic age effects account for some of the variation in prevalence estimates from previous studies. there was a sharp increase in the prevalence rate . As shown below.5% have headaches. migraine prevalence is higher in boys than in girls. the peak years of economic productivity. the overall prevalence of headache increases from preschool age to mid-adolescence. headache prevalence ranges from 57% to 82%. being 15/1000 in males and 3/1000 in females. is summarized in Table 2. the stability of prevalence in studies in the United States over the past decade does not support the view that prevalence is increasing (16.Epidemiology and Impact of Migraine 25 In the Danish population. performed in southern Iran. A meta-analysis.1% (95% CI. The exposure of subjects to sunlight. Prevalence peaked in younger women (20/1000) (10).15). and a family history of headache were the most significant factors associated with migraine and tensiontype headaches (25). type of food. The prevalence increases throughout childhood and early adult life until approximately age 40. 5.6–13. prevalence is highest between 25 to 55 years of age.to five-year-old boys than in three. 2) (14). The second study evaluated 1400 randomly selected Saudi children in grades 1 through 9.to five-yearold girls. The prevalence of migraine was 7. we present primarily studies that used the IHS definition (Table 1). the headache prevalence was 49. Two relatively recent studies report the prevalence of pediatric migraine in the Asian Middle East.to 15-year-olds. restricted to studies that used the International Headache Society (IHS) criteria and gender-specific models (females and males were modeled separately). Prevalence by Age Before puberty. The Prevalence of Migraine The published estimates of migraine prevalence have varied broadly. Migraine and tension-type headache were significantly associated.1%. 19. incidence and prevalence increase more rapidly in girls than in boys. Overall prevalence rate for migraine was 6. probably because of differences in the methodology (for reviews see 5.8%. headache occurs in 3% to 8% of children. Prevalence in Children and Adolescents The prevalence of headache in children. The first one. the gap between peak incidence in adolescence and peak prevalence in middle life indicates that migraine is a condition of long duration. It is possible that the demonstrable increases in medical consultation and diagnosis may have caused an apparent rather than a real increase. Overall.2) and for tension-type headache. The prevalence increases from ages 3 to 11 in both boys and girls with higher headache prevalence in three. the age-specific prevalence rate for nonmigraine headache rose steadily from around 15% at age 6 to age 7 to nearly 60% after age 15. as adolescence approaches. Although studies suggested that migraine prevalence may be increasing (9. For migraine. the annual incidence of migraine for ages 25 to 64 was of 8/1000. By age 3.1% (95% CI. In 7. after which it declines (Fig.17). 26 Table 1 Gender-Specific Prevalence Estimates of Migraine from 25 Population-Based Studies Using IHS Diagnostic Criteria Migraine prevalence (%) Female 11.007 2.3 9.061 51.5 9.833 1 yr United Kingdom Sweden Telephone interview Face-to-face Mail SAQ Clin interview Community Face-to-face 16.3 12.9 9.9 2–48 hr duration allowed Breslau (1991) United States Community Cruz (1995) Ecuador Community Face-to-face/ telephone Clin interview Cull (1992) 1.7 5.9 1 yr Lifetime All 21–30 1.0 8.257 813 538 1 yr 1 yr 10.0 16.5 9.0:1) 5.14:1).3 12. (2000) Barea (1996) Malaysia Peru Hungary Brazil Community Community Community School Face-to-face/ clin interview Face-to-face Clin interview Questionnaire Clin interview 9.0 4.158 4.0 Author (year of publication) Method Clin interview 1.0 12. (2003) Deleu et al.0 .4 9.2 6.4 5.8 3.6 3.9 7.0 7.2 Alders (1996) Arregui (1991) Bank et al. Norway (2000) Lipton and Bigal Community Community Community 11.0 16.630 All 6. (2002) Saudi Arabia Gobel (1994) Germany ¨ Hagen et al.754 1 yr 5–15 Sample size Time frame Age range Country Source Abu-Arefeh (1994) Scotland School al Rajeh (1997) 595 2.7 10.5 4.668 1.2 6.7 4.8 13.002 16þ 18–74 1 yr Lifetime 1 yr 10þ 18þ 20þ 11.6 Male Total Comments Prevalence is higher in boys prior to age 12 (1. After age 12.5 7.2 Community endemic for cysticercosis Without aura only Community Dahlof et al.723 1 yr 5þ All 15–80 10–18 11.6 Saudi Arabia Community 22.6 9.6 15.0 8. more common in girls (2. 891 3.863 379 9.1 10.007 20. (2003) Lenore et al.2 3.0 5.5 Epidemiology and Impact of Migraine United States Community Switzerland Community Henry (1992) Henry et al.6 24.9 1 yr 28–29 32.0 10.2 4.9 11.0 4.7 7.7 3. (2003) Stewart (1992) Mail SAQ England Community CATI 4.2 6 16.445 740 3.6 5.5 13. (2002) Lamp et al.5 15.2 2.Haimanot (1995) 4.000 1 yr 20þ 4.1 13.9 8.246 1. (2001) Lipton et al.3 Ethiopia Community 15.3 17. Regional differences 1 yr 1 yr 18–65 12–80 14.0 13.0 France France Saudi Arabia Peru Turkey Community Community Community Community Community Face-to-face/ clin interview Face-to-face Face-to-face Face-to-face Clin interview Face-to-face Sweden Netherlands Community Community United States Community Telephone Clin interview Mail SAQ Telephone Telephone Clin interview Clin interview Clin interview Mail SAQ Face-to-face Questionnaire and telephone Telephone 1 yr Lifetime 1 yr 1 yr 13.7 3.0 8.0 France Puerto Rico Community Community Canada Italy Denmark Denmark Japan Community School Community Community Community Steiner et al.6.610 2.4 Weighted prevalence 12þ 15þ 18–65 1 yr 1 yr Lifetime 1 yr 1 yr 15þ 15þ 15þ 15þ All 11.3 7.727 11.0 17.8 33 25 18.491 29.0 6 21. (1999) Lipton et al.2 1.9 3.7 6.7 18.922 1.029 1 yr 1 yr 1 yr Lifetime 1 yr 18þ 11–14 25–64 40 15þ 3 mo 1 yr 18þ All 18.0 23.411 1.7 12.2 6.320 7.9 997 6.3 7.585 5. (2002) Jabbar (1997) Jaillard (1997) Kececi et al.6 1 yr 18–65 17. (2002) Merikangas (1993) Michel (1995) Miranda et al.8 17.3 12.7 8.0 11.204 10.5 6.1 7.471 4.0 16.4 2. (2003) O’Brien (1994) Raieli (1994) Rasmussen (1992) Russell (1995) Sakai (1996) Female:male prevalence ratio ¼ 3.6 7.3 15.468 United States Community 27 (Continued) .1 8. International Headache Society.328 5.7 0. (2004) United States Community Japan Community van Roijen (1995) Wang (1997) Wong (1995) Zivadinov et al. (2001) Netherlands China Hong Kong Croatia Community Community Community Community Abbreviations: CATI.3 14.758 1 yr 1 yr 18–65 18þ Sample size Time frame Age range Country Source Stewart (1996) Takeshima et al.5 22.1 8.28 Table 1 Migraine prevalence (%) Female 19.533 7.0 4. SAQ.0 3.0 0.173 1 yr 1 yr 1 yr Lifetime 1 yr 12þ 65þ 15þ 15–65 12. structured administered questionnaire.0 19 12.3 9.0 1.7 1.480 1. IHS.9 18 5.356 5.0 9.6 14. computer assisted telephone interview.7 6 Male Total Comments Racial differences Study done in the rural area of western Japan Gender-Specific Prevalence Estimates of Migraine from 25 Population-Based Studies Using IHS Diagnostic Criteria (Continued ) Author (year of publication) Method Telephone Questionnaires and telephone Face-to-face Clin interview Telephone Telephone and face-to-face 10.8 12.2 2. Lipton and Bigal . Table 1 summarizes several prevalence studies conducted in the last 12 years. In his studies of children. 3).8% (27). Age-adjusted prevalence for migraine between ages 6 and 15 was 6.19). the prevalence of migraine was about 18% in women and 6% in men (Fig. (from around 2% to around 9%) at age 10 to 11. International Headache Society. After four years. in adults. Finally. Source: From Ref. Similarly. in its first research phase. both in boys and girls. Sixty-four subjects out of 80 previously selected were reevaluated. the American Migraine Prevention and Prevalence (AMPP) study replicated.4% and 3.1% of cases. Bille did not find association between migraine prevalence and intelligence (18. Prevalence of Migraine by Socioeconomic Status The relationship between migraine prevalence and socioeconomic status is uncertain. In these three very large studies. changed to episodic tension-type headache in 12.2%. migraine without aura persisted in 56. respectively. Thirty-two (50%) had migraine without aura.and clinic-based studies.5%. Abbreviation: IHS. and remitted in 18. The AMS-II used virtually identical methodology 10 years later (17).S. We present the prevalence of migraine in different geographic locations.2% (26). population in 1989 (16).Epidemiology and Impact of Migraine 29 Figure 2 Adjusted prevalence of migraine by age from a meta-analysis of studies using IHS criteria. Another study evaluated the evolution over five years of juvenile migraine without aura in adolescents.000 households representative of the U. epidemiologic studies do not support a relationship between occupation and migraine . migraine appears to be associated with high intelligence and social class. the methods of the AMS-I and AMS-II (28). converted to migrainous disorder or nonclassifiable headache in 9. 14. In physician. Prevalence in the United States In the United States. the American Migraine Study-1 (AMS-1) collected information from 15. overall and by gender. 9 3.7 3. nausea.7 4.0 4.7% School Children 1.4% 7.2 – Lipton and Bigal a age adjusted definitions: N.3 4.400 6.868 1.8a 23.6 – – 3. .9 1 yr IHS 40. VA.1% Time Frame Migraine definition Headache prevalence Migraine prevalence Overall – 7.3 Lifetime Vahlquist 58.1% 10.9 3. V. NS.784 3. U. unilateral. visual aura. not specified. vomiting.1 3.1 2.0 59.993 Community 10.754 School Children 8.1 School Children School Children 1.0 Author (Y) Country Sample Type of population size Overall Males Females School teenage girls School Children 1.083 Ayatollahi (2002) Iran Al Jumah M (2002) Saudi Arabia Abu-Arafeh (1994) U.6a 1 yr 2 of NV/U/VA 90 95 36.8 84.825 Sillanpaa (1983) Finland School Children 3.3 5.3 NS IHS NS IHS 6.3 1 yr IHS – – 38.2 – 3.132 General Practice 1.4 14 2.30 Table 2 Prevalence of Headache and Migraine by Age in Selected Community and School-Based Studies Age range (years) Males – Females 11–18 6–18 5–15 7–15 12–29 3–11 11–14 3 1 yr NS IHS 19.2 8. Bille (1962) Sweden Linet (1989) USA Mortimer (1992) UK Raielli (1995) Italy Sillanpaa (1976) Finland 7 13 NS 1 yr Vahlquist Vahlquist 79.445 4.2 15.9a 28.K. which has an impact on both the individual sufferer and on society (17. severe attack a month. Similar frequency patterns were observed for men (18. In the United States. and AMPP. a recent study in England showed this relationship (31). 38% experience one. migraine prevalence was inversely related to household income (i. In the AMS-II. a meta-analysis of prevalence studies suggests that migraine is most common in North and South America and Europe.S. migraine prevalence fell as household income increased) (17. If and how these differences apply to the pediatric population (of if these differences have later expression) is still to be determined. American Migraine Prevention and Prevalence. intermediate in African Americans. 35% experience one to four severe attacks a month. In addition to the attack-related . overall and by gender. Similar findings were reported by the AMPP.18. and often lowest in studies from Asia (Fig. AMS-II. Nearly one in four U. American Migraine Study. although the genetic epidemiology of migraine study (GEM) failed to demonstrate an association between migraine and socioeconomic status (30). In both the AMS-I and AMS-II and the AMPP. AMPP. study based on the members of a managed care organization and in the National Health Interview Study (29). The influence of reporting bias on these findings cannot be excluded. it is highest in Caucasians. Prevalence of Migraine by Geographic Distribution Migraine prevalence also varies by race and geography. or less than one.Epidemiology and Impact of Migraine 31 Figure 3 Prevalence of migraine in the AMS-I. This inverse relationship between migraine and socioeconomic status was confirmed in another U. 4) (4). About half were severely disabled or needed bed rest (32).28). THE BURDEN OF MIGRAINE Individual Burden of Migraine Migraine is a public health problem of enormous scope. prevalence (29).. Finally. Nonetheless the data suggest that race-related differences in genetic risk may contribute.e. Abbreviations: AMS.28). Twenty-five percent of women in the United States who have migraine experience four or more severe attacks a month. Similarly. but lower in Africa.S.18). and lowest in Asian Americans (5). 92% of women and 89% of men with severe migraine had some headache-related disability. households have someone with migraine. 42). April 2000. Societal Impact of Migraine Migraine has an enormous impact on society. (Consumer Healthcare Products Association.) Gross sales for the triptans are about US $1 billion per year in the United States. OTC Sales Statistics—1995 to 1999. The National Ambulatory Medical Care Survey.35–37).40).32 Lipton and Bigal Figure 4 Adjusted prevalence of migraine by geographic area and gender in a meta-analysis of studies using IHS criteria. The largest component of indirect costs is the productivity losses that take the form of absenteeism and reduced productivity while at work. Migraine’s impact on health care utilization is marked as well. Vast amounts of prescription and over-the-counter (OTC) medications are taken for headache disorders. Recent U. many migraineurs live in fear. conducted from 1976 to 1977. found that 4% of all visits to physicians’ offices (over 10 million visits a year) were for headaches (39. PROBABLE MIGRAINE—AN IMPORTANT MIGRAINE SUBTYPE Most epidemiologic studies focus on the two common forms of migraine. Source: From Ref. knowing that at any time an attack could disrupt their ability to work. estimated that productivity losses due to migraine cost American employers 13 billion dollars per year (35). Hu et al.S. AC Neilsen. in household work. migraine without aura (1. Abundant evidence indicates that migraine reduces health-related quality of life (33. studies have evaluated both the indirect costs of migraine and the direct costs (32.2 billion dollars in 1999 (United States) and headache accounts for about one-third of OTC analgesic use. 5. These issues have been reviewed in more detail elsewhere (38). Clinic. care for their families. Migraine also results in major utilization of emergency rooms and urgent care centers (41.and some population-based . disability.1) and migraine with aura (1. OTC sales of pain medication (for all conditions) were estimated to be 3.34).2). and in other roles. or meet social obligations. Indirect costs include the aggregate effects of migraine on productivity at work (paid employment). being 3. strict migraine.6% in women and 13.7%.6%. Strict migraine and PM were associated with an increased risk of depression.1% for PM.2% (38.9% in men and 5. strict migraine. respectively.Epidemiology and Impact of Migraine 33 Figure 5 Prevalence of probable migraine. 22%. in their study. the one-year prevalence for migraine with and without aura (strict migraine) was 14. Among 8579 respondents. and seizure disorder in terms . high blood pressure. and treatment response profiles. it is likely that PM involves the same pathophysiological process as with strict migraine. and 3.9. for PM it was 14. PM was more prevalent than migraine with or without aura.5%.6% in men) (Fig. AM.2.8% in women and 19.8.1.2% in women and 6. Abbreviations: SM. This condition is termed ‘‘probable migraine’’ in the IHS classification (1). The one-year period prevalence in the AMS-II was 2. and all migraine groups. the overall prevalence of PM was 4. 5). Diagnosis of this large group of headache sufferers is an important issue in clinical practice. 50. Migraine parallels other chronic illnesses such as asthma. and 53. We recently conducted a study assessing the prevalence and impact of PM within a health plan (43).7% (19.1% in women (28). 31%. In a French population study. The proportion of subjects with high disability relative to control was elevated in PM. (47) found a prevalence of 9.0001). Interestingly. Given the overlap of symptom features. respectively. and those in early middle life relative to controls. Caucasians. strict migraine. the profile of familial aggregation. p < 0. and 51. The prevalence of strict migraine and PM was higher in females. The impact of PM is poorly understood. and all migraine groups [migraine disability assessment (MIDAS) III and IV: 13%. CONCLUSIONS Migraine is a lifelong illness for many sufferers and imposes an enormous and prevalent health care burden on society. hypertension.5% (19. These patients often fulfill all criteria but one for migraine with or without aura. 48.8. pooling strict migraine and PM. p < 0. Estimates of the prevalence of PM vary widely. 48. and all migraine within participants of a health plan. PM.6% in men). In the AMPP. Henry et al. physical health scores 46.2. 47. probable migraine.2.0001]. all migraine. strict migraine. Health related quality of life (HRQoL) was reduced in the PM. respectively—p < 0. compared to controls (mental health scores 50.8.0001. studies show that a large number of patients with migrainous features fail to fully meet the IHS criteria for these two types of migraine (43–46). the prevalence of all migraine was 29.1% in men). Bigal ME. Waters WE. 6. Olesen J. Rasmussen BK. Joint 1994 Wolff Award Presentation. Littleton. . 38:87–96. 45(suppl 1):S3–S13. Medical consultation for migraine: results from the American Migraine Study. Bigal ME. Bille B. Steiner TJ. 8. Tepper SJ. Silberstein SD. Linet MS. 40:331–338. cranial neuralgias. Jensen R. eds. Lipton RB. Migraine and Other Headaches. Stewart WF. Breslau N. Headache 2001. impact. Headache 1998. Ziegler D. and a 30-year follow-up (1989). 17. Migraine and major depression: a longitudinal study. Cephalalgia 1995. Rasmussen BK. behavioral approaches. Minnesota. Cephalalgia 2003. et al. 34: 1111–1120. Neurology 2004. MMWR. and risk factors for progression.34 Lipton and Bigal of the impact of disease and requirement for long-term management. J Clin Epidemiol 1995. Diamond ML. Stewart WF. Bigal ME. 1980–89. 15:45–68. Van Natta M. Prevalence of migraine headache in the United States. 13. Classification and Diagnostic criteria for headache disorders. and preventive treatments that will be discussed in detail in the following chapters. MMWR 1991. Incidence of migraine in a Danish population-based follow-up study [abstr]. The epidemiology and impact of migraine. based on a stratified care treatment approach. Lipton RB. and facial pain. Jorgensen T. Lipton RB. Acta Paediatr Scand 51(suppl 136):1–151. 1999:159–170. including patient satisfaction and treatment success. 4(2):98–104. Headache 2005. et al. 23:596. Stewart WF. 16. 10. Cephalalgia 2004 (suppl 1):1–160. The classification of the headaches. Davis GC. Celentano DD. Neurology 1992. Bille B. Dahlof CG. Migraine in children: prevalence. ed. Headache 2004. clinical features. Headache 1994. In: Ferrari MD. Scher AI. 1986. 14. Population variation in migraine prevalence: a meta-analysis. 19. 9. Shechter A. Reed ML. establishment of a disease management plan for the patient. Lipton RB. Lipton RB. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Lipton RB. Lipton RB. 7. 2001. 44(9):856–864. 4. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Lipton RB. 5.. Migraine in school children (1962). Schultz LR. Stewart WF. 2nd ed. Seattle. Epidemiology of Pain. 11. Celentano DD. Migraine and headache: a meta-analytic approach. patient education. 41:646–657. Age and sex-specific incidence rates of migraine with and without visual aura. 15. In: Crombie IK. 63(3):427–435. Yanagihara T. Migraine: epidemiology. Am J Epidemiol 1993. Stewart WF. Stewart WF. 3. Stewart WF. Lataste X. 267:64–69. Peterson EL. Headache (Series in Clinical Epidemiology). 34(7):387–393. Prevalence of chronic migraine headaches—United States. REFERENCES 1. Simon D. and ongoing assessment of illness severity and disease impact (using a disability measure such as MIDAS) is likely to improve long-term outcomes. Identification of and screening for migraine. Curr Neurol Neurosci Rep 2004. Dowson A. Swanson JW. Stang PE. This effort must be part of a broader strategy that includes effective assessment and follow-up. MA: PSG Co Inc. Headache Classification Committee of the International Headache Society. Incidence of migraine headaches: a population-based study in Olmstead County. Washington: IASP Press. Simon D. Lyngberg A. 48:269–280. Epidemiology of headache. 2. Diamond S. JAMA 1992. New Jersey: Parthenon. Reed M. 18. 42:1657–62. 12. 11:239–242. Kolodner K. 39. Sillanpaa M. Migraine diagnosis and treatment: results from the American Migraine Study II. 42. Vital and Health Statistics of the United States. Osterhaus JT. 27. 37. 42(4): 287–290. Hyattsville. et al.. et al. Sillanpaa M. Sternfeld B. Advance data. Saudi Arabia. Prevalence of headache at preschool age in an unselected child population. The sensitivity and specificity of the case definition criteria in diagnosis of headache: a school-based epidemiological study of 5562 children in Mersin. Changes in the prevalence of migraine and other headaches during the first seven school years. 21. demographics. Headache in children. Arch Intern Med 1999. 23:15–19. Holmes WF. 36:69–76. Prevalences of migraine and tensiontype headache in adolescent girls of Shiraz (southern Iran). Improvement in migraine-specific quality of life in a clinical trial of rizatriptan. 22(10):791–798. 4(suppl 1):3–11. Sasmaz T. Hartmaier SL. 56(suppl 1):S13–S19. Migraine prevention patterns in a community sample. Bigal ME. D. 43. Plachetka JR. J Headache Pain 2003. Piekkala P. 23(7):519–527. gender and ethnicity. In: Olesen J. 23:10–14. Sillanpaa M. Headache 2005. Awada A. Bordini CA. Cortelli P. Fry J. 32:223–228. Headache 1996l. 41:638–645. 15:288–290. MacGregor A. Headache syndromes amongst schoolchildren in Riyadh. A multinational investigation of the impact of subcutaneous sumatriptan. Liberman J. Stang PE. Cephalalgia 2003. National Center for Health Statistics. Kramer MS. Migraine-related disability: impact and implications for sufferers’ lives and clinical issues. Bouchard J. Freitag F. Cephalalgia 2002. The prevalence and characteristics of migraine in a population-based cohort: the GEM Study. Stewart W. Sillanpaa M. Sillanpaa M. 29. Reed M. Gutterman DL. Scher AI. Markson LE. Burden of migraine in the United States: disability and economic costs. 25. 17(8):867–872. Prevalence of migraine and other headache in Finnish children starting school. Steiner T. Lipton R. Diamond S. Stewart WF. Headache Classification and Epidemiology. National Center for Health Statistics. 53. 30. and the full spectrum of migraine within a health-plan population. Block GA.H. 1994:273–281. Profiles of Disease. 31. Ozge A. 23. Moradi F. Cephalalgia 1997. Bugdayci R. 53:537–542. Headache in an emergency room. Bigal ME. Berger ML. 11(suppl 1):24–34. 26. Prevalence of headache in prepuberty. 28. Bigal ME. 33. Reed ML. Lipton RB. Pharmacoeconomics 1997. Cephalalgia 1991. Sao Paulo Med J ˜ 2000. probable migraine (migrainous headache). Launer LJ. 38. physiological and behavioral factors.Epidemiology and Impact of Migraine 35 20. Celentano DD. Ayatollahi SM. Headache 1976. Stewart WF. 118(3):58–62. Patel N. New York: Raven Press. 36. Diamond ML. Lipton RB. Dodick D. et al. 45: 792. Headache 2002. 40. 41. Lipton RB.E. Headache 2002. Migraine headache in a pre-paid health plan: ascertainment. Pharmacoeconomics 1992. Ferrari MD. Cephalalgia 2003. Ayatollahi SA. Diamond D. 32. Al Jumah M. Results from the American Migraine Prevalence and Prevention (AMPP) study. 2:67–76. Headache 1983. The prevalence and disability burden of adult migraine in England and their relationships to age. II: Health-related quality of life. PHS Publication No. 34.W. Kero P. Scher A. et al. Hu XH. Headache 1983. Dahlof C. ed. Neurology 1999. 35. Medication use and disability among migraineurs: a national probability sample. The one-year period prevalence of strict migraine. Polis AB. Kolodner K. Al Azzam S. Health care resources and lost labor costs of migraine headaches in the United States. . Headache 2001. 24. The global burden of migraine. Speciali JG. Silberstein SD. Sidney S. Bigal ME. 1996. 1979. Edinburgh: Livingstone. Stewart WF. Terwindt GM. Headache 1992. Neurology 2001. MD. 23:594. 22. Lipton RB. Stewart WF. Lipton RB. 42(4):281–286. 159:813–818. Santanello NC. Lipton RB. Cephalalgia 1996. Dodick D. et al. Gaudin AF. 59:232–227. Cady R. Prevalence and clinical characteristics of migraine in France. 16(6):431–435. Auray JP. Russell MB. Diamond M. Cephalalgia 2001. 21:584–595. Neurology 2002. Headache 2002. Lipchik GL. Diagnosis of migraine: empirical analysis of a large clinical sample of atypical migraine (IHS 1. . et al. Penzien DB.36 Lipton and Bigal 44. 42:440. Migrainous disorder and its relation to migraine without aura and migraine with aura.7) patients and proposed revision of the IHS criteria. 46. A genetic epidemiological study. Demographics of migrainous headache sufferers in the United States: additional data from the American Migraine Study II [abstr]. 45. Olesen J. Henry P. Rains JC. 47. 3 Progressive Headache: Epidemiology. less commonly. U. and risk factors for CDH identified in population studies. Evidence from placebo-controlled trials of treatment strategies for CDH is limited (15–20) and. and hypnic headache) and long-duration types (21). Despite recent insight from animal models (1–3). chronic paroxysmal hemicrania. it is possible that migraine 37 . Uniformed Services University of the Health Sciences. A slightly greater proportion of the migraine population experience CDH than of the non-migraine headache population [8% vs. such as chronic cluster headache. and Risk Factors Ann I. with roughly equal prevalences of both (22–26). some individuals (about 4% of the adult population) chronically experience attacks on a daily or near daily basis.A. odd’s ratio (OR) ¼ 1. CLASSIFICATION CDH can be secondary (attributable to an underlying disorder) or primary (not attributable to an underlying disorder). Natural History. and. and epidemiology (11–14). unfortunately.S. Primary CDH is further subdivided into the shorter duration headaches (less than four hours. natural history. INTRODUCTION While most headache sufferers experience attacks once or twice per month. 24). focused clinical studies (4–10).6 (1. Maryland. In the population.3–1. the etiology of CDH remains uncertain in most cases. we review the epidemiology. clinical trials of headache-specific agents often exclude individuals with very frequent headache.9)] (unpublished data from Ref. The term ‘‘chronic daily headache’’ (CDH) is defined by convention as headache on 15 or more days per month. most CDH sufferers can be classified as either chronic migrainous headache or chronic tension-type headache. CDH patients in tertiary referral centers primarily have chronic migrainous headaches. presumably due to higher rates of consultation (24). hemicrania continua and new daily persistent headache (21). Therefore. Long duration types include chronic tension-type and chronic migrainous headache. 5%. In this chapter. Bethesda. Scher Department of Preventive Medicine and Biometrics. although remission was lower in an elderly Chinese population (33% had remitted over a four-year period) (26). A similar remission rate was reported in Taiwan (65% remitted to fewer than 15 headaches per month after two years) (23). Socioeconomic Status CDH appears to be more common in individuals of less education or lower income (14.S. in the U.26).30.38 Scher headache is either a risk factor for CDH onset or is associated with a poorer prognosis (longer duration) than nonmigrainous CDH. However. For example.25. This higher incidence rate among consulting headache patients could be due to these patients having more severe disease than the population sample or because such patients have a higher prevalence of comorbid conditions or other exposures that influence incidence and might influence rates of physician consultation. This relatively constant prevalence of CDH is in contrast to the pattern seen with episodic migraine and. two prospective studies found that individuals with migrainous CDH were no more or less likely to remit by two to four years of follow-up than individuals with chronic tension-type headache (23. DEMOGRAPHIC FACTORS ASSOCIATED WITH CHRONIC DAILY HEADACHE Gender CDH affects women more than men by a factor of roughly two to one (27) and this increased prevalence in women is evident even after the age of menopause (23.30). CHRONIC DAILY HEADACHE EPIDEMIOLOGY AND NATURAL HISTORY Prevalence CDH affects about 4% of the adult and elderly population 23. Incidence In a U.S.29. prospective study.26.30a).28) and about 2% of children or adolescents (11. to a lesser extent. based population study of adults aged 18 to 65. both of which tend to become less prevalent with age. tension-type headache. individuals with less than a high-school education were at . the one-year incidence of CDH was approximately 3% among those with episodic headache (14). compared to those with a graduate education. more than half (60%) of CDH cases at baseline had remitted to less than 180 headache days per year at follow-up.23. Incidence rates were much higher (14%) in a German clinic-based study of migraine sufferers (31). Remission Three prospective population-based studies suggest high rates of remission over time periods ranging from one to four years. In a prospective study in the United States. remission to less than 1 headache per week was less common (16%) (14).24.26.32).25–27. 9)] and men [RR ¼ 1.6)] and men [RR ¼ 1. income.1). incidence. prospective study (14).6 (1.0–2.7)] but not for women [RR ¼ 0. or social class (32).34. At follow-up at least two years later.0)].1–3.. and will remain uncertain absent evidence from well-designed clinical trials.2 (0. although obesity is associated with other conditions [e.9)] and were less likely to have remission after one year [OR ¼ 0.9 (0. was predictive of one-year CDH incidence in the U. However.8 (1. Lu et al. diabetes. or separated) were found to be at a higher risk of CDH at baseline [OR ¼ 1. Results indicated that the risk of CDH was higher in those with less than 10 years of education relative to those with 13þ years of education for both women [relative risk (RR) ¼ 2. 36 (34%) of who overused medication at baseline. and Risk Factors 39 increased risk of CDH at baseline [OR ¼ 3. may be a marker of headache intractability.25. As medication overuse is obviously a consequence of headache progression.7)] among the episodic headache controls.4 (1.5)] (14). OTHER FACTORS ASSOCIATED WITH CHRONIC DAILY HEADACHE PREVALENCE OR INCIDENCE Obesity Obesity. osteoarthritis (see below).4)]. Hagen et al.(23) followed a group of 106 CDH sufferers for two years.. prospective study (14). Natural History.g.35).1–2.5 (0.4 (1.1–5. 19/70 (27%) of the nonoverusers had persistent CDH and 18/36 (50%) of the overusers had persistent CDH. educational level was not associated with one-year incidence in this study. defined as a body-mass index !30.1–4. widowed.26. Wang et al. In a second study in an elderly population. corresponding to a relative risk of 1.1–0. At follow-up two years later. approximately one-third of CDH sufferers overuse medication as defined based on criteria by Silberstein (22. (26) identified 15 (25%) CDH sufferers. The reason why obesity would predispose individuals to headache progression is unknown. In a large prospective population study from Norway. and for low income for men [RR ¼ 1.g.3)] and were at reduced risk for remission at one year [OR ¼ 0. and remission. and cardiovascular disease (33)] that might also influence headache frequency.23.6–5.3–0. Compared to married individuals.2–2. who overused medication. Medication Use Medication overuse for headache may be an aggravating or causal factor for headache progression. Marital Status In the previously mentioned U.6–1.9)]. marital status at baseline was considered as a risk factor for CDH prevalence. marital status was not associated with CDH incidence [OR ¼ 1.8 (1. 21/37 (57%) of non-overusers .5–4. Similar results were seen for low social class for women [RR ¼ 2.35 (2.S. divorced. In population samples. considered whether the risk of CDH was greater in those with lower educational level. the role or even existence of medication overuse as a cause of headache progression is difficult to demonstrate in observational studies.1)].Progressive Headache: Epidemiology.S. However.1–1.5 (1.6 (1. although a somewhat higher proportion of CDH sufferers (41–54%) were found to be overusing medication in a large study from Norway (36). or both. previously married individuals (e.8 (0. but do not answer the question of whether medication overuse is itself a risk factor or is a marker for headache intractability.40 Scher had persistent CDH versus 14/15 (93%) of overusers.S. case-control study. and CDH of recent (less than two years) onset. CDH sufferers who had not consulted physicians. The migraine sufferers. This association was independent of factors known to be associated with snoring and sleep apnea (e. coexisting depression. whether episodic or chronic. if the association is causal. because headache frequency at baseline (and the ‘‘at-risk’’ population for CDH) was not known. male gender. . high blood pressure. and for both married and unmarried CDH sufferers. consumed more medicinal or dietary caffeine than the other headache sufferers. In a U... Snoring and Sleep-Related Factors Habitual snoring was much more common in a population sample of CDH sufferers compared to episodic headache controls (12). for both younger and older CDH sufferers. because individuals with CDH were not identified in the baseline survey. This suggests that. 12).g. Therefore. The previously mentioned German clinic-based study found that medication overuse predicted incidence of CDH in episodic migraine-specialty patients. They found that individuals who used analgesics daily or weekly at baseline were more likely to have chronic pain at follow-up compared to individuals who used analgesics less than weekly. (37) interviewed a large population-based sample of individuals two times over a 10-year period. although the association was modest. weight. alcohol consumption) as well as other headache-related factors that can affect sleep (e. this finding cannot be taken to support the hypothesis that CDH sufferers with medication overuse have a worse prognosis than CDH sufferers without medication overuse. increased age.2–2. the reason for medication use at baseline was not known. and caffeine consumption). Caffeine Consumption The role of caffeine as a causal or aggravating factor in CDH is of particular interest.g. particularly younger women. CDH cases were also more likely to report sleep problems and to be either short or long sleepers (unpublished data from Ref. Unfortunately.6 (1. for both men and women. the effect of snoring on very frequent headache is from a different mechanism than that from sleep apnea/hypopnea. Results showed that the CDH sufferers were more likely to have been high caffeine consumers than the comparison group before CDH onset. These studies thus support the hypothesis that medication overuse predicts a worse prognosis. For similar reasons. There was no difference in current caffeine consumption between the episodic and chronic headache sufferers. as caffeine is the only component of pain medication shown to cause withdrawal headache in placebo-controlled trials (38). corresponding to a relative risk of 1. even after adjusting for baseline headache frequency (31). CDH sufferers with daily episodic (as opposed to daily continuous) headache. Zwart et al. High caffeine consumption appeared to be more important as a risk factors in some subgroups of CDH sufferers.3). The finding that CDH sufferers were more likely to snore was evident for both chronic migraine and chronic tension-type headache sufferers. use of sedating pain medication. this finding cannot be taken to support the hypothesis that medication overuse predicts CDH incidence. dietary and medicinal caffeine consumption both before and after CDH onset was compared in CDH cases to episodic headache controls (39). 6 (1. p < 0. and other factors. job changes.6 for severe depression)].and fifth-grade Finnish schoolchildren (42).41 (1. depression. von Korff et al.5 for moderate depression and OR¼ 4. No difference was found for post-CDH events. However. They were reevaluated after one and four years to determine factors related to the prognosis of musculoskeletal pain. 2. It may also be that one condition directly leads to the development of the second (e. Natural History. children were examined for the presence of nontraumatic musculoskeletal pain symptoms and were tested for hypermobility. Having a baseline pain condition was a more consistent predictor of a new pain condition than having . and Risk Factors 41 Stressful Life Events Certain life changes (moves.S.Progressive Headache: Epidemiology. ranksum test). or abdominal pain although it was associated with severe headache incidence [adjusted odds ratios of 1.41). In the previously mentioned study from Norway (13). individuals with CDH were more than four times more likely to report musculoskeletal symptoms than those without CDH [RR ¼ 4. Overall. child-related changes.7 for moderate depression and 5.. deaths in the family or of close friends. In a study by El-Metwally et al.g. Baseline headache once or more a week (not characterized by type) was found to be a negative prognostic factor—that is.0.7 vs.3)]. and ongoing ‘‘extremely stressful’’ life events) were found to be associated with CDH onset in the case-control study. Participants were assessed at baseline for chronic pain. the children with comorbid headache were more likely to have persistent musculoskeletal pain at follow-up compared to the children without comorbid headache. study (14). changes in marital status.001. At the three-year follow-up. CDH sufferers over age 40 were considerably more likely to report physician-diagnosed arthritis [OR ¼ 2. Pain conditions might be comorbid because of diagnostic uncertainties [for example. physician-diagnosed arthritis was also associated with incident CDH. They found that the CDH students had about a 10% higher score on this scale—suggesting that the presence of these negative life events might be involved in the onset of adolescent CDH.3)] than individuals with episodic headache. there may be shared genetic or nongenetic factors that influence the development of pain at different sites. strengthening a causal interpretation. neck pain triggering headache). in a U. conducted a three-year longitudinal study of 803 adult Group Health enrollees to measure factors that were associated with the onset of chronic pain (43).0–5. particularly when there is an overlap in the symptomatology of the pain syndromes or when diagnosis is not based on objective markers.0 for severe depression and for chest pain incidence (OR ¼ 4. although results were attenuated after adjusting for obesity..g. Similarly.8–3. A large study based on adolescent students from Taiwan measured the presence of childhood stressors (e. parental divorce and child abuse) using the global family environment scale and compared scores between students with CDH and a control group (11). Comorbid Pain The co-occurrence of different pain syndromes has been noted in a number of studies (29. baseline depression was not associated with incidence of TMD pain. chronic tension-type headache and temporomandibular disorder (TMD)]. back pain.40. of 1756 third. Among the episodic headache controls. cases reported more such events in the same year or year before CDH onset than the controls in an equivalent time period (2. L-Arginine/nitric oxide pathway in chronic tension-type headache: relation with serotonin content and secretion and glutamate content. Wang SJ. CDH often remits over a one. 5. Factors associated with the onset and remission of chronic daily headache in a population-based study. J Neurol Sci 2002. Russo S. Sarchielli P. . 24:54–59. Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid. 23(3):166–174. Srikiatkhachorn A. Govitrapong P.3). Cephalalgia 2004. Heine JA.1). Ca2þ. Stewart WF. headache (OR ¼ 4. Stewart WF. Welch KM. Gallai V. Hagen K. CONCLUSION CDH affects about 4% of the population. Ricci JA. Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Walsh M. Gallai V. Tarasub N. Svebak S. The co-occurrence of headache and musculoskeletal symptoms amongst 51 050 adults in Norway. Floridi A. Gelman N. Alberti A. Nitric oxide pathway. 42(7):566–574. 9. habitual snoring. Lipton RB. et al. Neurology 2003.3). abdominal pain (OR ¼ 6. Lu SR. Gallai V. Zwart JA. Cephalalgia 1999. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache: J Head Face Pain 2001. Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients. 40(5):343–350. 41(7): 629–637. Alberti A.7). Cephalalgia 2003. 4. Bahra A.42 Scher baseline depression. Risk factors identified in population studies include stressful life events. REFERENCES 1. Eur J Neurol 2002. Sarchielli P. Menon S. Floridi A. 19(9):810–816. 3. Scher AI. Lipton RB. 34(6):491–498. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. 8. Floridi A. 7. with significant risk for new onset back pain (OR ¼ 2. Headache: J Head Face Pain 2002. 10. CDH is more common in women than men and is inversely associated with measures of socioeconomic status. Habitual snoring as a risk factor for chronic daily headache. Goadsby PJ. 11. Alberti A. 13. Suwattanasophon C. Srikiatkhachorn A. Tarasub N. Phansuwan-Pujito P. Neurology 2001. Sarchielli P. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache: J Head Face Pain 2003. Acetaminophen-induced antinociception via central 5-HT(2A) receptors. In the general population. 14. 57(1):132–134. 106(1/2):81–89. Association between adolescent chronic daily headache and childhood adversity: a community-based study. Ruangpattanatawee U.to four-year period. Aurora SK. 43(3):179–190. Scher AI. 12. and serotonin content in platelets from patients suffering from chronic daily headache. Einarsen C. Pain 2003. Fuh JL. and comorbid pain. Coppola F. Neurochem Int 1999. Bovim G. Gallai B. 5-HT2A receptor activation and nitric oxide synthesis: a possible mechanism determining migraine attacks. Alberti A. 198(1/2):9–15. Sarchielli P. Chen YS. Srikiatkhachorn A. Becker WJ. Headache 2000. Wilkinson SM. Juang KD. Nagesh V. 60(8):1366. 9(5):527–533. 6. and TMD pain (OR ¼ 3. Govitrapong P. Headache: J Head Face Pain 2001. 2. 41(3):303–309. Colas R. Turkel C. Guitera V. Chronic daily headache in Chinese elderly: prevalence. Gabapentin in the prophylaxis of chronic daily headache: a randomized. 41(2):178–182. 24(1):60–65. impact. 33. Stewart WF. Zwart JA. Vuong KD. Chen WT. . Ferretti C. Chronic daily headache in Taipei. Double-blind trial of fluoxetine: chronic daily headache and migraine. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Headache: J Head Face Pain 1994. Spira PJ. et al. Cardiovascular risk factors and migraine: the GEM population-based study. 2000(54):314–319. 17. Temprano R. Taiwan: prevalence. Lipton RB. Cephalalgia 2001. Schneeweiss S. Vatten L. Amitriptyline treatment in chronic drug-induced headache: a Double-Blind Comparative Pilot Study. 22(5):401–408. 20(10):900–906. Hagen K. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Launer LJ. Anttila P. Eeg-Olofsson O. Wang SJ. Risk factors for chronic daily headache. 31. 20. Silberstein SD. Chronic Tension-Type Headache. Fuh JL. Headache: J Head Face Pain 2001. Prevalence of headache in Swedish school children. J Neurol Neurosurg Psychiat 2001. 66:193–197. 22. Chronic daily headache in adolescents. Wolff Award 1998: Prevalence of frequent headache in a population sample. and Risk Factors 43 15. et al. 32. 18. Pascual J. Neurology 2004. Cantrell DT. Headache: J Head Face Pain 2005. Castillo J. Gomez C. Incidence and predictors for chronicity of headache in patients with episodic migraine. and biannual follow-up. 2001:247–282. 64(4):614–620. 16. Fuh JL. Ferrari MD. Vatten L. Headache: J Head Face Pain 2002. Headache: J Head Face Pain 1999. Krokstad S. 23. Lake AE III. placebo-controlled trial. Low socio-economic status is associated with increased risk of frequent headache: a prospective study of 22718 adults in Norway. et al. Laurell K. Verschuren WMM. Juang KD. 27. 22(8):672–679. Gibson J. Munoz P. 35. Lipton RB. 42(6):470–482. Casini AR. Bovim G. Fuh JL. placebo-controlled. 62(5):788–790. Neurology 2000. Natural History. 30a. Bovim G. 39:190–196. Frishberg BM. 70(3):377–381. 26. Stovner LJ. placebo-controlled. Mathew NT. Gawel M. Scher AI. 24(5):380–388. Kurth T. Stewart W. Katsarava Z.Progressive Headache: Epidemiology. risk factors. Liberman J. 47(4):871–875. Derman HS. Headache: J Head Face Pain 1998. parallel design study. Neurology 1996. Kaplan Award 1998: Epidemiology of chronic daily headache in the general population. Lipton RB. Prevalence of headache in an elderly population: attack frequency. Wang SJ. Descombes S. Metsahonkala L. disability. Prevalence. Winters ME. Botulinum toxin A for chronic daily headache: a randomized. Saper JR. Including Transformed Migraine. Pascual J. Brefel-Courbon C. Silberstein SD. Wang SJ. Hagen K. with a focus on tension-type headache. a large population-based study. White JR. Lu SR. Cephalalgia 2004. Silberstein SD. Curr Pain Headache Rep 2002. Sliwinski M. Ondo WG. Determinants of tension-type headache in children. 25. 29. placebo-controlled study. Oxford: Oxford University Press. 19. 62(8):1338–1342. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized. 28. Terwindt GM. Stovner LJ. 30. et al. Prevalence of migraine and nonmigrainous headache—head-HUNT. 21. Chronic daily headache prophylaxis with tizanidine: a double-blind. Zwart JA. Winner PK. follow-up and outcome predictors. Lu SR. 61(12):1753–1759. Scher AI. Cephalalgia 2000. Cephalalgia 2004. and use of medication. Aromaa M. Neurology 2004. 45(4):293–307. Cephalalgia 2002. Cephalalgia 2002. 38:497–506. Saper JR. Scher AI. Neurology 2006. 34. Wolff’s Headache. and Medication Overuse. Chronic Daily Headache. 6(6):486–491. et al. Neurology 2003. and medication overuse. Dimitrova R. Prencipe M. Juang KD. Larsson B. multicenter outcome study. Picavet HSJ. double-blind. Lu SR. Lipton RB. 34(9):497–502. Beran RG. 21(10):980–986. 24. Munoz P. Lake AE. Neurology 2005. Pain 1993. J Head Face Pain 2005. 39. 38. 42. Svebak S. Stewart WF. Neurology 2004. N Engl J Med 1992. Evans SM. El Metwally A. Holmen J. Hagen K. 55(2):251–258. Griffiths RR. and low-back pain. Salminen JJ. Auvinen A. 110(3):550–559. Ann Intern Med 2001. Scher AI. Zwart JA. lifestyle. 134(9 Pt 2):868–881. Le Resche L. Mikkelsson M. Prognosis of non-specific musculoskeletal pain in preadolescents: a prospective 4-year follow-up study till adolescence. Lipton RB. Silverman K. First onset of common pain symptoms: a prospective study of depression as a risk factor. Croft PR. Caffeine as a risk factor for chronic daily headache: a population-based study. Kautiainen H. 327(16):1109–1114. Strain EC. Dyb G. . Zwart JA. Buchwald D. sleep. Holmen J. 43. von Korff M. Dworkin SF. Aaron LA. Stovner LJ. Millson DS. Thomas E. and comorbid associations with headache. Withdrawal syndrome after the double-blind cessation of caffeine consumption [see comments]. 61(2):160. Boardman HF. Pain 2004. Hagen K. Dyb G. A review of the evidence for overlap among unexplained clinical conditions. 62(9):1540–1544. Analgesic use: a predictor of chronic pain and medication overuse headache: The Head-HUNT Study. Neurology 2003. Psychological. 41. neck. 63(11):2022–2027. 37.44 Scher 36. Neurology 2004. Svebak S. 45:657–669. 40. Analgesic overuse among subjects with headache. refers to the presence of any additional coexisting ailment in a patient with a particular index disease (3). 1 and 2. 45 . and the lack of an appropriate comparison (or control) group with which to account for factors that confound the association between the two conditions. assessment bias. In addition.4 Comorbidity of Migrainea Nancy C. and mortality (5–7). Intramural Research Program. therapeutic selection. in which the co-occurrence of two conditions is an artifact of overlap in the diagnostic criteria or in the assessments employed to ascertain the criteria. Most of the early descriptions of such associations were based on clinical case series. Bethesda.A.’’ introduced by Feinstein.S. prognostic anticipations. Mood and Anxiety Disorders Program. National Institute of Mental Health. and post-therapeutic outcome of an index diagnosis (4). P.e. Low and Kathleen Ries Merikangas Section on Developmental Genetic Epidemiology. response to somatic treatment. Several factors that complicate the investigation of comorbidity of migraine and other conditions include discrimination from ‘‘migraine a Adapted in part from Refs. Maryland. Department of Health and Human Services. Comorbidity can alter the clinical course of patients with the same diagnosis by affecting the time of detection. METHODOLOGY OF COMORBIDITY STUDIES Associations between migraine and a variety of somatic and psychiatric conditions have been reported in the literature since it was first described as a discrete syndrome.. so empirical evidence was lacking. Nonrandom co-occurrence of two conditions may be attributable to several methodologic artifacts including: samples selected from clinical settings that are nonrepresentative of persons with the index disease in the general population (i. Failure to classify and analyze comorbid diseases can create misleading medical statistics and may cause spurious comparisons during the evaluation and treatment planning for patients. National Institutes of Health. U. ‘‘Berkson’s Paradox’’) (8). it can also affect the length of hospital stay. INTRODUCTION The term ‘‘comorbidity. as noted above. In contrast. population-based studies are necessary to identify such biases in treatment samples.e. There is dramatic variability in the methodology of studies of comorbidity and migraine. including abdominal pain. standardized definitions of both disorders were rarely included in clinical or community studies. Cardiovascular Diseases Hypertension In the classic epidemiologic study by Waters (9). Case–control studies and cross-sectional epidemiologic studies mainly generate hypotheses about possible associations. clinical series and case–control studies have employed the most thorough clinical evaluations of subjects. Indeed. and psychiatric systems and allergies or asthma. the inter-relationships between the comorbid disorders themselves are often unaccounted for in multivariate analyses. gastrointestinal. which could explain the association between several diseases and migraine. Similar results .. Community studies generally have sufficient statistical power to detect associations between migraine and rare diseases. The most widely implicated are disorders of the cardiovascular. Finally. case–control studies. the samples of both the clinical series and case–control studies may be biased with respect to the increased probability that persons with two or more conditions are represented in clinical samples (i. the negative associations in the smaller sample sizes of the clinical and case–control studies are often the result of b-type errors rather than a true lack of association between migraine and other diseases. and epidemiologic surveys. EVIDENCE FOR MIGRAINE COMORBIDITY Comorbidities of migraine and several other disorders have been reported in clinical series. followed by case–control studies. community studies tend to apply less rigorous definitions of the disorders because collection of extensive diagnostic information on both conditions was precluded by the sheer magnitude of the studies. The majority of migraine comorbidity studies was conducted prior to the introduction of the International Headache Society criteria and employed idiosyncratic definitions of migraine ranging from recurrent headaches to classical migraine with neurologic prodromes. Berkson’s paradox) (8). and the involvement of several systems including the cardiovascular. neurologic. In general. In addition. and longitudinal population-based studies are necessary to test the hypotheses and reliably identify patterns of comorbidity. gastrointestinal. thereby yielding spurious associations. Moreover. In general. This chapter will focus on associations between migraine and selected medical and psychiatric conditions for which evidence has been presented in the literature. Studies of comorbidity require valid definitions and reliable ascertainment of each of the disorders under consideration. which limits the conclusiveness of the findings. community studies will be presented first. as well as both the peripheral and central nervous systems. lack of specificity of symptom expression or constellations within individuals over time. or visual symptoms. dizziness or vertigo. for each condition of interest. Another methodologic limitation of the majority of studies of migraine comorbidity is the failure to incorporate confounding risk factors. and sensory organs. no differences emerged between the levels of systolic and diastolic blood pressure among migraineurs.46 Low and Merikangas ‘‘migraine equivalents’’ defined as alternate manifestations of migraine that occur in an ‘‘attack-like’’ fashion. Thus. there is little evidence for an association between heart disease and migraine.20.Comorbidity of Migraine 47 were obtained from other large studies of community surveys (10–14). a modest association between elevated blood pressure and migraine was observed (15). symptomatic migraine of established disease. coronary artery disease. patent foramen ovale and atrial septal aneurysm). angina. a definite association between migraine and hypertension is yet to be established. In the examination of migraine and mitral valve prolapse. Neurologic Diseases Regarding migraine and neurologic diseases.22–27) have been essentially negative.e. There are few large-scale.. The first systematic study was conducted by Gardner et al.18). i. there are many case–control studies. In summary. in a recent epidemiologic survey of 5755 adult participants. However. and angina) after controlling for well-known cardiovascular risk factors (17. Several family studies reporting on the relative risk/odds ratio among relatives of migraineurs compared to controls (19. Research has also shown that relatives of migraine patients are more likely to be hypertensive (19. congenital heart defects (e. prospective epidemiologic studies specifically examining the association between migraine and the above-named heart diseases. Heart Disease Heart diseases including mitral valve prolapse. for example.. in addition to insufficient power to test this association adequately.20). multiple sclerosis (MS).28. however. and arrhythmias have also been purportedly associated with migraine. to migraine after stroke. in view of the largely negative studies done among large-scale community surveys. Whether high blood pressure precedes the onset of migraine or rather is caused by the presence of migraine with recurrent headaches is unknown. This pertains. are likely reasons for the discrepant findings among case–control studies (17.21). which did find that those over 45 years old having migraine with aura were more likely to be at risk for coronary heart disease (15). except one cross-sectional community study. and tumors.5. coronary heart disease. inconsistent measures and definitions of mitral valve prolapse and migraine. Moreover. reported a twofold increase in the rates of hypertension among cases when compared to controls (17. and despite the positive though inconsistent results of case– control studies.g. nearly all case–control studies examining the association between migraine and hypertension have reported a positive association.29) with heart disease show an average relative risk/odds ratio of approximately 1. all findings should be qualified by the fact that pain may result in higher blood pressure. Findings from case–control studies considering the relationship between migraine or recurrent headache and heart disease (heart attacks. who found that the mean systolic blood pressure was greater in migraineurs over age 40 than among age-matched controls. Both Featherstone and Markush et al. Neurologic disorders may cause both symptomatic migraine . In contrast to the epidemiologic studies above. (16) in 1940. Thus. it is important to note that migraine may be secondary to these disorders. after considering the effects of the other cardiovascular risk factors including smoking and hypertension. ischemic heart disease. overall. 380 adults. (45) confirmed that migraine in women using oral contraceptives is a risk factor for stroke.29) cited previously.48 Low and Merikangas and epilepsy.S.1–3. and found that those with migraine have an increased risk ratio of 1. One case–control study failed to report an association between stroke and migraine (17). prospective longitudinal study of the efficacy of aspirin in male physicians. Among the U. at age 60 the risk ratio is 1. Leviton et al.2. but no . also examined the rates of stroke. the most striking finding is that the elevation of risk for ischemic stroke is among female migraineurs aged 15 to 45.6).5. The family studies (19. decreased with increasing age—for example. In contrast.0 to 6.53–57). compared to a risk ratio of 2. the risk of stroke. (33) reported an association between migraine and stroke in data from the Physician’s Health Survey—a large-scale. there have been many systematic (47–52) and controlled (47. (20) selected parental mating types in which only one parent had recurrent severe migraine headache and found no increase in the history of stroke in the parent with headache compared to the unaffected parent. which compared parents of migraine patients and controls. the family history study of Galiano et al. the main interest is on primary migraines.0 (95% CI 1. studies. (29) observed an odds ratio of 1. given a history of migraine. In summary. In general. In addition. When assessed after five years. In examining comorbidity. The majority of case–control studies that have included both sexes and a wider age range suggest an association between migraine and stroke. though their findings vary according to the sex and age group in which the risk of stroke is elevated. epidemiologic and case–control. and thus. (28) reported a nearly two-fold increased risk of stroke among the relatives of subjects with migraine compared to controls. Buring et al.7. The results are variable. provide convincing evidence for an association between migraine and stroke. give a false association. Epilepsy Since Paskind’s (46) first study of the relationship between seizures and migraine in 1934.1–3. Kurth et al.49.000 professional women aged over 45 followed prospectively over nine years and observed a hazard ratio of 1. with the magnitude of association ranging between an odds ratio of 3.9) for stroke among relatives of child and adolescent migraineurs compared to age-matched psychiatric/neurological controls. (34) examined the association in a large-scale epidemiologic study of 13.2) for all stroke. and 1. Merikangas et al. Lanzi et al.1–2.8 at 40 years. Curtis et al.2 (95% CI 0.7 (95% CI 1. in their review of the literature between 1995 and 2001. Several population-based studies have found an association between migraine and stroke (32–38). Stroke The association between migraine and stroke has received renewed attention because of a recent paper reporting that persons with migraine have an increased prevalence of cerebellar infarcts (of the posterior circulation) compared to controls (30). yielding a risk ratio of 2. (35) used the Women’s Health Study collection of 40. In addition. there has been growing interest in subclinical white matter hyperintensities observed in migraineurs (31).6) for ischemic stroke. In addition. nearly all the studies.20.8 (95% CI 1. men with migraine exhibited an elevated risk of stroke when compared to those without a history of migraine.7–1. and classic migraine carrying a larger risk than common migraine (39–44). and rhinitis) was increased among children with migraine compared to those without it. Earlier studies of adults and children by Chen et al.75–78). In a study of 64. findings have been inconsistent. In a 1999 U. In a prospective longitudinal study. In a community-based survey of adults in California. Mortimer et al. (71) examined the incidence of wheezing illness in 18. (11. Davey et al. Of the dozen or so controlled studies of adults in clinical samples. eczema. Von Behren et al. and found weak. and 33. (79) further observed that in a ‘‘general practice’’ cross-sectional group of 1077 children aged 3 to 11 years.678 matched pairs from the General Practice Research Database of the United Kingdom.Comorbidity of Migraine 49 large-scale community-based population studies of this association. the prevalence of atopic disease (asthma.9 for asthma and 4. One recent case–control study of risk factors for MS found that migraine was both associated with MS and was an independent risk factor for the development of MS (70).53). and bronchitis has been nearly as widely investigated as cardiovascular disorders.6. eczema. In a family study of epilepsy of 1948 adult probands with epilepsy and 1411 of their parents and siblings.4. The relative risks for chronic obstructive pulmonary disease. 16. Ottman and Lipton (59–61) reported a twofold increase in migraine among both epileptic probands and their relatives. Likewise.1 for allergies.559 subjects at ages 7.74) reported relative risks of 1. Additional studies are necessary to confirm an association between migraine and epilepsy. independent associations with the occurrence of wheezing illness with migraine during childhood and adulthood.S. there is scant evidence for an association in controlled studies. In contrast. Diamond (73) observed increased rates of allergies and sinusitis among migraineurs. Strachan et al. another family study found no significant difference in the prevalence of migraine among relatives of patients with epilepsy and controls (62). 23. 11. hay fever. population–based survey (American Migraine Study II). respiratory symptoms. Bille (58) reported that children with migraine had twice the risk of allergies as those without migraine. only two reported a significant association between these two conditions (49. and hay fever were also increased among the . asthma. The variability in the definitions and subtypes of epilepsy investigated across studies precludes accurate risk estimation based on aggregate findings. the two controlled studies of sufficiently large samples of children found no systematic association between convulsions and migraine (58). (80) found that the relative risk of asthma in patients with migraine was 1. In his classic study. (72) reported that migraine was associated with asthma among women. Immunologic Diseases Allergies/Asthma The association between migraine and allergic conditions including food allergies. In another group of studies (63–67) on specific types of childhood epilepsy and migraine. Controlled clinical samples among children and adults have consistently yielded significantly greater rates of allergies or asthma among migraine subjects compared to controls (10.69) of an increased risk of migraine among patients with MS. Multiple Sclerosis Although there have been numerous reports (68. The average magnitude of the association between allergic conditions and migraine across these earlier studies was approximately 2. and somatoform disorders to problems with personality. Greater rates of hiatal hernia.86). but the findings have been inconsistent (17.5. There is a long history of attempts in epidemiologic studies to address this association (82–84).9 to 2. Especially in children. In summary. and community studies (112. it is difficult to discriminate whether these conditions are truly independent or whether they represent manifestations of the gastrointestinal component of migraine. Other studies have examined the association between migraine and other gastrointestinal disorders with variable findings. especially gastric ulcers. Irrespective of the specific type of allergic condition assessed in the studies.’s (78) case–control study of 1104 children registered with a general practice clinic did not. and Helicobacter pylori infection have been reported among migraineurs than among controls. but Mortimer et al. large-scale. It is important to note that some of the associations reported between migraine and some gastrointestinal disorders. anxiety. colitis. and substance use (87–105). The odds ratio for migraine and depression varies between 2. (11) reported that ulcers were only associated with migraine among smokers. Anttila et al. population-based study (85) of 1290 school-aged children found that children with migraine reported more abdominal pain than those without migraine. the distinction between recurrent abdominal pain and undiagnosed abdominal migraine often presents problems in examining the relationship between migraine and abdominal pain (81). no definitive associations have been established between migraine and specific gastrointestinal disorders. may be due to confounding analgesic (nonsteroidal anti-inflammatory drugs) use.’s prospective. a strong and consistent association between the allergic conditions and migraine has been found in both community and clinical studies of children and adults. This review will mainly focus on the relation between migraine and mood and anxiety disorders. impulse control. community studies using standardized psychiatric assessments. Depression The vast majority of the literature on the relationship between migraine and mood disorders has centered on migraine and major depression where the association has been well-established in community-based surveys. Gastrointestinal Disorders Although various gastrointestinal conditions have also been linked with migraine. Psychiatric Disorders There have been numerous writings on the comorbidity of migraine and psychiatric syndromes. in whom there was no increased risk of migraine when compared to rates from the general community. eating. ranging from mood. The association with gastric ulcers was observed in case–control samples (17) from clinical settings and yielded relative risks ranging from 1.50 Low and Merikangas migraine patients.113) (N ¼ 772. 1139) reporting . Additional populationbased studies using questionnaires to assess depression (106–111) confirm associations in a similar range. Table 1 presents the association between migraine and mood and anxiety disorders in numerous prospective. The only negative study (54) was an uncontrolled series of asthma patients. whereas Chen et al.2 and 4.0. 9 2.2 1.1 1. 2000 (128)b Non-IHS-based Merikangas et al.8–3.0 1..8 2. 2000 (129)a Breslau et al.0 3.3 1. 1990 (136) Social Phobia Odds ratio 51 95% Confidence interval 4.5 2.4 5.Comorbidity of Migraine Table 1 Psychiatric Disorders Associated with Migraine in Prospective...4 3. 2000 (129)a Breslau et al.5 2. 1998 (137)b Bipolar I Migraine with aura Migraine without aura Bipolar II Migraine with aura Migraine without aura Non-IHS-based Merikangas et al.1–1. 2004a (145) Panic Disorder IHS-based Breslau. 2001 (146)d Non-IHS-based Merikangas et al.1–4. Community Studies Psychiatric disorder by migraine diagnoses Depression HIS-based (144) Breslau.2 2.5–11.2 2.7 2.1–6.2 0.8–13.5–24.0 1.4 2.1 5.0 2.3 3.1 1.9 0..9 1.8 1.9 10.7 3.2–4.8 1.2 2. 1990 (136) Phobia IHS-based Swartz et al.0 1. Large-Scale.0–3. 2004a (145) Bipolar Disorder IHS-based Breslau.3 2.5 2.2–24.4 1.0–9.0–4.2–7..3–13.3 4..5 (Continued) ..2 2. 1998 (137)b Migraine with aura Migraine without aura Non-IHS-based Merikangas et al.1–8. 1998 (137)b Migraine with aura Migraine without aura Non-IHS-based McWilliams et al.4 1.4–19.. 1998 (137)b Migraine with aura Migraine without aura Swartz et al.4 3. 1990 (136) Bipolar spectrum Generalized Anxiety Disorder IHS-based Breslau..4–3..6–4. 1998 (137)b Migraine with aura Migraine without aura Swartz et al.4–11.6 1. 1990 (136) McWilliams et al.6 4.9 1.6 0.5 3.7–5. 2000 (129)a Breslau.1 7.5 2.9 1.4 2..5–11.2–6.1–1. these clinical and community studies provide substantial evidence for a positive association between migraine and major depression and suggest their association results from common risk factors that may increase the risk of acquiring either condition rather than a causal relation.52 Low and Merikangas Table 1 Psychiatric Disorders Associated with Migraine in Prospective.8–12. 13. .3 3.9 1.128).130–134) with sizes ranging from 21 to 327 have reported migraine rates varying overall from 13% to 49%.7% to 31. irrespective of the index disorder for which the subjects sought treatment. 2000 (129)a Non-IHS-based Merikangas et al. Large-Scale.99. the prevalence of migraine in depressed clinical populations (N ¼ 116–423). However.4%. 2000 (129)a Breslau. Taken together.3 5. Swartz et al.and major depression-adjusted relative risk b only rates show migraine in 19% to 26% of depressed women and 6% to 10% of depressed men.and sex-adjusted relative risk sex-adjusted relative risk c age-adjusted relative risk d sex. the migraine rates range from 27% to 44%.8–14.95. among men. Studies looking at the reverse relation. 1990 (136) Obsessive-Compulsive Disorder IHS-based Swartz et al.101.7 age.8 1. 1998 (137)b Migraine with aura Migraine without aura a Odds ratio 1.123–126). reported a bidirectional relationship between the onset of migraine and depression in two prospective studies (127.. and among bipolar type II subjects.. Community Studies (Continued ) Psychiatric disorder by migraine diagnoses IHS-based Swartz et al.4 95% Confidence interval 0.8% to 57. Breslau et al.9 1. Studies examining the prevalence of depression in migraine patients (N ¼ 34–500) report rates ranging from 3.8 0.90..6 1. 65% to 78%.1–10. among women. but much higher than that in males (6%) (Ferrari 1998). Clinical samples employing standardized diagnostic criteria also reveal consistent associations between the two disorders. have found that migraine rates vary between 19% and 84% (73.9–1. the evidence to support an association between bipolar disorder and migraine has not been as rigorously pursued. The migraine rates in male bipolar subjects are consistently elevated over those in the general population.98.114–121) compared to general population lifetime rates of 16% (122).6–2. The lower value of this range is comparable to general rates of migraine in females (16%).0 4.96.0% (19. Clinical bipolar samples (124. Bipolar Disorder To date. (129) did not confirm the bidirectional association finding in a prospective population-based sample of the Baltimore area. 6% for the entire bipolar spectrum disorders. epilepsy. compared to the general population where the rate is 1%. Two community studies (136.6) and 5. it is critical to treat the entire syndrome rather than limiting the treatment goal to headache cessation. 2. Switzerland. and anxiety disorders.1% for bipolar type I. and that the onset of depression followed that of migraine in three three-fourths of the comorbidities. In fact. Anxiety Anxiety disorders are also associated with migraine in both clinical and community studies (93.123.8% bipolar NOS.111.2–24.138–143). panic.136. Both studies report a distinct elevation of bipolar illness among migraineurs.6). The only other community study examining bipolar disorder and migraine was in a Detroit sample of young adults. stroke. Investigation of comorbidity of migraine and depression or anxiety states in family study data revealed that migraine. but this elevation is not as prominent.9) for Bipolar II (137). depression.8% and the odds ratio was 2. This total was similar to the rate found in Merikangas and Angst’s community study (136) of young adults in Zurich. especially given some samples reporting migraine rates up to 20%. anxiety.104. perturbation of a particular system or systems may produce symptoms of all three conditions. These findings underscore the importance of systematic assessment of depression and anxiety in persons with migraine. in the community and the clinic.3 (2. One study (135) has investigated the rate of bipolar spectrum disorders among 1000 clinical migraineurs and found rates of 2.121. Because disturbances in the same neurochemical systems have been implicated in migraine. making a total of 8. allergies. where the OR for Bipolar I was 7.3% for cyclothymia. mania or the bipolar subtype of mood disorders is more strongly associated with migraine than any other psychiatric disorder. and asthma (Table 2). thereby producing one syndrome rather than three discrete entities. where the rate of bipolar spectrum disorder (as defined by a manic or hypomanic episode) in 61 migraineurs was 8.108. Methods for diagnosing migraine among the clinical samples vary from administration of a structured diagnostic interview of all migraine criteria to a single yes or no question of a history of migraine. Table 1 reports the association between generalized anxiety.4–19. Single-agent.2 (1. and depression may result from a partially shared diathesis (93.4% for bipolar type II.139) have shown that the onset of anxiety disorders tends to precede that of migraine in about 80% of the cases of migraine with comorbid anxiety or depression.1–8. and migraine. If there is a subtype of migraine associated with anxiety and mood disorders. CONCLUSION Migraine is most consistently associated with mood and anxiety disorders. therapeutic choices that may treat migraine and a specific . and 2. 1. The prevalence of migraine is also clearly elevated in individuals with bipolar disorder. This temporal sequence was also confirmed in an eight-year follow-up of childhood migraine (115). The most important implications of this comorbidity include its consideration in the treatment and etiology of both disorders.8 (1. phobic and obsessive-compulsive disorders.Comorbidity of Migraine 53 Female subjects with bipolar disorder also demonstrate higher rates of migraine.141). limited. Merikangas K. and source of the sample. sampling differences with respect to gender. comorbid disorder can include: a beta. Rasmussen B. In press. Low NC. It is particularly critical to formulate the hypotheses regarding the associations in advance in order to avoid the possibility of false-positive errors due to multiple testing. Tfelt-Hansen P. Such extrinsic mechanisms can provide targets of prevention for the development of both conditions or for the secondary disorder as a consequence of the index disease. moderate. Therefore. Aggregation of the findings of previous studies has been precluded by differences in methodology.or calcium-channel blocker for hypertension or heart disease. The salient methodologic factors included: a lack of standardized diagnostic definitions of both the index and comorbid disorder. þþþ. Merikangas KR. the identification of purported ‘‘confounding’’ risk factors may be the most important finding with respect to the nature of non-random associations between comorbid disorders. strong. colitis Mood disorders Bipolar disorder Major depression Anxiety disorders Strength of evidence 0 0 þþþ þþ þ þþ þþ 0 þþþ þþþ þþþ þþþ Immunologic Gastrointestinal Psychiatric Note: þ. REFERENCES 1. Welch K. 437–444. Moreover. 8(6):433– 434. CNS Spectr 2003. future studies need to focus on the application of standardized diagnostic definitions with reliable methods of assessment of both the index and comorbid conditions. þþ. particularly in large samples.54 Low and Merikangas Table 2 Summary of Medical Disorders Most Strongly Associated with Migraine System Cardiovascular Neurologic Disorders Myocardial infarction Hypertension Stroke Epilepsy Multiple sclerosis Allergies Asthma Ulcers. a risk factor for both conditions. 2. In: Olesen J. hernia. Indeed. Low N. and wide variability in the inclusion of confounders in the analyses of the associations. The comorbidity of migraine. For example. and tricyclic antidepressants for depression. valproic acid or topiramate for epilepsy or bipolar disorder. was included in the analyses. eds. specific risk factors for each of the conditions need to be identified carefully and their effect on the association investigated systematically. age. The Headaches. the association was not significant when smoking. Migraine comorbidity. . although a weak association between heart disease and migraine was reported. lack of statistical power to detect associations with rare conditions. . The relationship of migraine to hypertension and to hypertensive headaches. Leviton A. epistaxis. 13. Relation of high blood pressure to headache. mortality. 21. Featherstone HJ. Further evidence on the association of mitral valve prolapse and migraine. Schele R. Am J Prev Med 1991. Migraine and coronary heart disease in women and men. The implications of DSM-III personality disorders for patients with major depression. 145(2):233–237. J Affect Disord 1984. 7. 11. N Engl J Med 1972. 6. 12. Chen TC. 15. Cardiovascular risk factors and migraine: the GEM population-based study. 318:262–264. Am J Psychiatr 1988. Rasmussen BK. Baseline characteristics of participants in the Women’s Health Study. Ahlborg B. 175(11):674–680. Findings from the aspirin component of the ongoing Physicians’ Health Study. and migraine in the parents of migraine patients. Stangl D. Biometrics 1946. 72(4):463–466. Winokur G. Blood pressure and risk of headache: a prospective study of 22 685 adults in Norway. 25(5):430–435. Group. Gamberini G. The influence of smoking on observed associations. 20.HSR. Rose KM. Couch JR. 19. Migraine and other headaches: associations with Rose angina and coronary heart disease. Physical characteristics and allergic history in young men with migraine and other headaches. 64(4):614–620. 42(8):715–727. 42(6):1225–1231. Br Med J 1971. Rexode KM. Berkson J. Pfohl B.t. et al. Neurology 2005. et al. Symptomatic and nonsymptomatic headaches in a general population. Waters WE. Black DW. and selected other symptoms. et al. 7:150–154. 29(1):49–54. The importance of classifying initial co-morbidity in evaluation the outcome of diabetes mellitus. N Engl J Med 1988. 22. Graham JR. 16. J Myocardial Ischemia 1992.W. Hennekens C. Black DW. Feinstein AR. Zimmerman M. 14. Markush RE. Olesen J. Gardner J. et al. 10. 22:50–53. Limitation of the application of the 4-fold table analysis to hospital data. The United States Health Examination Survey of Adults. Mountain G. Headache 1985. et al. Epidemiologic study of migraine symptoms in young women. Weiss NS. 9. 24. Buring JE. 5. Hinew E. Hassanein RS. background and summary of the study design. 18(2):80–86. Winokur G. Is death from natural causes still excessive in psychiatric patients? A follow-up of 1593 patients with major affective disorder. 8. 44(10):1024–1028. J Nerv Ment Dis 1987. 287(13):631–633. 27(7–8):387–404. 9:19–27. 1(741):142–143. 25(3):136–140. Baseline characteristics of participants in the Physicians’ Health Study: a randomized trial of aspirin and beta-carotene in US physicians. f. et al. Neurology 1992. Malvea B. Headache and blood pressure in the community. et al. 17. Medical diagnoses and problems in individuals with recurrent idiopathic headaches. Ekbom K. Neurology 1975. Kaplan MH. 27. J Chronic Dis 1970. Manson J. Headache 2002. Headache 1989. 24(1):39–40. 18. J Neurol Neurosurg Psychiatr 2002. J Womens Health Gend Based Med 2000. J Chronic Dis 1974. 23:455–468. 4. The Women’s Health Study: Rationale. Am J Med Sci 1940. Cook NR. 23. Headache 1978.s. Migraine and other diseases in women of reproductive age. 30–40. et al. 7(3–4):309–318. 4:27–29.Comorbidity of Migraine 55 3. Hagen K. Headache 1984. Headache as a risk factor in atherosclerosis-related diseases. Depressions secondary to other psychiatric disorders and medical illnesses. The pre-therapeutic classification of co-morbidity in chronic disease. Nasrallah A. 25. Neurology 2004. 63(12):2233–2239. Nasrallah A. 26. Arch Neurol 1987. Scher AI. et al. 24(7):669–672. Vascular diseases. Neurology 1974. 2:47–53. Feinstein A. Are vascular disorders more prevalent in the relatives of children and adolescents with migraine? Cephalalgia 2003. JAMA 291(4) 2004 427–434. Cephalalgia 1993. Kase C. Incidence of migraine headache: a population-based study in Olmsted County. Migraine and Epilepsy. Kruit MC. et al. 29. Tzourio C. epilepsy and some other neuropsychiatric disorders. Arch Neurol Psychiatr 1930. Mitchell P. Basser LS. 36. recency. 347(9014):1503–1506. 35. . 23(9):887–891. BMJ 1999. A controlled study of ischemic stroke risk in migraine patients. The Italian National Research Council Study Group on Stroke in the Young. 32:45–50. Headache. Migraine and risk of ischaemic stroke: a case-control study. Minnesota. Poulter N. 1987:281–291. Arch Neurol 2004. 46. Paskind H. Andermann F. Marks DA. Contraception for women in selected circumstances. 28(5):627–632. Arch Neurol Psychiatr 1934. et al. Barolin GS. 52(2):129–134. Migraine and subsequent risk of stroke in the Physicians’ Health Study. J Clin Epidemiol 1989. 61(9):1366–1368. et al. Migraine-related seizures in adults with epilepsy. History of migraine and risk of cerebral ischaemia in young adults. and the risk of stroke in women. et al. 51. 73(6):747–750. Ehrenberg BL. Arch Neurol 1997. Migraine as a risk factor for subclinical brain lesions. 57(10): 1805–1811. BMJ 1993. Leniger T. 40. Tzourio C. Neurology 1992. et al. Prevalence and vascular associations with migraine in older Australians. 24:943–949. and type of migraine and the risk of ischaemic stroke in women of childbearing age. Slomke M. Epilepsia 2001. A case-control study of the associated factors with migraine. Migraine-epilepsy syndrome: statistical study of heredity. 42(8):773–780. Galiano L. Donaghy M. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis. De Matteis G. 7(7):53–66. Neurology 2001. Brain 1969. et al. 43. Association between migraine and stroke in a large-scale epidemiological study of the United States. with EEG correlation. 45. Henrich JB. Buring JE. 13(suppl 13):9. Neurology 2004. Chrisman CE. 42. Poulter N. 52. Lanzi G. 38. Peterson HB. Merikangas KR. 30. 34. Kurth T. Curtis KM. 231(7):718–722. In: Lugaresi E. Obstet Gynecol 2002. 42(9):1657–1662. 307(6899):289–292. et al. Donaghy M. Cephalalgia 1999. Andermann E. Horwitz RI. Seizure-associated headache in epilepsy. et al. 33. Carolei A. 99(6):1100–1112. 54(4):362–368. J Am Med Assoc 1975.56 Low and Merikangas 28. 42(9):1176– 1179. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Migraine-elipepsy relationships: epidemiological and genetic aspects. migraine. Lancet 1996. 41. et al. 37. Kern RZ. Milhaud D. Migraine and stroke in young women: case-control study. et al. 39. ed. 43(12):2476–2483. 31. Aust NZ J Med 1998. 318(7175):13–18. Ozmenoglu M. Relationship of migraine. Collaborative. 310(6983):830–833. Migraine-related seizures in an epileptic population. et al. Ischemic stroke and active migraine. Chang CL. et al. Case-control study of migraine and risk of ischaemic stroke in young women. Boston: Butterworths. Neurology 1993. 19(9):797–801. J Neurol Neurosurg Psychiatr 2002. 44. 62(suppl 5):A187. Duration. BMJ 1995. Chang CL. 48. Stang PE. frequency. Oral contraceptives and stroke in young women: associated risk factors. The relation of migraine and epilepsy. 32. Swartz RH. 47. 49. 92(2):285–300. 53. Ely F. Marini C. 50. Arch Neurol 1995. Velioglu SK. discussion 766. Migraines and epilepsies—a relationship? Epilepsia 1966. 15:356–361. Cephalalgia 1993. 55. Brown and Co. Neurology 1994. Arch Neurol 1966. Abu-Arafeh IA. Study of dietary exclusion and RAST. Dalsgaard-Nielson A. et al. 35(3):243–248. Leviton A. Montreal: McGill. 1987. Diamond ML. Atkinson P. Neurology 2002. Bladin P. Lipton RB.1. The prevalence of headache and migraine in atopic children: an epidemiological study in general practice. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. Headache 1997. Food allergy in migraine. et al. Neurology 1982. Br J Gen Pract 2002. 73. Speight JW. Current controversies—abdominal migraine. et al. Migraine and petit mal absence: familial prevalence of migraine and seizures. 79. D’Amico D. 64. 58(9 suppl 6):S3–S9. 56. Migraine in school children. Bille B. et al. The role of concomitant headache types and non-headache comorbidities in the underdiagnosis of migraine. et al. 74. Cephalalgia 2004. Migraine and Epilepsy. et al. Zorzon M. 2(8184):1–4. Doose H. 61. Dev Med Child Neurol 1993. Matias-Guiu J. Migraine and benign epilepsy with Rolandic spikes in childhood: a case-control study. 33(8):427–431. Von Behren J. Santucci M. et al. 312(7040):1195–1199. 15(4):271–273. Lancet 1980. Headache 1993. 52(482):723–727. 39(5):429–440. 24(11):980–984. 63. et al. J Asthma 2002. Anthony M. Neurology 1994. Lennox W. 70. . 81. Kraus D. Migraine in patients with history of centro-temporal epilepsy in childhood: a Hm-PAO SPECT study. Arch Neurol 1990. 80. BMJ 1996. Clinical epidemiology of childhood abdominal migraine in an urban general practice. Russell G. Risk factors of multiple sclerosis: a case-control study. Anderson HR. Kreutzer R. Baier W. 60. Ottman R. Monro J et al. 51(suppl 136):3–151. Dev Med Child Neurol 1985. Epilepsy and Related Disorders. 24(4):242–247. 67. 1960:Vol. Diamond S. 78. ed. Acta Paediatr Scand 1962. 11(4–6):313–314. Ugesdkr Laeger 1964. In: Lugaresi E. Lipton RB. D’Amico D. 37(1):21–25. 58. 68. 57. ed.Comorbidity of Migraine 57 54. Lance J. Food allergy in migraine. 72. Septien L.. 47(11):1227–1230. Headache 1976. Comorbidity of migraine: the connection between migraine and epilepsy. 11(6):281–284. Asthma and eczema in children born to women with migraine. Kinast M. Boston: Butterworths. 1978 (Faculty of Graduate Studies and Research). Neurol Sci 2003. 65. Prevalence of primary headaches in people with multiple sclerosis. Mortimer MJ. 59. 27(1):60–62. Self-reported asthma prevalence in adults in California. Strachan DP. Comorbidity of migraine and epilepsy. 126:185–191. 62. In: Lugaresi E. 44(10 suppl 7):S28–S32. Chen TC. 32(11):1309–1311. Mortimer MJ. 75. 44(11):2105–2110. Hernandez A. Neuroepidemiology 1992. 69. 71. Butland BK. Benign focal epileptiform discharges in childhood migraine (BFEDC). The association of benign rolandic epilepsy with migraine. 47(4):918–924. Migraine and Epilepsy. Kay J. 76. Migraene og epilepsi. et al. Boston: Little. Lennox M. 2(8193):532. Some clinical aspects of migraine. Lipton RB. Lancet 1980. A case-control study to evaluate the association of epilepsy and migraine. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology 1996. 1987: 293–311. Jaron A. Cephalalgia 1991. 77. Davey G. Ottman R. 13(2):138–139. et al. 66. Boston: Butterworths. Mediana JL. Coexistence of migraine and cluster headache: report of 10 cases and possible pathogenetic implications. Migraine and atopy. Migraine and Epilepsy: A Case for Divorce. Association between migraine and asthma: matched case-control study. Depression and anxiety disorders associated with headache frequency. Terwindt GM. et al. 107. Association between major depressive disorder and physical illness. Headache 1999. Analan E. The impact of migraine on quality of life in the general population: the GEM study. 1966. Comorbidity of other pains in schoolchildren with migraine or nonmigrainous headache. Migraine and the eating disorders. 23(3):755–761. A comparison of MMPI personality data and frontalis electromyographic readings in two groups of daily headache sufferers. Naish N. 92. 42(2):392–395. 138(2):176–180. 89. Monzon MJ. Butler NR. Harden RN. George MS. 1(2):118–124. Neurology 1992. panic disorder and depression: comorbidity or a spectrum? Neuropsychobiology 1995. Headache syndromes and psychiatric disorders: association and familial transmission. J Am Acad Child Adolesc Psychiatr 2004. 86. 23(4):271–275. The prevalence of migraine in patients with bipolar and unipolar affective disorders. 31(3):125–129. Arq Neuropsiquiatr 2004. London: Oxford University Press. Apley J. Int J Clin Pract 2005. 181(11):704–706. Pringle MLK. Radat F. et al. The HUNT Study. Court SDM.58 Low and Merikangas 82. . et al. 88. Juang KD. et al. 46(2):201–202. Verri AP. Eur J Neurol 2003. 106. Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache. 102. Harden RN. Davie R. Sutkus BJ. 62(3-B):774–777. 84. 101. Examination of anxiety. George MS. Anttilla P. and suicide attempts. 21(9):894–899. Angst J. Marazziti D. suicidal ideation. 1974. Merikangas KR. MMPI pattern specificity in primary headache disorders. Miller FJW. Headache 2000. et al. Association between Helicobacter pylori cytotoxic type I CagApositive strains and migraine with aura. Curr Neurol Neurosci Rep 2001. Weeks R. Oedegaard K. Psychiatric symptoms in children with primary headache. 95. 39(7):477–480. 14(4):247–251. 40(10):818–823. et al. Recurrent abdominal pains: a field survey of 1000 school children. 27(2):197–210. 33:165–170. Cephalalgia 2001. 59(5):515–521. Psychol Med 1993. Headache 1983. Zwart JA. 19(1):18–24. Co-morbidity of migraine and major depression in the Turkish population. 55(5):624–629. 85. Breslau N. Mitsikostas DD. 11. J Pediatr 2001. 91. Hacihasanoglu R. et al. Kudrow L. 43(4):412–419. 105. Merikangas JR. Galego J. et al. hostility and psychiatric disorders in patients with migraine and tension-type headache. Int Clin Psychopharmacol 1999. Headache 1979. 20(6):561–565. 100. Chronic daily headache. J Psychiatr Res 1993. Cephalalgia 1998. 98. 90. 10(2):147–152. Moldin SO. Psychiatric comorbidity is related to headache induced by chronic substance use in migraineurs. Thomas AM. Bulimia nervosa in outpatients with migraine: a pilot study. J Nerv Ment Dis 1993. 23(2):83–85. Psychiatr Res 1993. Cephalalgia. Depression and migraine. Dener S. Brewerton TD. 104. London: Longman. Psychiatric comorbidity in chronic daily headache. et al. Cephalalgia 2003. et al. 97. et al. Knox EG. In press. 108. 87. 93. The Nord-Trondelag Health Study. et al. Cephalalgia 2000. Gasbarrini A. 83. Comorbidity of headache and depressive disorders. Neurology 2000. Migraine with and without aura: association with depression and anxiety disorder in a population-based study. 103. Prevalence of headache syndromes in panic disorder. Migraine. 99. 94. Lainez MJ. et al. Arch Dis Child 1958. 96. Marazziti D. Kececi H. Anttila P. Fasmer OB. 19(4):211–217. Bag B. 18(suppl 21):45–49. The School Years in Newcastle upon Tyne.000 Seven-Year-Olds. et al. Cephalalgia 1999. Tufekci F. Brewerton TD. Pain 1999. 170(1):34–40. Cephalalgia 1998. J Neurol Neurosurg Psychiatr 1960. Sandler M. 118. 123. Some clinical. Hung C. 33(10):659–663. 131. 43(9):940–949. 110. Comorbidity of headaches and depression in the elderly. Migraine. 113. Migraine headache and mood disorders: a descriptive study in an outpatient psychiatric population. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Bigal M. Neurology 2004. Paulin JM. Headache in a psychiatric population. et al. Headache 1985. Hunter M. Guidetti V. Headache and psychiatric disorders. J Affect Disord 1999. 16(1):33–36. 23:23–32.Comorbidity of Migraine 59 109. Patel N. 116. Migraine headaches and depression. J Nerv Ment Dis 1982. Dis Nerv Syst 1972. 132. Personality traits. Anxiety and depression in migraine. 1(4):364–368. 117. J Affect Disord 2004. depression and migraine in women: a longitudinal study. Tollefson GD. Mahmood T. 121. New York: Oxford University Press. Price WH. Prevalence. 120. 87:338–341. et al. 129. JAMA 2003. 18(7):455–462. Selby G. Marchesi C et al. 25(3):147–151. and treatment of migraine in bipolar disorder. J Am Med Assoc 1957. Risk factors associated with migraine or chronic daily headache in out-patients with major depressive disorder. Swartz KL. The biochemical basis of migraine predisposition. 19(4):919–925. Headache and major depression: is the association specific to migraine? Neurology 2000. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. 111:310–315. 52(1–3):239–241. Low NC. Lance J. 54(2):308–313. eds. Breslau N. Prevalence of migraine in bipolar disorder. Silverstone T. Joint 1994 Wolff Award Presentation. Cervantes P. Am J Psychiatr 1984. 133. et al. 114. et al. Schaffer CB. Arch Gen Psychiatr 2000. et al. Manic-depressive illness in children: treatment with lithium carbonate. Wetzel RD. 63:1432–1438. et al. Romans S. Blehar MC. 115. 127. 134. Younes RP. 55(5):629–635. 111. 1990. Mongini F. 112. Kessler RC. Philips C. Clinical observations in manic-depressive disease. Kashiwagi T. 126. et al. J Affect Disord 1989. 130. J Roy Soc Med 1994. J Child Neurol 1986. et al. Migraine and major depression: a longitudinal study. Crisp AH. et al. Women with bipolar disorder: findings from the NIMH Genetics Initiative sample. 34(3):239–243. Flanagan NB. 141(8):986–988. clinical correlates. Prevalence of migraine and muscle tension headache in depressive disorders. Du Fort GG. 81(2):157–160. Garvey MJ. Franchini L. Psychol Med 1989. 53(625):691–697. Acta Psychiatr Scand 2005. 289(23):3095–3105. . 125. 34(7):387–393. 23(3):186–192. The prevalence of headache in a small New Zealand town. 119. Neurology 2000. 57(10):945–950. Headache 1994. et al. Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore Epidemiologic Catchment area follow-up study. and depression: a population-based casecontrol study. 124. 128. The prevalence of psychiatric disorder among female new referrals to a migraine clinic. Migraine: A Spectrum of Ideas. Psychopharmacol Bull 1998. Cephalalgia 2003. Devlen J. et al. McClure JN Jr. Observations on 500 cases of migraine and allied vascular headache. Wang SJ. Postgrad Med J 1977. Morrison DP. Prevalence and impact of migraine and probable migraine in a health plan. et al. 82(3):239–243. In: Sandler M. Breslau N. Kolodner K. Cassidy WL. 122. Lipton RB. Headache 2003. et al. social and psychological characteristics of migraine subjects in the general population. quality of life. 164:1535–1546. Glover V. et al. Collins GM. 8(suppl 7):1–96. 139. Headache the bipolar spectrum in migraine patients. . Merikangas KR. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. 18(suppl 22):56–58. Stewart W. Breslau N. 37(1):11–23. 1996:254–281. 47:849–853. 44(10 suppl 7):S23–S27. Harper M. Neurology 1994. 10:167–170. 137. J Psychiatr Res 1993. Comorbidity of migraine and panic disorder. Pain 2004. Arch Gen Psychiatr 1990. 141. Arch Intern Med 2003. Headache types and panic disorder: directionality and specificity. discussion 58–61. Breslau N. Breslau N. Harnett S. 145. Migraine and psychopathology. 3:129–151. Merikangas KM. Am J Pain Manage 2000. Temporal lobe epilepsy and the phobic anxiety-depersonalization syndrome. Keck PE Jr. and suicide attempts: an epidemiologic study of young adults. 146. Angst J. Andreski P. 56(3):350–354. Davis GC. A comparative study. New York: Cambridge University Press. psychiatric disorders. Cox BJ. McWilliams LA. I. 27(2):211–221. Roth M. 136. Compr Psychiatr 1962. In: Sandler M.60 Low and Merikangas 135. Migraine. Ludmer C. Robbins L. Migraine: Genetics. Cephalalgia 1988. Breslau N. 140. Psychiatr Res 1991. physical health and psychiatric disorder: a prospective epidemiologic study in young adults. Davis GC. 138. 142. 163:2041–2050. Isler H. Migraine. Smoller J. 143. eds. 111(1–2): 77–83. Prevalence and correlates of panic attacks in postmenopausal women: results from an ancillary study to the Women’s Health Initiative. 144. Sources of genetic complexity of migraine. et al. Goodwin RD. Cephalalgia 1998. Psychiatric comorbidity in migraine. Breslau N. Classification and diagnostic criteria for headache disorders. et al. Ferrari MD. cranial neuralgias and facial pain. Neurology 2001. Headache Classification Committee of the International Headache Society. In addition. all of which pass information to the trigeminal (gasserian) ganglion. As there is a dual convergence of inputs of sensory information into the TNC from both trigeminal and cervical afferents. Michigan Head Pain and Neurological Institute. upper cheek and lip as well as a portion of the jaw and the palate. The mandibular division (V3) subserves the lower lip. The sensory trigeminal nerve has three main branches. lesser occipital nerve (cervical ventral ramus 2). and a portion of the scalp. orbit. 2). but the brain parenchyma itself is not one of them. bridge of the nose. The maxillary division (V2) provides sensory input from the lower eyelid. and cerebral veins and arteries. tongue. meningeal blood vessels. ANATOMY OF HEAD PAIN The sensory innervation of the head is supplied by the trigeminal nerve and the upper cervical nerve roots. inferior portion of the nose. lower jaw.S. could cause head pain (Fig. Michigan. and the front of the ear (1). trigeminal activation 61 . The trigeminal ganglion then relays information centrally. Rozen Department of Neurology. The ophthalmic division (V1) provides sensory information from the upper eyelid.5 Pain Sensitivity: Intracranial and Extracranial Structures Todd D. This chapter will look at the potential pain sensitive intracranial and extracranial structures. The trigeminal sensory system also provides innervation to the sinus cavities. The posterior portion of the head gets its sensory innervation from the greater occipital nerve (cervical dorsal rami 2 and 3). 1). lower face and cheek region. which is located in the lower medulla and upper cervical spine region (Fig. The brain has either no or minimal sensory innervation with pain fibers. U. Ann Arbor. to the main sensory nuclei of the trigeminal system termed the trigeminal nucleus caudalis (TNC). the coverings of the brain (meninges). The brain parenchyma itself has no sensory innervation and thus is insensate.A. and the upper cervical nerve roots. and large cerebral arteries and veins all are highly innervated. greater auricular nerve (cervical ventral rami 2 and 3). neck structures and paranasal sinuses can contribute to head pain. Head pain can be generated by a multitude of structures. However. and thus when stimulated. via the sensory root of the trigeminal nerve. meninges. Figure 2 Anatomy of the sensory trigeminal nerve. Source: From Neurology Ambassador Program of the American Headache Society. Source: From Neurology Ambassador Program of the American Headache Society. .62 Rozen Figure 1 Pain sensitive intracranial structures. or head. most commonly involving the anterior head region. Irritation of the vertebral artery would produce pain in the occiput region. neck. Internal carotid artery dissections usually present with pain involving the face. and occiput. Headache. Distension of the vertebral artery at the level of the foramen magnum produced pain from the ipsilateral occiput region to the shoulder. More recently. cerebral artery pain referral patterns have been demonstrated during procedures of arteriovenous malformation embolization.Pain Sensitivity: Intracranial and Extracranial Structures 63 can be felt clinically as both head and neck pain whereas cervical nerve–root activation can be sensed as both neck and frontal head pain (2). The vascular supply to the brain is highly innervated by the trigeminal nerve. the most common symptom of ICA dissection. which usually noted pain referral to the neck and occiput with distension of the vertebral–basilar arterial system. and even in the cheek. occurs in 84% of patients. that pain was felt lateral to the eye. Clinically. with balloon distension of the distal internal carotid artery and proximal middle cerebral artery (MCA). in the orbit or periorbital region. and thus cranial arterial manipulation can induce head pain. Facial pain occurs in about 30% of . Pain felt above the eye was noted when the distal one-third of the MCA was dilated. and occiput and neck pain occurred with vertebral or basilar artery occlusion. forehead. Fisher (8) noted pain referral patterns in patients with headache along with arterial occlusive syndromes. Martins et al. posterior auricular region. The intracranial segment of the internal carotid artery and the proximal 2 cm of the middle and anterior cerebral arteries would produce eye pain and forehead and temple discomfort ipsilateral to the side of the stimulated arterial segment. whereas distension of the middle portion of the MCA produced pain in a retro-orbital distribution. whereas pain in the forehead and retro-orbital region occurred with MCA occlusion. (5) noted. In all patients. Distension of the vertebral artery midway between the foramen magnum and the vertebral basilar junction produced pain behind the ipsilateral ear. Pain from the vertebral–basilar circulation was felt in the orbit and in the medial frontal and medial supraciliary regions. Dissection of cerebral arteries also causes distinct pain referral patterns (9). Manipulation of the pericallosal arteries led to discomfort in the parietal region. and the area lateral and inferior to the orbit. The headaches are usually one sided and focal. Blood Vessels For decades. but also different arteries would produce varying pain referral patterns (4). at the level of the mastoid and in the upper neck. discomfort was felt at the skull vertex. They found that not only would arterial stimulation produce pain in conscious subjects. blood vessels must play some role in migraine pathogenesis. Middle meningeal artery distension produced pain in the ipsilateral retro-orbital and temple region. (7) documented pain referral patterns during endovascular procedures (embolization or balloon inflation). Nichols et al. MCA and penetrating subcortical artery stimulation produced pain in the temple or supraorbital region. After distension of the inferior basilar artery. Nichols et al. This is somewhat incongruous with past studies. Internal carotid artery occlusion led to pain in the ispilateral forehead region. the pain was focal and ispilateral to the manipulated vessel. neck. migraine was referred to as the vascular headache. (6) also noted pain referral patterns with balloon distension of the vertebral and basilar arteries. Indeed. but it is now believed that cerebral vascular changes are secondary to neuronal activation. Distention of the upper vertebral artery caused pain in the posterior lateral portion of the neck and posterior auricular region. The pain sensitivity of cranial blood vessels was established by Wolff and colleagues (3). then venous dilation during a migraine attack should be a painful event. Interestingly. The cervical roots fire centrally to the trigeminocervical complex. Cerebral Veins and Sinuses Wolff described the pain referral pattern of cerebral veins as he described that of cerebral arteries (3). The most common symptoms of vertebral artery dissection are neck pain and headache. which are highly innervated by the trigeminal system. Diffuse meningeal irritation such as occurs with infectious meningitis causes diffuse holocranial head pain. clinically neck pathology can be felt as head pain whereas dural pathology or irritation can be felt as neck and subocciput discomfort (typical migraine pain location is in or around the eye and at the occipitonuchal junction) (12). About 30% of patients with primary meningeal tumors have headache. Clinically. Because both dural and cervical afferents converge into the TNC. whereas up to 75% of individuals with leptomeningeal metastases have headache (11). Meninges The meninges are highly innervated by trigeminal afferents. The spinal C2 root is the primary afferent to this system and is represented peripherally by the greater occipital nerve.and extracranial veins. stimulation of the superior saggital sinus produced pain that was less intense than arterial-based pain. The authors concluded that the cranial venous system does not play an important role in migraine pathogenesis. At present. There is little literature that describes pain referral patterns when localized parts of the meningeal system are stimulated.64 Rozen internal carotid artery dissections. headache location is variable including holocranial pain or focal pain even with a one-sided thrombosis. Patients during a headache underwent either the Queckenstedt’s maneuver or a placebo maneuver (pressure over sternocleidomastoid muscles) for 10 seconds. Cervical Spine The role of the cervical spine in head pain pathology is gaining increasing acceptance. Recently. There was no significant difference between the Queckenstedt’s maneuver group and the placebo maneuver group in regard to headache worsening. Meningeal irritation from neurovascular extravasation is believed to play a large role in migraine pain. (10) wanted to test if cephalic veins played a role in migraine pathogenesis. Headache usually occurs at the base of the head (occipital area). . Certainly. These structures include the median and lateral atlantoaxial joints. Stimulation of neck structures including cervical roots and the cutaneous tissue innervated by the greater occipital nerve can result in frontal headache. Queckenstedt’s maneuver (compression of jugular veins) will induce dilation in both intra. when cerebral vein thrombosis occurs. could produce head pain when stimulated. which comprises the TNC and the upper C2–3 cervical segments. the pain referral patterns have not been as well documented as the arterial system. often in association with neck pain. Daugaard et al. and the pain referral pattern over the frontal–temporal region was more diffuse. Bogduk (13) states that the sources of cervical spinal pain that refer to the head corresponds to those spinal structures that are innervated by the upper three cervical spinal nerves. Neck paraspinal muscles and cervical ligaments and joints are innervated by the upper cervical nerve roots. They hypothesized that if the venous system plays some part in migraine pain genesis. the venous structures. The sinus cavities include the frontal. Philadelphia: Lippincott Williams & Wilkins. The current literature states that headache may occur from contact between the nasal septum and the superior and middle nasal turbinates or the nasal septum and the medial wall of the ethmoid sinus (14). The reason for this is that the pain of both migraine and sinus cavity inflammation is in the same location. in the orbit. and ethmoid sinus V1 (superior portion of sinus cavity) and V2 (inferior portion of sinus cavity). Once the cervical irritation is quelled (occipital nerve blockade and cervical facet rhizolysis). tendons. whereas others will argue that even a C5 herniated disc can produce head pain. Piovesan EJ. Lance JW. Contact point headaches can resemble migraine and present as intractable one-sided head pain. The innervation of the frontal sinus is via V1 (supraorbital and supratrochlear branches). whereas the nasal septum was less pain inducing. In: Olesen J. blood vessels. the upper prevertebral muscles. pain would occur in the region of the lateral and medial canthus. the chronic daily head pain can be alleviated. whereas the sphenoid sinus is innervated by both V1 and V2. and Nitric Oxide. the superior portion of the nasal septum is innervated by V1. 7:3–10. and that is because both the migraine pain system and the sinus cavities are innervated by the trigeminal nerve. Welch KMA. and in the ear. Anatomy of muscles. Tfelt-Hansen P. retro-orbital pain. eds. 2nd ed. Edvinsson L. McAuliffe et al. Ribas LC. Ethmoid pressure led to pain in the outer and inner canthus region. including infection. medial canthus. 3. tumors. and an abnormal contact between the nasal turbinates and the nasal septum. and the trapezius and sternocleidomastoid muscles (13). Some specialists believe that anything causing irritation below C3 will not cause headache. which is refractory to typical migraine treatment. In: Olesen J. Headache Pathogenesis: Monoamines. Stammberger and Wolf (16) noted that when a probe was pressed on the superior portion of the nasal septum. Migraine pain originates from blood vessels. Purines. Tatsui CE. . and associated lacrimation and photophobia. and the suboccipital and upper posterior neck muscles. eds. Philadelphia: Lippincott-Raven. joints. maxillary sinus V2 (greater palatine nerve and branches of the infraorbital nerve). Frontiers in Headache Research. Edvinsson L. 1963. 1997. Kowacs PA. 2. Werneck LC. the C2–3 disc. Lange MC. 4. and meninges. The Headaches. the C2–3 zygapophysial joint. Nasal and Paranasal Structures In many instances. whereas pressure on the superior turbinate induced pain in the frontal area of the head. patients will misinterpret the pain of migraine as sinus-based pain. Referred pain after painful stimulation of the greater occipital nerve in humans: evidence of convergence of cervical afferents on trigeminal nuclei.(15) in the early 1940s noted that pain sensitivity was highest in the nasal turbinates and sinus ostia. Cephalalgia 2001. New York: Oxford University press. Wolff HG. Anything causing inflammation in the paranasal sinus cavities can theoretically produce pain referred to the head. and sphenoid sinuses.Pain Sensitivity: Intracranial and Extracranial Structures 65 the atlanto-occipital joint. whereas the middle and inferior parts of the septum are innervated by V2 (14). 2000:55–76. 21:107–109. polyps. In the nasal cavity. maxillary. Patients with chronic daily headache who are refractory to standard treatment in many instances have an underlying cervicogenic syndrome. Neuropeptides. ethmoid. REFERENCES 1. Headache and Other Head Pain. Dahl E. 33:87–89. Bruyn GW. Headache in spontaneous carotid and vertebral artery dissections. Silberstein SD. Hilal S. Nichols FT. Handbook of Clinical Neurology. Wolf G. Olesen J. Wolff HG. Neurologic Clinic: Secondary Headache Disorders. 33:227–233. Mohr JP. Hilal S. Behin D. 11. No relation between cephalic venous dilatation and pain in migraine. Hammack J. Adams RJ. Mawad M. Daugaard D. Focal headache during balloon inflation in the vertebral and basilar arteries. Mueller GC. 6. eds. 1997:327–354. Bartsch T. 7:371–376. Mawad M. Curr Headache Rep 2003. In: Vinken PJ. 12. Experimental studies on headache: pain from the nasal and paranasal structures. In: Goadsby PJ. Headaches during intracranial endovascular procedures: a possible model of vascular headache. 15. 2004:151–172. The trigeminocervical complex and migraine: current concepts and synthesis. Behin B. Behin F. 1968. Headaches in cerebrovascular disease. Mohr JP. 14. Philadelphia: Saunders. Headache. Boston: Butterworth-Heinemann. Stein B.66 Rozen 5. Thomsen LL. 10. Headache 1993. The neck and headaches. McAuliffe GW. Martins IP. Headache 1993. Arch Neurol 1996. Baredes S. Amsterdam: North Holland. Stroke 1990. Surgical management of contact point headache. 8. Paiva T. 16. Stammberger H. Goadsby PJ. 13. Leptomeningeal-presenting features and prognostic factors. Baeta E. Nichols FT. Headache 2005. eds. Headaches and sinus disease: the endoscopic approach. Bogduk N. 45:204–210. Michelsen WJ. 65:260–262. Mokri B. . Gomes L. Ann Otol Rhino Laryngol 1988. 23:185–206. 134(suppl):3–23. ed. Campos J. 5:124–151. J Neurol Neurosurg Psychiat 1998. 7. 21: 555–559. 9. 53:626–632. Balm M. In: Evans RW. Res Publ Assoc Res Nerv Ment Dis 1950. Focal headache during balloon inflation in the internal carotid and middle cerebral arteries. Fisher CM. potassium. confirms the rate of progression of 3. Sanchez del Rio Department of Neurology. Strong et al. glutamate. Germany INTRODUCTION Since the initial description of cortical spreading depression (CSD) by Leao. Spain U. pinprick. there has been growing evidence that CSD is the underlying pathomechanism of the migraine aura (Table 1). The NMDA receptor antagonist MK-801 has 67 . Department of Neurology. NEUROPHYSIOLOGICAL MECHANISMS Spreading depression–like phenomena have been observed in cerebral ischemia models and experimental trauma. The fact that. the visual aura is the most common (4) may reflect the hyperexcitability of the occipital cortex of migraineurs. recently demonstrated CSD or a CSD-like phenomenon developing in the boundary zone of the lesion by electrocorticography (5). A key transmitter in the initiation and propagation of CSD appears to be glutamate. In experimental animal studies. Assessment of the speed of progression of the visual field defect during migraine aura. It is accompanied by a short-lasting dramatic increase in regional cerebral blood flow (rCBF) followed by a long-lasting rCBF hypoperfusion. Recent functional magnetic resonance imaging (fMRI) (1) and magnetoencephalography (MEG) (2) studies in men strongly support the occurrence of CSD during visual migraine aura. Glutamate binds to N-methyl-D-aspartate receptor (NMDA) and alpha-amino-3-hydroxy-5-methyl isoxazole-propionic acid receptors on neuronal and glial tissue and by doing so causes depolarization of these cells. Charite Universita ¨tsmedizin Berlin. The detailed molecular mechanisms initiating CSD are not understood. indicating that this phenomenon is triggered by primary neuronal–glial homeostasis imbalance. CSD is a slowly propagating wave of neuronal and glial depolarization that spreads across the cortex with a speed of 3 to 5 mm/min. using Humphrey field chart. In the injured human brain.6 mm/min (3). Headache Program. Berlin. Hospital Ruber International. among all aura symptoms. Reuter ´. and electrical stimuli cause CSD. Madrid.6 Pathophysiology of Aura M. CSD þ 3–4. and no trials have been performed in migraine aura so far. without causing ischemia (12). pointing to a primary endothelial factor as a trigger for CSD. neuronal and vascular mechanisms may apply.5 min 1–2 h þ 2–5 mm/min þ 15–30 min (evoked) þ þ 3. In addition to neuronal events. However. the astrocytic . However. In fact. When CSD is terminated. Therefore. although a CSD-like phenomenon called periinfarct depolarization has been suspected of contributing to tissue damage (9). In stroke. The role of astrocyctic Ca2þ waves with respect to the migraine aura and migraine headache remains elusive. More evidence can be derived from a study in a knock-in mouse model carrying the human pure FHM-1 R192Q mutation (8). NMDA receptor antagonists are not beneficial for the clinical outcome. indicating the crucial function of glutamate and the NMDA receptor in this neurophysiological event (6).and/or glutamate-mediated neurotransmission (10). they have no effect on the migraine aura. Interestingly. In line. Both antiepileptic substances enhance GABA-mediated inhibition. because the application of an NO donor requires higher concentrations of endothelin to induce CSD. cerebral angiography or carotid artery dissection is known to initiate migraine aura in a subset of susceptible patients. topical application of the potent vasoconstrictor endothelin-1 has recently been shown to induce typical CSD in a rat model at concentrations between 10 nM and 1 mM.5 Æ 1. However.1 mm/min þ 15 min (80%) þ been demonstrated in several experimental animal studies to inhibit CSD initiation and propagation. cortical spreading depression. leading to enhanced neurotransmission and enhanced CSD. This mutation in the CaV2. blockade of the NR2B subunit of the NMDA receptor by ifenopril also abolishes CSD in a murine model.9 min 2h þ 3. It has been speculated that astrocytes may carry the propagating wave front of CSD. In addition. supporting the critical role of glutamate for CSD (7). The preventative antimigraine drugs valproate and topiramate are likely to affect nociception by modulating GABA. It remains to be determined whether NMDA receptor antagonists are able to abort the migraine aura. L-type calcium channel mRNA expression is enhanced after CSD (13). CSD determines the velocity of an accompanying astrocytic Ca2þ wave. and at least valproic acid has not been proven so far to affect CSD (11). at least to our knowledge NMDA receptor antagonists are not available for clinical use. The effect of gamma-aminobutyric acid (GABA) in CSD and migraine aura is not entirely clear. Endothelin modulates endothelial cells and smooth muscle cells as well as neurons and astrocytes.68 del Rio and Reuter Table 1 Comparison Between Imaging Finding During Migraine Visual Aura and Experimental CSD Visual aura Cortical gray matter Hyperemia Hypoperfusion Suppression of activation Rate of spread Terminates at major sulci Amplitude recovery First activated/first to recovery Abbreviation: CSD.1 (calcium channel type P/Q) channels that control the release of glutamate from cortical neurons has given multiple gain-of-function effects.3 Æ 1. the mode of action is supposed to be vascular in this experimental model. However. was considered as an epiphenomenona of lesser importance (Fig. . However. Together with the depolarisation.4 Æ 0. Indeed. which is a distinct feature of CSD in the rat and cat. Together these findings indicate that neuronal CSD and astrocytic Ca2þ waves use different propagation mechanisms. Cortical hypoperfusion was not observed in the aforementioned study. high extracellular potassium and blockade of nitric oxide synthases abolish CSD hyperperfusion and cause CSD-induced pronounced hypoperfusion that spreads with a speed of 3. the aura in migraineurs occurs without subsequent headaches or even during the headache. calcium waves travel through gap junctions. A similar phenomenon could account for migrainous strokes or strokes in subarachnoid hemorrhage. which covers a larger territory. CSD-associated short-lasting cortical hyperperfusion. in more than 90%.6 mm/min across the cortex. resulting in cortical infarction (17). there is a striking timely link as the aura is followed by typical migraine Figure 1 Cortical spreading depression (CSD) is defined as a wave of neuronal and glial depolarisation (A) that slowly spreads along the cortex at a rate from 2–5 mm/min. In contrast. gap junctions could serve as a link between CSD and pain sensitive structures in cortical proximity. Therefore. In rare cases.Pathophysiology of Aura 69 Ca2þ wave moves on and propagates as a self-reliant mechanism. CSD hyperperfusion was demonstrated in 2002 in primates (cynomolgus monkey) for the first time using positron emission tomography (PET) (15). Recent data suggest that blockade of CSD hyperperfusion leads to detrimental consequences. 2) (1). (C) CSD is also associated with changes in ion homeostasis and release of glutamate. Recent fMRI studies of the human migraine aura point to the presence of an initial cortical hyperperfusion followed by a longer-lasting wave of hypoperfusion (Fig. 1). laser blood flow measurements have documented (B) dramatic increases in blood flow lasting 2–5 minutes followed by a long lasting hypoperfusion. and astrocyte–pia arachnoid communication also occurs through these structures. CSD hyperperfusion is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers (16). For a long time. but spreads with a lower velocity (14). delayed meningeal blood flow increase is mediated by a trigeminal–parasympathetic brain . In line. Source: Modified from Ref. 1. 3) (18). Surprisingly. Finally. CSD is able to activate the ipsilateral trigeminal nerve system as demonstrated by c-fos expression in TNC and meningeal PPE. CSD resulted in ipsilateral enhanced c-fos expression within the trigeminal nucleus caudalis (TNC). hippocampal CSD activates the TNC albeit bilaterally with a c-fos staining pattern in TNC that is very similar in both studies (primarily Laminae I and II) (19). which was dependent on trigeminal nerve integrity. This is a remarkable finding with respect to the observation that patients describe memory disturbance before the onset of migraine (20). Blood flow changes during CSD (gray line) is superimposed over the MRI-BOLD signal obtained during migraine visual aura. PPE is a model that has been used to assess the efficacy of antimigraine drugs. In summary. Importantly. thereby indicating trigeminal nerve activation during CSD.70 del Rio and Reuter % 250 200 150 MR signal CBF 100 50 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (minutes) Figure 2 Blood flow changes in cortical spreading depression (CSD) and migraine. Delayed blood flow increase was abolished by ipsilateral acute and chronic trigeminal nerve sectioning and trigeminal rhizotomy. Note that the time scale is the same for both measurements. Moskowitz and colleagues demonstrated a pathophysiological connection between CSD and meningeal events consistent with the notion of headache (Fig. CSD leads to plasma protein extravasation (PPE) in the ipsilateral dura mater of rats. headaches. In addition. CSD results in delayed blood flow increases selectively in ipsilateral meningeal vessels. electrophysiological studies failed to demonstrate CSD-induced activation of neurons within the TNC (21). which can be blocked by trigeminal nerve transection on the same side and an antagonist at the substance P–binding site (NK-1 receptor). sectioning of parasympathetic nerve fibers also abolished delayed blood flow increase (18). In both cases an initial hyperemia is followed by a long lasting hypoperfusion. into the extracellular and perivascular space and causes transient hyperemia and vasodilation in cortex pial vessels and duramater (2). From trigeminal nucleus caudalis the impulses are transmitted centrally for further pain processing (4). CSD releases potassium. stem connection. Source: From Ref. a cis benzopyran. leads to stimulation of the superior salivary nucleus (SSN) (6) and parasympathetic activation (7). nitric oxide. 18. effectively attenuates abnormally high levels of neuronal excitation and is also successful in assays that have been used to determine the efficacy of antimigraine drugs. This molecules are able to activate and sensitize the perivascular trigeminal afferents and transmit impulses centrally (3) to trigeminal nucleus caudalis via the trigeminal ganglion. Activation of ipsilateral trigeminal nucleus caudalis in turn. Inhibition of CSD may abort the human migraine aura and may prevent subsequent headache. metabolites of arachidonic acid (AA) and glutamate. This substance reduces CSD-induced . hydrogen ions. leading to dural vasodilation and inflammation (5). A novel drug has been proposed for the treatment of migraine aura. substance P and NK-1. This work (18) was the first to demonstrate that intrinsic brain events are able to activate extracerebral meningeal nociceptors. This leads to release of VIP and acetilcholine.Pathophysiology of Aura 71 Figure 3 Link between cortical spreading depression (CSD) and trigeminovascular activation (1). Dural trigeminal afferents release CGRP. which in turn favours further dural vasodilatation. Tonabersat. and the presence of direct current shifts measured with MEG. For example. MOLECULAR MECHANISMS The role of gene expression in headache generation due to CSD is not known.72 del Rio and Reuter nitric oxide release and enhanced cGMP levels in cortex and brainstem (22). Prostaglandins. If also successful in men. Alternatively COX-2 could promote inflammation. While hyperemia is the response to increased neuronal activation. In addition. . This findings may provide insight into the cerebrovascular changes reported in the headache phase of migraine.1 mm/min (Fig. 4) (1). contribute to the stimulusinduced CBF increase in the somatosensory cortex (30). Upregulation of these cytokines after CSD may therefore be a protective mechanism or may also be a physiological stress response. this drug could be the first one for the treatment of the migraine aura. Contrary to the well-defined propagating CSD initial waves. to CSD-induced gene expression.29). CSD leads to reduced COX-2 gene expression in mice overexpressing the antioxidant enzyme copper/ zinc-superoxide dismutase gene compared to control mice (32). These findings. application of an independent component analysis to fMRI has aided in detecting for the first time delayed nonpropagating cerebrovascular changes following the initiation of CSD in cats (24). IMAGING STUDIES The initial groundbreaking work using xenon blood flow studies was done by Olesen and Friberg (25). One may speculate that increased COX-2 expression and activity after CSD may contribute to the reconstitution of decreased CBF and may therefore participate in the prevention of migraineous infarcts. which are expressed in microglia (31). whereas vascular changes represent an epiphenomenona (2.26.27).3). the product of COX-2 activity. together with direct evidence that local oxygen supply is more than adequate. tonabersat reduced the number of CSDs dose dependently (23). Hyperemia is then followed by a wave of hypoperfusion that crosses vascular boundaries of contiguous cortex at a rate of 3.5 Æ 1. In an animal study by Nestini and colleagues. While the significance of these findings for antimigraine action remains to be determined. primates and rodents express the COX-2 gene in cortical neurons after CSD (28. Here. in part. Other proinflamatory enzymes that are elevated in CSD are tumor necrosis factor (TNF)–a and interleukin (IL)-1b. support the concept of migraine as a primarily neuronal disorder. Today we know that migraine aura is characterized by a short phase of hyperemia that is likely to be the correlate of the flashing. jagged lights described during the visual hallucinations (1. This finding supports the hypothesis that free radicals contribute. hypoperfusion reflects depressed neuronal function and is still clearly present when the headache starts. TNF-a and IL-1b are known to protect neurons in vitro against hypoxic or excitatory injury. It also shows that noninjurious metabolic stimulation increases the concentration of oxygen radicals. Subsequent functional imaging studies have both corroborated the previous findings and further elucidated the underlying mechanisms of migraine aura. these localized waves were suppressed by sumatriptan as well as by tonabersat. stronger evidence is derived from an experimental study in the cat. on a computationally inflated surface. (A) A drawing showing the progression over 20 min of the scintillations and the visual field defect affecting the left hemifield. which indicates the transition of cells to a different cellular state. this finding may be of critical importance for the differentiation of CNS cells posttrauma or ischemia. Nestin is expressed in neuronal cells under stress. based on anatomical magnetic resonance (MR) data. The posterior medial aspect of occipital lobe is shown in an inflated cortex format. from the posterior pole to more anterior location.. GST-5. Each time course was recorded from one in a sequence of voxels that were sampled along the calcarine sulcus. as described by the patient. As shown in the logo in the upper left. but not for migraine headache (33).5 eccentricity). However. This finding was consistent with the progression of the aura from central to peripheral eccentricities in the corresponding visual field (A and C). in the primary visual cortex (V1). A similar BOLD response was found within all of the extrastriate areas. Enhanced expression of nestin in CSD most likely reflects a response to stress. respectively. compared with more eccentric representations of retinotopic visual cortex. Source: From Ref. as indicated by arrowheads. In this format. voxels that show retinotopically specific activation in the fovea are coded (centered at 1. An increased expression of other genes related to oxidative stress such as PRP.Pathophysiology of Aura 73 Figure 4 Spreading suppression of cortical activation during migraine aura. along with changes . The MR perturbations developed earlier in the foveal representation. (B) A reconstruction of the same patient’s brain. 10. and apolipoprotein E was observed by Choudhuri et al. acquired during interictal scans. differing only in the time of onset of the MR perturbation. (C) The MR maps of retinotopic eccentricity from this same subject. the cortical sulci and gyri appear in darker and lighter gray. MR signal changes over time are shown to the right. Elevated cGMP levels seem to be neuroprotective. and migraine. vasoactive peptides such as ANP could contribute to vasodilation in dura mater vessels and neurogenic inflammation. lower thresholds of ‘‘low-level visual’’ processing in the primary visual cortex. In general. Some of these genes are clearly related to CSD propagation. In a similar way. and deficient habituation (39–42). especially in occipital cortex. stroke. Moskowitz and colleagues demonstrated striking upregulation of MMP-9 mRNA and protein expression in cortex after CSD. This abnormal responsiveness of the visual cortex is now a widely appreciated characteristic of the migrainous brain. These preliminary results on MMP-9 formation offer a valuable explanation for how CSD could affect the BBB and may thereby result in the activation of pain-sensitive meningeal structures and headaches. considering that CSD causes short-lasting cortical hyperperfusion and subsequent reduced rCBF. Moreover. Galanin is involved in the regulation of neuronal excitability of hippocampus and cerebral cortex. probably via effects on cyclic guanosine monophosphate (cGMP) production (34). High cGMP concentrations can be induced by an increase of NO. While vasoconstrictor peptide neuropeptide Y mRNA was downregulated. manifested as an increased sensitivity to various physiologic environmental stimuli. or neuroprotection. CSD has been shown to upregulate the expression of clusterin mRNA (35). Matrix metalloproteinases (MMP) were also identified to play a role in CSD (38). and mRNA upregulation rather reflects the plasticity of the galanin system. MMP are extracellular proteinases that are capable of degrading matrix components. Alternatively. indicating the effects of CSD on a variety of genes. and MKP-1 mRNAs expression after CSD in experimental trauma. Others resemble a response to oxidative stress or indicate the breach of the BBB. Upregulation of vasoactive peptides is expected. Clusterin is a sulfated glycoprotein produced by neurons and by resting and activated astrocytes. This protein is associated with endothelial tight junction formation in the BBB. reducing the threshold for cortical activation. which is also elevated in CSD. atrial natriuretic peptide (ANP) gene expression was increased. Collagen IV and laminin are the targets of MMP-9. upregulation of MMP results in tissue injury and inflammation. Nevertheless galanin may be of importance in headache because galanin is known to release a variety of neurotransmitters and is involved in nociception (37).74 del Rio and Reuter of vasoactive peptide mRNA (13). In summary. CSD causes upregulation of a host of genes. Although the striate cortex accounts for only 3% of the cerebral . More recently galanin gene upregulation and peptide release has been observed in cortex ipsilateral to CSD (36). MMPs are regulated by gene transcription. OCCIPITAL CORTEX EXCITABILITY It is unclear what triggers migraine aura. Long-lasting activation of cortical neurons in layers II to IV and VI was also demonstrated by c-fos. junB. enhanced ANP expression after CSD could resemble a feature of CSD-induced neuroprotection. but it is increasingly evident that there seem to be factors that modify neuronal excitability. enhanced MMP-9 expression was associated with a breach of the blood–brain barrier (BBB) as demonstrated by evans blue leakage and degradation of ZO-1. and degradation is indicative of a BBB breach. vascular responses. Moreover. which is expected due to the occurrence of this phenomenon in several disorders such as trauma. with a protective function in response to brain injury. Lactate so generated is transported and oxidized within neurons to support the excessive energy needs of synaptic activity. Kþ-ATPase removing sodium from inside cells. These Figure 5 A pivotal role for glutamate is proposed to explain the susceptibility to cortical spreading depression. Kþ-ATPase (FHM type II) expressed by astrocytes raise extracellular glutamate and potassium. familial hemiplegic migraine (FMH) is caused by missense mutations in CACNA1A. (CADASIL) or mitochondrial energy defects [mitochondrial encephalomyopathy. approximately 10% of cortical neurons are said to be located here. 5) (44).1 (FHM type I) and increased synaptic release of glutamide from neurons. Energy is required and achieved by glucose utilization after uptake from blood vessels. Sodium gradients are maintained by activity of Naþ. alone or in combination with magnesium deficiency. This dense packing of neurons may hypothetically contribute to the abnormal excitability of the occipital cortex. cell-surface receptor dysfunction. 43. and environmental factors such as stress and ovarian steroid may also play a relevant role in cortical excitability.1 gating calcium influx. GENETICS In approximately half of the families tested.Pathophysiology of Aura 75 surface. . and stroke-like syndrome (MELAS)] may also contribute to lowering the threshold for neuronal excitation. glutamate is released into the synaptic cleft regulated by Cav2. Synaptic activity is terminated in part by astrocytic uptake of glutamate via transporters (GLAST) driven by sodium gradients. lactic acidosis. the gene encoding the pore-forming a1A-subunit of voltage-gated P/Q-type Ca2þ (CaV2. as seen in MELAS. Source: From Ref. After depolarization. Other factors such as mitochondrial energy impairment. and even in migraine with and without aura. Loss of function mutation in Naþ. direct glucose uptake may occur in neurons as well. Under basal conditions. implicated in migraine aura. Susceptibility to cortical spreading depression is enhanced by gain of function mutation in Cav2. Genetic factors that lead to calcium channelopathies (FHM).1) channels (Fig. we are completing the puzzle of the pathogenesis of migraine aura.1 channels to hyperpolarized voltages. whereas missense mutations cause FMH and disrupted reading frames cause EA-2 (44).76 del Rio and Reuter FMH1 mutations in vitro alter both the single-channel properties and the density of functional channels in the membrane. which encodes the a2 subunit of the Naþ/Kþ pump in astrocytes (47). which promotes an increase in intracellular Ca2þ through the Naþ/Ca2þ exchanger.1 channels. In the latter case.1 channels by shifting the activation curve of CaV2. Based on modern functional imaging. CONCLUSIONS CSD is a complex neurovascular event that triggers a cascade of mechanisms leading to upregulation of genes. Overall the mutations lead to (i) an increase in the Ca2þ influx through single human CaV2. the mechanism underlying the migraine aura resembles the neurovascular changes observed in CSD. These mutations lead to a reduced Ca2þ entry through CaV2. leakage of the BBB. The functional consequences of these amino acid replacements are a loss of function of the a2 subunit. The nature of the mutation distinguishes both disorders. This knock-in mouse carrying the human pure FHM-1 R192Q mutation may explain the apparently contradictory findings observed until now in the knock-out mice with spontaneous CaV2. and (ii) a decrease in the density of functional CaV2. Slowly and by a multidisciplinary approach. making the cortex more resistant to CSD.1 channels and consequently to a reduced neuronal cortical network excitability. in the gene ATP1A2. Genetic conditioning and probably environmental factors render the system excitable. Consequently the haploinsufficiency of the Naþ/Kþ pump activity in astrocytes provokes an increase in extracellular Kþ due to an impaired clearance of brain Kþ by neurons and glial cells D. The presence of cerebellar ataxia as part of the clinical spectrum of FHM is not unusual because the cerebellum is rich in P/Q calcium channels. without precluding the correct incorporation of the mutant. facilitating the appearance of CSD. Two mutations lead to two amino acid replacements. leucine to proline and tryptophan to arginine. Several mutations in the a1A-subunit cause FHM but may also be responsible for episodic ataxia type 2. Recently a study performed in a CACNA1A knock-in mouse has shown increased susceptibility for CSD. FHM2 is caused in approximately 15% of cases by recently described mutations in chromosome 1q23. PPE. This produce a wide cortical depolarization and a local boost of intracellular Naþ. and central transmission of pain signal via the brainstem. and thus increase their open probability. as well as enhanced neurotransmission at the neuromuscular junction (8). the final consequence being the facilitation of CSD. the glutamate transporter is slowed or even reversed. causing an increase in extracellular glutamate levels (47). which varies according to the cell type (45). demonstrating that those spontaneous mutations were not functionally identical as those found in men. . both due to a decrease in the threshold and due to an increase in the speed of progression of CSD. the Naþ/Kþ pump as integral membrane protein.1a1 mutations (46). a striking elevation of the threshold for initiating CSD in the neocortex was found. Another possibility is that as a consequence of the increase in extracellular Kþ and Naþ. sensitization of perivascular nerve fibers. This increase in intracellular Ca2þ would mimic the effect of the CACNA1A mutation seen in FHM1. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Huang Z. et al. Brain 1996. and nociception that might cause migraine headache? Ann Neurol 2001. 10. 8. Cui L. Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex. Mies G. Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. Kaube H. 33:2738–2743. Faria LC. Schaible HG. 6. neurogenic inflammation. Upton N. Parsons AA. Dreier JP. Neuro-ophtalmology 2003. Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Yokota C. Bowyer SM. Nat Med 2002. Fabricius M. Ebersberger A. Porooshani AH. 17. J Cereb Blood Flow Metab 2002. Petzold GC. Strong AJ. 34:30–35. Wauquier A. 2. 12. Review. et al. 60:935–940. Giffin NJ. 4:709–711. 51:499–506. et al. et al. Cephalalgia 2000. Dreier JP. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. 13. 98:4687–4692. Willems R. 457:226–240. 92:2610–2614. 18. Brain Res 1988. Am J Physiol Heart Circ Physiol 2003. Olesen J. J Neurosci 2003. . Gannon L. Weber JR. Hunter AJ. 125:102–112. Major S. Peters O. Ebert N. Bowyer S. Kettenmann H. 18:978–990. Dunn AK. 8:136–142. inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat. Hasegawa Y. Neuron 2004. et al. A nosographic analysis of the migraine aura in a general population. 49:7–13. Speed of progression of migrainous visual aura measured by sequential field assessment. J Neurophysiol 2004. The role of anticonvulsants in preventive migraine therapy. Unique profile of spreading depression in a primate model. Korner K. Kyle GM. Yong C. et al. Bolay H. Sanchez del Rio M. 5. Gold L. Reuter U. Proc Natl Acad Sci USA 2001. Welch KM. Kuge Y. 28:101–105. Endothelin-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Ruggiero L. 119:355–361. 9. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Perivascular nerves contribute to cortical spreading depression-associated hyperemia in rats. Hippocampus 2003. Is there a correlation between spreading depression. 41(5):701–710. Kunkler PE. 20:92–99. 20. Choudhuri R. 7:63–66. Pizzorusso T. J Cereb Blood Flow Metab 1998. 3. De Prins E. Am J Physiol 1998. Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. 23:9888–9896. Cortical spreading depression and gene regulation: relevance to migraine. Eur Neurol 1994. Kleeberg J. Moskowitz MA. Ann Neurol 2002. et al. Evidence for a role of the N-methylD-aspartate (NMDA) receptor in cortical spreading depression in the rat. Moran JE. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when Kþ is increased in the subarachnoid space. 15. Porooshani H. Premonitory symptoms in migraine: an electronic diary study. 13:835–844. Schipke CG. Corbo J. Russell MB. 14. Hadjikhani N. et al. 22:835–842. a potential novel antimigraine agent. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Neurology 2003. 22. Hashimoto Y. Tepley N. SB-220453. 19. 50:582–587. 16. Different mechanisms promote astrocyte Ca2þ waves and spreading depression in the mouse neocortex. Aurora KS. Mody I. Marrannes R. 21. 274:H1979–H1987. Ann Neurol 2001. 11. Read SJ. Lipton RB. 7. Kraig RP. Van den Maagdenberg AM. Wu O. Smith MI. Iijima T. Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Dirnagl U. Curr Pain Headache Rep 2003. Averbeck B. 4. Pietrobon D. Boutelle MG. Goasdby PJ. Stroke 2002. Richter F. Reuter U. Neuroreport 1993.Pathophysiology of Aura 77 REFERENCES 1. Boas DA. Hossmann KA. 23:395–398. Ross ME. Schoenen J. Lendahl U. Delayed. Shen PJ. Sanchez del Rio M. Chan PH. Larm JA. Holmin S. Bhardhwaj P. Araki E. Yrjanheikki J. 32. Atrial natriuretic peptide expression is increased in rat cerebral cortex following spreading depression: possible contribution to sd-induced neuroprotection. but prolonged increases in astrocytic clusterin (ApoJ) mRNA expression following acute cortical spreading depression in the rat: evidence for a role of clusterin in ischemic tolerance. Maertens dN. Mathiesen T. 44:209–215. Proc Natl Acad Sci USA 1997. 1991:121–130. 29. Kuge Y. Migraine and Other Headaches: The Vascular Mechanisms. 20:763–770. 31. Cao Y. Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. de Crespigny A. 23:468–474. Magn Reson Imaging 2003. Welch KM.78 del Rio and Reuter 23. Effects of repetitive transcranial magnetic stimulation on visual evoked potentials in migraine. J Neurotrauma 2000. ed. New York: Raven Press Ltd. Neurology 1998. A delayed class of BOLD waveforms associated with spreading depression in the feline cerebral cortex can be detected and characterised using independent component analysis (ICA). Induction of astrocytic nestin expression by depolarization in rats. Ramadan NM. Bohotin V. 24. 39. Brain 2002. Vandenheede M. Mascia A. 21:218–225. 94:6500–6505. Visual processing in migraineurs. Vikingstad EM. Inoue H. 125:912–922. 34. 37. Matsuoka N. 56:548–554. Stoll G. Wray SH. J Cereb Blood Flow Metab 2001.. et al. Cortical spreading depression activates and upregulates MMP-9. Brain 1995. The participation of galanin in pain processing at the spinal level. 118:25–35. et al. Neurosci Lett 2001. Smith MI. Moseley ME. Ahmad BK. Netsiri C. Afra J. von Gertten C. 36. Eur J Neurosci 2003. 114:20–30. Wu O. Gundlach AL. 33. 30. Jander S. 25. 27. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. oligodendrocyte progenitors and proliferative zones in normal brain and after spreading depression. Gundlach AL. J Neurosci 2000. Aurora SK. Fumal A. et al. J Cereb Blood Flow Metab 2003. Wiggins AK. Koistinaho J. et al. Fusco FR. Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine. 314: 151–155. Wiggins AK. Xenon 133 SPECT studies in migraine with aura. In: Olesen J. Miettinen S. et al. 18:1362–1376. Neuroscience 2003. Gursoy-Ozdemir Y. Yrjanheikki J. Yokota C. Trends Pharmacol Sci 2002. Welch KM. Aurora S. et al. . Sandberg-Nordqvist AC. Friberg L. Shen PJ. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. Takeda T. Interictal cortical excitability in migraine: a study using transcranial magnetic stimulation of motor and visual cortices. 172:342–353. 118:715–726. Bakker D. Shen PJ. Arch Neurol 1999. Diffusion-weighted MRI used to detect in vivo modulation of cortical spreading depression: comparison of sumatriptan and tonabersat. 35. Cephalalgia 1999. J Clin Invest 2004. et al. Olesen J. 38. Expression and plasticity of galanin systems in cortical neurons. 113:1447–1455. 17:713–718. Netsiri C. 19:701–707. Gundlach AL. Bradley DP. Mijovic-Prelec D. Niwa K. Functional MRI-BOLD of visually triggered headache in patients with migraine. 41. Copin JC. Peters O. Kosslyn SM. Ann Neurol 1998. Iadecola C. Brain Res Mol Brain Res 2003. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. 26. Witte OW. 28. Cyclooxygenase-2 expression associated with spreading depression in a primate model. Qiu J. Hokfelt T. Spreading depression-induced expression of c-fos and cyclooxygenase-2 in transgenic mice that overexpress human copper/zinc-superoxide dismutase. 21:1097–1110. Exp Neurol 2001. Morham SG. Gerard P. 42. Liu HX. Schroeter M. Bradley DP. 40. 50:1111–1114. 55:276–280. Moskowitz MA. Bolay H. 95:639–645. Shimizu-Sasamata M. 33:192–196.1 channels and decrease maximal CaV2. Ann Neurol 2004. 44. Moskowitz MA. Trends Pharmacol Sci 1998. Ferrari MD. et al. Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Marconi R.1 current density in neurons. 47. Fellin T.Pathophysiology of Aura 79 43. et al. Frants RR. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. 99:13284–13289. Haploinsufficiency of ATP1A2 encoding the Naþ/Kþ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Pagnutti S. 19:121–127. Lo EH. P/Q-type Ca2þ channel defects in migraine. Ophoff RA. Tottene A. 46. Nat Genet 2003. ataxia and epilepsy. 45. Silvestri L. Proc Natl Acad Sci USA 2002. . De Fusco M. Ayata C. Terwindt GM. Neuroscience 2000. Familial hemiplegic migraine mutations increase Ca (2þ) influx through single human CaV2. Noebels JL. . and ultimately provide insights that lead to new treatments.7 Pathophysiology of Migraine Peter J. and in particular migraine (1) and cluster headache (2). it is important to remember that migraine is not simply a pain problem. Queen Square. INTRODUCTION An understanding of the pathophysiology of migraine should be based upon the anatomy and physiology of the pain-producing structures of the cranium integrated with knowledge of central nervous system modulation of these pathways. in essence. a familial episodic disorder whose key marker is headache with certain associated features (Table 1). MIGRAINE—EXPLAINING THE CLINICAL FEATURES Migraine is. U. London. This chapter will discuss the current understanding of migraine.  physiology and pharmacology of activation of the peripheral branches of ophthalmic branch of the trigeminal nerve. Headache in general. the trigeminocervical complex. 81 . It is these features that give clues to its pathophysiology. The National Hospital for Neurology and Neurosurgery. particularly that of the trigeminovascular system.K. Migraine is a form of sensory processing disturbance with wide ramifications within the central nervous system. is better understood now than the last four millennia (3). physiological basis for the aura. in particular its caudal most part. Although pain pathways are used as an example. anatomy of head pain. physiology and pharmacology of the trigeminal nucleus. The essential elements to be considered are:     genetics of migraine. Goadsby Institute of Neurology. and  brainstem and diencephalic modulatory systems that influence trigeminal pain transmission and other sensory modality processing. 15–17). Indeed. It is clear from clinical practice that many patients have first-degree relatives who also suffer from migraine (3. familial hemiplegic migraine (FHM) has been assigned to chromosome 19p13 (12. Mutations in the ATP1A2 gene (21.13.5). 4.82 Table 1 International Headache Society Features of Migraine Repeated episodic headache (4–72 hrs) with the following features Any two of:  Unilateral  Throbbing  Worsened by movement  Moderate or severe Any one of:  Nausea/vomiting  Photophobia and phonophobia Source: From Ref.05). Several studies have attempted to analyze the possible mode of inheritance in migraine families. The biological basis for the linkage to chromosome 19 is mutations (19) involving the Cav2. and numerous published studies have reported a positive family history (7).22) have been . The most striking exception is cerebellar ataxia. Few clinical differences have been found between chromosome 19–linked and unlinked FHM families. FAMILIAL HEMIPLEGIC MIGRAINE (FHM) In approximately 50% of the reported families. Another less striking difference includes the fact that patients from chromosome 19–linked families are more likely to have attacks that can be triggered by minor head trauma or that are associated with coma (18). Now known as FHM-I. which occurs in approximately 50% of the chromosome 19–linked. Goadsby GENETICS OF MIGRAINE One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder. Both twin studies and population-based epidemiological surveys strongly suggest that migraine without aura is a multifactorial disorder.1 (P/Q)-type voltage-gated calcium channel (20) CACNA1A gene. but in none of the unlinked families (12. The pairwise concordance rate was significantly higher among monozygotic twin pairs (P < 0. the clinical phenotype does not associate particularly with the known mutations (14). this mutation is responsible for about 50% of migraines in identified families. and conflicting results have been obtained (9–11). caused by a combination of genetic and environmental factors. Genetic Epidemiology Studies of twin pairs are the classical method to investigate the relative importance of genetic and environmental factors.13). A Danish study included 1013 monozygotic and 1667 dizygotic twin pairs of the same gender. Transmission of migraine from parents to children has been reported as early as the 17th century (6). obtained from a population-based twin register (8). and in the posterior fossa. indeed. from the upper . Tonabersat is a CSD inhibitor that has entered clinical trials in migraine. Topiramate inhibits trigeminal neurons activated by nociceptive intracranial afferents (57). Tonabersat (SB-220453) inhibits CSD. in fact. It is seen in about 30% of patients (29). large venous sinuses. and it starts at the center of the visual field and propagates to the periphery at a speed of 3 mm/min (35). This pattern is repeated with experimental spreading depression (40–42). topiramate. MIGRAINE AURA Migraine aura is defined as a focal neurological disturbance that manifests as visual. sensory. and it is clearly neurally driven (30. while it has also been suggested that alternating hemiplegia of childhood can be due to ATP1A2 mutations (25). or at least the neurological manifestations currently called the aura. triggers the rest of the attack. but not by a mechanism local to the trigeminocervical complex (58). the phenotype of some FHM-II involves epilepsy (23. but does inhibit trigeminally induced craniovascular effects (49). and thus CSD inhibition may be a model system to contribute to the development of preventive medicines. Blood flow studies in patients have also shown that a focal hyperemia tends to precede the spreading oligemia (36). An area of controversy surrounds whether aura. and again this is similar to what would be expected with spreading depression. Tonabersat is inactive in the human NO model of migraine (54). Interestingly. visual aura has been described as affecting the visual field. painful (44).24). The latter cases are most unconvincing for migraine. a proven preventive agent in migraine (50–52). or potential treatments.47). the cerebrovascular response to hypercapnia in patients is blunted while autoregulation remains intact (37–39). this does not diminish the importance of understanding its role. Tonabersat does not constrict isolated human blood vessels (48). as is propranolol (55). The case for the aura being the human equivalent of the CSD of Leao (32. also inhibits CSD in cats and rats (53). Remarkably. and is. although valproate showed some activity in that model (56). This is very similar to the spreading depression described in rabbits (33). or motor symptoms (4). pial vessels. suggesting the involvement of the visual cortex. In humans. the known mutations suggest that migraine. however.33) has been well made (34). HEADACHE—ANATOMY The Trigeminal Innervation of Pain-Producing Intracranial Structures Surrounding the large cerebral vessels. Based on the available experimental and clinical data. After this passage of oligemia. are caused by a channelopathy (26).31). CSD-induced nitric oxide (NO) release. and dura mater is a plexus of largely unmyelinated fibers that arise from the ophthalmic division of the trigeminal ganglion (59). this author is not convinced that aura is painful per se (45). Taken together. Human observations have rendered the arguments reasonably sound that CSD in animals is equivalent to human aura (43).Pathophysiology of Migraine 83 identified to be responsible for migraines in about 20% of the FHM families. and cerebral vasodilation (46. Linking the channel disturbance for the first time to the aura process has helped to demonstrate that human mutations expressed in a knock-in mouse produce a reduced threshold for cortical spreading depression (CSD) (27). which has some profound implications for understanding that process (28). caudalis and C1/C2 dorsal horns Ventrobasal complex Medial n. The pharmacology of abortive antimigraine drugs has been reviewed in detail (69).71). which contains substance P and calcitonin gene–related peptide (CGRP) (61). In addition. indomethacin. can be seen after trigeminal ganglion stimulation in experimental animals. and particularly the initiation of a sterile inflammatory response.84 Table 2 Neuroanatomical Processing of Vascular Head Pain Structure Target innervation:  Cranial vessels  Dura mater 1st 2nd 3rd Ophthalmic branch of trigeminal nerve Trigeminal ganglion Trigeminal nucleus (quintothalamic tract) Thalamus Comments Goadsby Modulatory Final Midbrain Hypothalamus Cortex Middle cranial fossa Trigeminal n.64). sumatriptan (68). Human dural nerves that innervate the cranial vessels largely consist of smalldiameter myelinated and unmyelinated fibers (65). although this has been a controversial area (45.75–78). acetylsalicylic acid. Although plasma extravasation in the retina. may cause pain (72. Plasma protein extravasation (PPE) can be blocked by ergot alkaloids. HEADACHE PHYSIOLOGY—PERIPHERAL CONNECTIONS Plasma Protein Extravasation Moskowitz (66) has provided a series of experiments to suggest that the pain of migraine may be a form of sterile neurogenic inflammation. Trigeminal fibers innervating cerebral vessels arise from neurons in the trigeminal ganglion. the model system has certainly been helpful in understanding some aspects of trigeminovascular physiology. Although this seems clinically unlikely. which almost certainly subserve a nociceptive function (Table 2). Preclinical studies suggest that CSD may be a sufficient stimulus to activate trigeminal neurons (74). of posterior group Intralaminar complex Periaqueductal gray matter Unknown  insulae  frontal cortex  anterior cingulate cortex  basal ganglia cervical dorsal roots (60). which is blocked by sumatriptan. there are structural changes in the dura mater observed after trigeminal ganglion stimulation. both of which can be released when the trigeminal ganglion is stimulated either in humans or in cats (62). no .73). These include mast cell degranulation and changes in postcapillary venules including platelet aggregation (70. While it is generally accepted that such changes. it is not clear whether this is sufficient in itself or requires other stimulators or promoters. and the serotonin-5HT1B/1D agonist. Neurogenic plasma extravasation can be seen during electrical stimulation of the trigeminal ganglion in the rat (67). Stimulation of the cranial vessels such as the superior sagittal sinus (SSS) is certainly painful in humans (63. and this may contribute in part to this regions’ vulnerability to spreading depression. A limitation of this study was the probable sampling of both retina and choroid elements in rats.288 (114). Sensitization in migraine may be peripheral with local release of inflammatory markers. specific PPE blockers. notably the conformationally restricted analogue of sumatriptan. which is in essence typical migraine (108. Just as dihydroergotamine (DHE) can block trigeminovascular nociceptive transmission (93). which are blocked by sumatriptan (111). which would certainly activate trigeminal nociceptors (73). Clearly.95). In cats. in clinical trials. Compounds that have not shown activity in migraine (86. just as in spontaneous migraine (112). an endothelin antagonist (87). explaining why the aura is so very often seen to commence posteriorly. Sensitization and Migraine While it is highly doubtful that there is any significant sterile inflammatory response in the dura mater during migraine.104). probably at least by a local effect in the trigeminocervical complex (94.106). This finding is consistent with at least third-order neuronal sensitization such as sensitization of thalamic neurons and firmly places the pathophysiology within the central nervous system. were both ineffective inhibitors of CGRP release after SSS stimulation in the cat. and a neurosteroid (88). Human evidence that CGRP is elevated in the headache phase of migraine (103. blockade of neurogenic plasma protein extravasation is not completely predictive of antimigraine efficacy in humans as evidenced by the failure. A particularly interesting aspect is the demonstration of allodynia in the upper limbs. The recent development of nonpeptide. allodynia (89–91). neurokinin-1 antagonists (81–84). vasoactive intestinal polypeptide (VIP) (98. CP122. ipsilateral and contralateral to the pain. again releasing a powerful vasodilator peptide. and chronic paroxysmal hemicrania (107) supports the view that the trigeminovascular system may be activated in a protective role in these conditions. given that choroidal vessels have fenestrated capillaries (80).113). of substance P. 4991w93 (115). Moreover. More likely in migraine is a form of central sensitization. trigeminal ganglion stimulation also increases cerebral blood flow by a pathway traversing the greater superficial petrosal branch of the facial nerve (97).288 (85) and 4991w93 (86). it is clear that some form of sensitization takes place at this time because allodynia is common. DHE can block central sensitization associated with dural stimulation by an inflammatory soup (96). Stimulation of the more specifically vascular pain-producing SSS increases cerebral blood flow (101) and jugular vein CGRP levels (102). which may be classical central sensitization (72) or a form of disinhibitory sensitization with dysfunction of descending modulatory pathways (92). NO-donor–triggered migraine.Pathophysiology of Migraine 85 changes are seen with retinal angiography during acute attacks of migraine or cluster headache (79). About two-thirds of patients complain of pain from non-noxious stimuli. also results in increases in CGRP (110). cluster headache (105.99). however.109). The VIP-ergic innervation of the cerebral vessels is predominantly anterior rather than posterior (100). highly specific CGRP antagonists (116) and the announcement of proof-of-concept for a CGRP antagonist in acute . Neuropeptide Studies Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both CGRP and substance P (62). CP122. and the conformationally restricted analogue of zolmitriptan. while after stimulation of the SSS. Stimulation of the greater occipital nerve for five minutes results in substantial increases in responses to supratentorial dural stimulation.131). the demonstration that some part of this action is postsynaptic with either 5-HT1B or 5-HT1D receptors located nonpresynaptically (140. stimulation of a lateralized structure. and are consistent with the localization of these receptors on peptidergic nociceptors (137). these data suggest convergence of cervical and ophthalmic inputs at the level of the second-order neuron. Moreover. Fos-like immunoreactivity is seen in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in the cat (120) and monkey (121. Moreover. and zolmitriptan (135) can have actions at these second-order neurons that reduce cell activity and suggest a further possible site for therapeutic intervention in migraine. At the same time. These data demonstrate that trigeminovascular nociceptive information comes by way of the most caudal cells. Furthermore. the lack of any effect of CGRP blockers on plasma protein extravasation explains in some part why that model has proved inadequate at translation into human therapeutic approaches. i. sumatriptan (128. This concept provides an anatomical explanation for the referral of pain to the back of the head in migraine. .86 Goadsby migraine (117) firmly establish CGRP receptor antagonism as a novel and important emerging principle for acute migraine. In experimental animals.e. Similarly. the greater occipital nerve. These latter findings are in accord with data using 2-deoxyglucose measurements with SSS stimulation (123). produces Fos expression bilaterally in both cat and monkey brain (122). After meningeal irritation with blood.. Higher Order Processing Following transmission in the caudal brain stem and high cervical spinal cord. and 5-HT1F receptor subtypes (136). experimental pharmacological evidence suggests that some abortive antimigraine drugs such as ergot derivatives (93.129). acetylsalicylic acid (127).94). stimulation of a branch of C2. rizatriptan (134). stimulation of the middle meningeal artery dura mater with the C-fiber–irritant mustard oil sensitizes responses to occipital muscle stimulation (126). one can record directly from trigeminal neurons with both supratentorial trigeminal input and input from the greater occipital nerve. Taken together. the middle meningeal artery. Triptans also influence the CGRP promoter (138) and regulate CGRP secretion from neurons in culture (139). which can last for over an hour (125). information is relayed rostrally. trigeminal nucleus caudalis and C1/2 dorsal horn (124). naratriptan (132.141) offers a prospect of highly anatomically localized treatment options.133). eletriptan (130. a branch of the C2 dorsal root (125). 5-HT1D. HEADACHE PHYSIOLOGY—CENTRAL CONNECTIONS The Trigeminocervical Complex Fos immunohistochemistry is a method for looking at activated cells by plotting the expression of Fos protein (118).122). This action can be dissected out to involve each of the 5-HT1B. This group of neurons from the superficial laminae of trigeminal nucleus caudalis and C1/2 dorsal horns should be regarded functionally as the trigeminocervical complex. increases metabolic activity in the same regions. Conversely. Fos expression is noted in the trigeminal nucleus caudalis (119). in turn. suggesting a hitherto unconsidered locus of action for triptans in acute migraine.148) (Fig. and in SUNCT. 148. Human imaging studies have confirmed activation of thalamus contralateral to pain in acute migraine (147. medial nucleus of the posterior complex. capable of activating the trigeminovascular system as the initiating event in a positive feedback of neurally driven vasodilatation. 1). particularly in the VPM thalamus and in its ventral periphery. These neurons in the VPM can be modulated by activation of gamma aminobutyric acid (GABA) A–inhibitory receptors (144).151). Source: Brain stem changes after Bahra et al. as demonstrated by microiontophoretic application (146). Remarkably.Pathophysiology of Migraine 87 Thalamus Processing of vascular nociceptive signals in the thalamus occurs in the ventroposteromedial (VPM) thalamus. which define the associated symptoms and periodicity of the clinical syndrome. which can be triggered and are. triptans through 5-HT1B/1D mechanisms can also inhibit VPM neurons locally. and perhaps of more direct clinical relevance by propranolol through a b1-adrenoceptor mechanism (145). cluster headache (149). American Headache Society. Pain from cervical inputs that terminate in the trigeminocervical complex accounts for the nontrigeminal distribution of pain in many patients. Figure 1 Illustration of some elements of migraine biology. . Patients inherit dysfunctional brain control systems for pain and other afferent stimuli. Migraine has thus a pain system for its expression and brain centers and modulatory systems. short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (150. Genetic Cartoons Courtesy of Neurology Ambassador Program. and in the intralaminar thalamus (142). Zagami and Lambert (143) have shown by application of capsaicin to the SSS that trigeminal projections with a high degree of nociceptive input are processed in neurons. This area is crucially involved in several primary headaches. and in the dorsal pons. While a 25% overall reduction in cerebral blood flow is seen. as causing migraine-like headache when stimulated in patients with electrodes implanted for pain control. Moreover. including the PAG. near the locus coeruleus. SUNCT (151). . These areas are active immediately after successful treatment of the headache but are not active interictally. the midbrain dorsal raphe nucleus. the main central noradrenergic nucleus.164). What could dysfunction of these brain areas lead to? Animal Experimental Studies of Sensory Modulation It has been shown in the experimental animal that stimulation of nucleus locus coeruleus. extracerebral vasodilatation occurs in parallel (170). PAG is clearly included in the area of activation seen in positron emission tomography (PET) studies in migraineurs (155).and antinociceptive (162). PAG activation in turn feeds back to the trigeminocervical complex with an inhibitory influence (153. Orexinergic neurons in the posterior hypothalamus can be both pro. and with nitrogylcerin-triggered attacks (148. and chronic migraine can develop after a bleed into a cavernoma in the region of the PAG (168). In addition. The activation corresponds with the brain region that Raskin et al. notably cluster headache (2). reduces cerebral blood flow in a frequency-dependent manner (170) through an a2-adrenoceptor–linked mechanism (171). while blockade of P/Q-type voltage-gated Ca2þ channels in the PAG facilitates trigeminovascular nociceptive processing (92).154).88 Goadsby Activation of Modulatory Regions Stimulation of nociceptive afferents by stimulation of the SSS in the cat activates neurons in the ventrolateral periaqueductal gray (PAG) matter (152). and Veloso et al. (165) initially reported. This typical negative feedback system will be further considered below as a possible mechanism for the symptomatic manifestations of migraine. the main serotonin-containing nucleus in the brain stem. can increase cerebral blood flow when activated (173). the clinical features of the premonitory phase (159). Another potentially modulatory region activated by stimulation of nociceptive trigeminovascular input is the posterior hypothalamic gray (156). Similarly. paroxysmal hemicrania (157). CENTRAL MODULATION OF TRIGEMINAL PAIN Brain Imaging in Humans Functional brain imaging with PET has demonstrated activation of the dorsal midbrain. Furthermore. with the local GABAergic system in the PAG still intact (153). offering a further possible region whose dysfunction might involve the perception of head pain. in studies during migraine without aura (155). Welch et al. suggest dopamine neuron involvement. or with a lesion of the pons (169).161). This reduction is maximal in the occipital cortex (172). and other features of the disorder (160. confirmed (166). and hemicrania continua (158). (167) have noted excess iron in the PAG of patients with episodic and chronic migraine. stimulation of PAG will inhibit sagittal sinus-evoked trigeminal neuronal activity in cat (154). Dorsolateral pontine activation is seen with PET in spontaneous episodic (147) and chronic migraine (163). However. and why the involvement of the maxillary division causes facial pain. the basis of the problem must be abnormal central processing of a normal signal. so for that symptom. The convergence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary headache. and its cranial autonomic reflex connections. and many mention a sense of unsteadiness as if they have just stepped off a boat. and is seen in the other primary headaches. WHAT IS MIGRAINE? Migraine is an inherited. but there is much discussion as to how to interpret such changes (175). Some mention otherwise pleasant odors to be unpleasant. the pain pathways are clear. Normal movement of the head causes pain. all its manifestations could be accounted for in a single overarching pathophysiological hypothesis of a disturbance of subcortical sensory modulation systems (188). Perhaps the most reliable theme is that the migrainous brain does not habituate to signals in a normal way (176–179). an event related potential. aura can be experienced without pain at all. episodic disorder involving sensory sensitivity. contingent negative variation (CNV). They complain of discomfort from normal lights and the unpleasantness of routine sounds. there is no evidence at all after 4000 years that it occurs in more than 30% of migraine patients. is abnormal in migraineurs compared to controls (180). While it seems likely that the trigeminovascular system. Patients complain of pain in the head that is throbbing. Attempts to correlate clinical phenotypes with electrophysiological changes (183) may enhance further studies in this area. Changes in CNV predict attacks (181) and preventive therapies alter and normalize such changes (182). hypersynchronization (187). If migraine was basically an attentional problem with changes in cortical synchronization (186). or its treatment (185). and phonophobia and osmophobia. The genetics of channelopathies is opening up a plausible way to think about the episodic nature of migraine. Similarly.184). Perhaps electrophysiological changes in the brain have been mislabelled as hyperexcitability whereas dyshabituation might be a simpler explanation. ACKNOWLEDGMENTS The work of the author has been supported by the Wellcome Trust.Pathophysiology of Migraine 89 Electrophysiology of Migraine in Humans Studies of evoked potentials and event-related potentials provide some link between animal studies and human functional imaging (174). Migraine aura cannot be the trigger. where is the lesion. Authors have shown changes in neurophysiological measures of brain activation. but there is no reliable relationship between vessel diameter and the pain (31. act as a feed-forward system to facilitate the acute attack. There is not a photon of extra light that migraine patients receive over others. the fundamental problem in migraine is in the brain. what is actually the pathology? If one considers what patients say. for example. the ophthalmic division of the trigeminal nerve subserves sensation within the cranium and explains why its involvement at the top of the head causes headache. then perhaps they tell us the answer to this question. the trigeminal-autonomic reflex (99). . although having been nowhere near the water! The anatomical connections of. Unravelling its basis will deliver great benefits to patients and considerable understanding of some of the very fundamental neurobiological processes. Ducros A. Cephalalgia 1996. Nomenclature of voltage-gated calcium channels. Jurkat-Rott K.9Mb region on chromosome 1q23. Marconi R. Haan J. Olesen J. Teh BT. 18. 4. Hum Genet 1995. Sangiorgi S. et al. 8. New York: Elsevier. Ophoff RA. Terwindt GM. 62:1857–1861. et al. Marconi R. Ann Neurol 2003. Joutel A. Dreier JP. 14. 5:40–45. 22:21–26. Familial hemiplegic migraine: a clinical comparison of families linked and unlinked to chromosome 19. Am J Hum Genet 1995. Amstelaedami: Henricum Wetstenium.). Genetic heterogeneity of familial hemiplegic migraine. 10. Ann Neurol 1999. Familial cerebellar periodic ataxia without myokymia maps to a 19-cM region on 19p13. 13:389–394. 1:37–43. 9. Silburn P. 22. 96:244–249. Neuron 2000. et al. 2. et al. 1682.90 Goadsby REFERENCES 1. Ducros A. Kors EE. Ferrari MD. 16:153–155. Genomics 1994. Clin Neurol Neurosurg 1994. Goadsby PJ. 17. et al. Vergouwe MN. 19. De Fusco M. Evidence of a genetic factor in migraine with aura: a population based Danish twin study. Russell MB. et al. Hottenga JJ. Cortelli P. 16. 346:257–270. The International Classification of Headache Disorders (2nd ed. Lindblad K. Silberstein SD. London: Martin Dunitz. Goadsby PJ. Complex segregation analysis with pointers. 3. Ophoff RA. Ophoff RA. Biousse V. Nat Genet 1993. Campbell KP. Ann Neurol 2003. Russell MB. Goadsby PJ. Lipton RB. Neurology 2004. 55:1166–1172. et al.Kþ-ATPase pump gene ATP1A2 associated with Familial Hemiplegic Migraine and Benign Familial Infantile Convulsions. Vanmolkot KRJ. Nat Genet 2003. 33:192–196. Lalouel JM. Olesen J. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. et al. Headache Classification Committee of The International Headache Society. 23. 7. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Vahedi K. Iselius L. Bos PL. 31:312–321. 17:683–701. Genetic epidemiology of migraine and cluster headache. Sandkuijl LA. Familial hemiplegic migraine type 2 is linked to 0. Goadsby PJ. 5. Mechanism and Management of Headache. Genetic heterogeneity of familial hemiplegic migraine. Lancet Neurol 2002. 96:726–730. Am J Hum Genet 1994. 6. 2002. Ertel EA. Morton NE. Joutel A. Lipton RB. 56:1443–1449. 25:533–535. A gene for familial hemiplegic migraine maps to chromosome 19. 53:376–381. Kyvik KO. Joutel A. 20. Novel mutations in the Naþ. N Engl J Med 2001. Cephalalgia 2004. Terwindt GM. 21. Cell 1996. Ulrich V. Aridon P. Cephalalgia 1993. 45:242–246. Migraine-current understanding and treatment. 2005. Investigation of the inheritance of migraine by complex segregation analysis. et al. Haploinsufficiency of ATP1A2 encoding the Naþ/Kþ pump a2 subunit associated with familial hemiplegic migraine type 2. Cephalalgia 1997. Eijk Rv. 24:1–160. et al. Russell MB. Familial hemiplegic migraine in The Netherlands. Freilinger T. 345:17–24. Pathophysiology of cluster headache: a trigeminal autonomic cephalalgia. 15. Gervil M. . 13. Denier C. et al. Headache in Clinical Practice. et al. 54:360–366. Opera Omnia. De Fusco M. et al. Variability of familial hemiplegic migraine with novel A1A2 Naþ/Kþ-ATPase variants. 12. Willis T. N Engl J Med 2002. Haan J. Mochi M. Bousser MG. Terwindt GM. Hum Hereditary 1981. 24. 87:543–552. Silvestri L. 11. Testing models for genetic determination in migraine. Harpold MM. Lance JW. Ferrari MD. The Dutch Migraine Genetics Research Group. Kaube H. Larsen B. Knight YE. Cephalalgia 1999. 12:221–228. Patterns of cerebral integration indicated by the scotomas of migraine. Parsons AA. Arch Neurol Psychiatr 1941. Upton N. Migraine with aura and migraine without aura: an epidemiological study. Migraine aura: a knock-in mouse with a knock-out message. Kummer Rv. 31. Read SJ. Olesen J. In: Rose MR. 28:791–798. 7:359–390. 39. Lassen NA. Sakai F. 9:344–352. SB-220453. Olesen J. Effect of cortical spreading depression on activity of trigeminovascular sensory neurons. 36. Lauritzen M. Migraine. Ann Neurol 1983. Proc Natl Acad Sci (USA) 2001. Storer RJ. 41. Pizzorusso T. 46. 98: 4687–4692. inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat. Repetitive cortical spreading depression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453. Lambert GA. et al. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Neuron 2004. 43. et al. et al. Cephalalgia 2000. The changes of regional cerebral blood flow during the course of classical migraine attacks. Headache 1979. Ferrari MD. Migraine: a multifactorial. Neuron 2004. aura. 35. Skyhoj-Olsen T.Pathophysiology of Migraine 91 25. 46:331–339. episodic neurovascular channelopathy?. 7:391–396. Cephalalgia 1999. Cephalalgia 1992. a potential novel antimigraine compound. Cephalalgia 1999. 34. Lauritzen M. Weisskoff RM. et al. J Neurophysiol 1944. Hunter AJ. Ann Neurol 2001. Channelopathies of the Nervous System. Friberg L. 45. Timing and topography of cerebral blood flow. aura and cortical spreading depression: why are we still talking about it?. 32. Ann Neurol 1981. Ann Neurol 1998. 238:23–26. A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Smith MI. Lauritzen M. Leao AAP. et al. 30. Oxford: Butterworth Heinemann. 117:199–210. 40. 27. 38. Goadsby PJ. and headache during migraine attacks. Goadsby PJ. Wu O. 20:92–99. Dalkara T. Lashley KS. Cerebrovascular CO2 reactivity in migraine: assessment by transcranial Doppler ultrasound. Storer RJ. Pial circulation and spreading activity in the cerebral cortex. Goadsby PJ. Abnormal cerebrovascular reactivity in patients with migraine and cluster headache. 44. Read SJ. Sorensen AG. 19:257–266. Ann Neurol 1990. Cutrer FM. Xaidara A. . Smith MI. Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat. Swoboda KJ. 41:701–710. Eur Neurol 1994. Ann Neurol 2004. Pathophysiology of the migraine aura. van den Maagdenberg AMJM. 55:276–280. Kanavakis E. 43:25–31. Zagami AS. Bolay H. Olesen J. 2001:274–292. Sanchez del Rio M. Rasmussen BK. May A. Ann Neurol 2004. 26. 47. 13:633–641. Spreading depression of activity in cerebral cortex. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. 49:4–6. Griggs RC. 28. 33. Moskowitz MA. 41:679–680. Brain 1994. Kaube H. Harer C. 37. 19:592–597. Michalicek J. 42. 29. Hoskin KL. The spreading depression theory. Pietrobon D. Paulson OB. Goadsby PJ. Leao AAP. J Neurol 1991. Skyhoj-Olsen T. 19:631–638. J Neurophysiol 1944. Hadjikhani N. Meyer JS. 20:546–553. 34:30–35. 55: 884–887. Perfusion-weighted imaging defects during spontaneous migrainous aura. Goadsby PJ. Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. eds. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. et al. Chan WN. Dural headache and the innervation of the dura mater. 20:538–545. Saito K. Neurology 1960. 8:801–815. Diamond M. Svendgaard NA. Thomsen LL. J Neurol 2004. Saper JR. 225:187–192. a comparison with sumatriptan. Dahlof C. de Vries R. New targets for antimigraine drug development. 58. In: Goadsby PJ. Neurology 2005. Ekman R. Edvinsson L. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. Topiramate in migraine prevention: results of a large controlled trial. 65. Kingman T. J Neurosci 1987. Parsons AA. Cephalalgia 2004. Norregaard TV. et al. Gillespie SA. 52. 60. 69. Topiramate inhibits trigeminovascular neurons in the cat. Topiramate for migraine prevention: a randomized controlled trial. MaassenVanDenBrink A. Penfield W. Silberstein SD. 64:A150–A151. J Comp Neurol 1984. Topiramate inhibits cortical spreading depression in rat and cat: a possible contribution to its preventive effect in migraine. Waeber C. 10:555–563. Olesen J. Thompson M. Headache and Other Head Pain. Iversen HK. Yu X. 24:1049–1056. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. McNaughton F. Cutrer FM. Neurosci Lett 1985. Tfelt-Hansen P. 132:1549–1557. The effect of propranolol on glyceryltrinitrate-induced headache and arterial response. 7:4129–4136. 24:783–784. Ekman R. 61. 55. Feindel W. Arch Neurol Psychiatr 1940. 291:965–973. The prophylactic effect of valproate on glyceryltrinitrate induced migraine. 24:1076–1087. Saxena PR. 56. Goadsby PJ. Akerman S. Markowitz S. Wolff HG. Arch Neurol 2004. Cephalalgia 2004. The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium. 24:576–585. 68. Moskowitz MA. Thomsen LL. Cutrer FM. McNaughton FL. et al. Penfield W. McCulloch J. . SUMATRIPTAN: a receptor-targeted treatment for migraine. Raval P. Tvedskov JF. 67. Neurol Clin 1990. Tvedskov JF. 54. trigeminal and spinal ganglia investigated with retrograde and anterograde WGA-HRP tracing in the rat. 57. Topiramate has a locus of action outside of the trigeminocervical complex. Upton N. Brandes JL. Storer RJ. Basic mechanisms in vascular headache. Limmroth V. Origin and distribution of cerebral vascular innervation from superior cervical.92 Goadsby 48. 19:695–708. Moskowitz MA. 51. Moskowitz MA. Moskowitz MA. Bingham S. Liu-Chen L-Y. Ann Neurol 1988. A double-blind study of SB-220453 (Tonerbasat) in the glyceryltrinitrate (GTN) model of migraine. Moskowitz MA. 1997:59–72. Cephalalgia 2004. Gibson A. Annu Rev Med 1993. Storer RJ. et al. Cephalalgia 2004. Co-localization of retrogradely transported wheat germ agglutinin and the putative neurotransmitter substance P within trigeminal ganglion cells projecting to cat middle cerebral. Upton N. Olesen J. 62. eds. 44:43–75. Arbab MA-R. Goadsby PJ. 63. 59. 66. Neuroscience 1986. Iversen HK. Goadsby PJ. 251:943–950. 53. Read S. Wiklund L. Br J Pharmacol 2001. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. JAMA 2004. Cephalalgia 2000. Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reflexes. Philadelphia: Butterworth-Heinemann. Schmitt J. 44:145–154. 23:193–196. 24:875–882. The tentorial nerves and localization of intracranial pain in man. Diener HC. 1948. van den Broek RW. Goadsby PJ. Uddman R. Wiliams P. New York: Oxford University Press. 61:490–495. Topiramate in migraine prophylaxis— results from a placebo-controlled trial with propranolol as an active control. Iversen HK. Parsons AA. 49. Jacobs D. Cephalalgia 2004. 64. Silberstein SD. Neto W. Headache. Tvedskov JF. 50. Edvinsson L. 62:131–136. Gillies S. 384:560–563. Buzzi MG. 85. 73. Headache 1998. Diener H-C. Burstein R. Schaible H-G. Reuter U. 84. Jaworski A. Richter F. Diener HC. Retinal plasma extravasation can be evoked by trigeminal stimulation in rat but does not occur during migraine attacks. potent. Burstein R. Moskowitz MA. Buzzi MG. 23:183–185. is not effective in the treatment of migraine attacks. Connor HE. Cephalalgia 1999. Averbeck B. Endothelin antagonist bosentan blocks neurogenic inflammation. Nature 1996. Olsen UB. Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells.030) in the acute treatment of migraine. Boas DA. Goadsby PJ. . PAIN. Saper JR. The GR205171 Clinical Study Group. Neuroscience 1991. Britch K. but is not effective in aborting migraine attacks. in the acute treatment of migraine. The RPR100893 Study Group.Pathophysiology of Migraine 93 70. Hansen AJ. Dimitriadou V. CNS penetrating NK1 receptor antagonist in the acute treatment of migraine. Possible mechanism of c-fos expression in trigeminal nucleus caudalis following spreading depression. Goldstein DJ. et al. Cephalalgia 1998. 67:375–378. 75. and nociception that might cause migraine headache? Ann Neurol 2001. Yamamura H. Ingvardsen BK.288 blocks neurogenic inflammation. A double-blind study of ganaxolone in the acute treatment of migraine headaches with or without an aura in premenopausal females. 77. Wessing A. Sensitization of meningeal sensory neurons and the origin of headaches. Ward P. Hansen AJ. Pain 1998. 74. Data J. Clinical evaluation of a novel. Pain 1997. 83. Wang O. 41:7–13. 87. Jones R. Cephalalgia 2003. Diener HC. In vitro model of the outer blood-retina barrier. Hargreaves RJ. CP-122. but is not effective in aborting migraine attacks: results of two controlled clinical studies. 80. Dimitriadou V. Bolay H. 13:1167–1177. 82. Steuer H. Brain Res Brain Res Protoc 2004. Is there a correlation between spreading depression. a substance-P antagonist. Olsen UB. Cephalalgia 1998. Block GA.298 (a prodrug of the NK1 receptor antagonist L-754. 76. 71. Malick A. Kraig RP. Bertin L. Stoltz R. 88. Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat dura mater and tongue following antidromic trigeminal stimulation.. 17:785–790. Mathew NT. Strassman AM. Comment on Ingvardsen et al. Ellis P. 48:187–203. 4991W93 Investigator Group. Roon K. Neocortical spreading depression provokes the expression of C-fos protein-like immunoreactivity within the trigeminal nucleus caudalis via trigeminovascular mechanisms. Laursen H. A placebo-controlled. Efficacy and tolerability of the neurogenic inflammation inhibitor. 78. Lowy MT. Moskowitz MA. Dunn AK. 13:26–36. Theoharides TC. Beattie DT. Wallnoefer A. Huang Z. Ferrari MD. Nat Med 2002. Diener HC. 72. Nozaki K. Brain 1998. et al. 18:392. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. 72:407–415. 76:266–267. Raymond SA. 4991W93. 8:136–142. in-clinic study to explore the preliminary safety and efficacy of intravenous L-758. Stoll D. Cephalalgia 1997. Moskowitz MA. 18:407. RPR100893. Panebianco D. 44:97–112. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Strassman AM. 81. Earl NL. Shepheard S. J Neurophysiol 1998. Theoharides TC. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. 79. 19:357. Silberstein SD. Ingvardsen BK. Gijsman HJ. 38:380. Ebersberger A. 72 (1997) 407–415—reply to Moskowitz et al. 79:964–982. Westergaard N. Cephalalgia 1997. neurogenic inflammation. 17:245. 121:1231–1237. May A. Pain 1996. Moskowitz MA. May A. Laursen H. Schlosshauer B. 86. Norman B. Neuroscience 1992. J Neurosci 1993. McDonald SA. Sarchielli P. An association between migraine and cutaneous allodynia. Brain 1997. Increase in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerininduced cluster headache attack. Brain 2000. Selby G. Knight YE. Edvinsson L. 99. 60:119–123. 106:461–470. Macdonald GJ. 90. Boers P. 15:384–390. The spinal cord processing of input from the superior sagittal sinus: pathway and modulation by ergot alkaloids. Cephalalgia 1995. 253:R270–R274. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. Oshinsky M. 95. Yarnitsky D. Kaube H. Goadsby PJ. Neurology 2005. Pain 1989. 110. Goadsby PJ. et al. Observations on 500 cases of migraine and allied vascular headache. 10:89–96. 100. Comparative effects of stimulation of the trigeminal ganglion and the superior sagittal sinus on cerebral blood flow and evoked potentials in the cat. 106. 19:115–127. Zsombok T. Goadsby PJ. A c-Fos and electrophysiology study. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Lowy AJ. Brain Res 1988. Ransil BJ. Edvinsson L. J Neurol. 23:23–32. Geppetti P. Duckworth JW. 110:675–680. Goadsby PJ. Goadsby PJ. Effect of dihydroergotamine (DHE) on central sensitisation of neurons in the trigeminal nucleus caudalis. Floridi A. Basic characteristics. Neurosurg Psychiatr 1960.94 Goadsby 89. Goadsby PJ. 109. Kaube H. 123:1703–1709. Brain Res 1985. Goadsby PJ. Olesen J. The development of cutaneous allodynia during a migraine attack. Neuropeptides 1990. 107. 94. et al. 117:427–434. Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. 92. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. 120:2171–2177. 105. Matsuyama T. Neuropeptide changes in a case of chronic paroxysmal hemicrania—evidence for trigemino-parasympathetic activation. Cephalalgia 1996. 16:69–75. Hoskin KL. Goor-Aryeh I. Modos EA. 453:143–149. Lambert GA. Pozo-Rosich P. May A. Burstein R. Iversen HK. J Cereb Blood Flow Metab 1999. Brain 1996. Intravenous nitroglycerin as an experimental headache model. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. 119:249–256. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. 16: 448–450. Fanciullacci M. Matsumoto M. Zagami AS. 101. Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats. 47:614–624. 38:17–24. Juhasz G. Goadsby PJ. Edvinsson L. Kaube H. 102. 93. Edvinsson L. Duckworth JW. Figini M. et al. Neuroscience 1983. Brain 1994. 98. Ann Neurol 1990. Goadsby PJ. Shiosaka S. 104. Zagami A. Gallai V. Bajwa ZH. Human in vivo evidence for trigeminovascular activation in cluster headache. 22:1–6. 103. Yarnitsky D. . Alessandri M. 329:285–288. Ann Neurol 2000. Am J Physiol 1987. P/Q-type calcium channel blockade in the PAG facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 2002. The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation. Goadsby PJ. Cutrer MF. Pain 2003. Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Ekman R. Storer RJ. Overall distribution of vasoactive intestinal polypeptide-containing nerves on the wall of the cerebral arteries: an immunohistochemical study using whole-mounts. Burstein R. Pain 2004. 91. 597:321–330. Michelacci S. Zagami AS. Extracranial vasodilatation mediated by VIP (vasoactive intestinal polypeptide). 28:183–187. 64:A151. Pain 1995. 97. Tfelt-Hansen P. Goadsby PJ. Lance JW. Lambert GA. 108. 96. Angus-Leppan H. Brain Res 1992. Afridi S. Goadsby PJ. Bartsch T. 49:669–680. Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Levy D. Bartsch T. Proc Natl Acad Sci USA 2004. 47:238–241. Hoskin KL. 33:48–56. Hoskin KL. Hoskin KL. Hoskin KL. Blockade of CGRP release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122. 33:41–46. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Goadsby PJ.288. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Goadsby PJ. Kaube H. Goadsby PJ. 129:420–423. 125:1496–1509. 112. Hallermayer G. N Engl J Med 2004. Increased responses in trigeminocervical nociceptive neurones to cervical input after stimulation of the dura mater. Knight YE. Kaube H. Goadsby PJ. Pharmacological profile of BIBN4096BS. 119. Olesen J. Neuroscience 1992. Keay KA. Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. Brain 1991. et al. Kaube H. Boccalini P. 126. 194:579–588.Pathophysiology of Migraine 95 111. 116. Annu Rev Neurosci 1991. 4991W93 inhibits release of calcitonin generelated peptide in the cat but only at doses with 5HT1B/1D receptor agonist activity. Neuropharmacology 2001. 124. 25:179–183. 113. Juhasz G. 120. Wu D. Pain 1997.288. 122. 190:367–375. Morgan JI. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. 126:1801–1813. Burstein R. Goadsby PJ. Goadsby PJ. Goadsby PJ. No acute antimigraine efficacy of CP-122. Jakubowski M. 33:541–550. Bagdy G. Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. 118. 14:421–451. Goadsby PJ. Olesen J. Doods H. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists. 629:95–102. Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. 128. Bandler R. Brain Res 1993. Calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks. Br J Pharmacol 2000. 40:520–525. Neuropeptides 1999. Edvinsson L. Bartsch T. Brain 2003. Zsombok T. Knight YE. Headache 1993. Goadsby PJ. the first selective small molecule CGRP antagonist. Nozaki K. Moskowitz MA. Goadsby PJ. J Anat 1999. Br J Pharmacol 1993. 125. Cephalalgia 2005. 127. Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. . 109:788–792. Zagami A. Ann Neurol 2000. Edvinsson L. 123. Curran T. 117. et al. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. Knight YE. Brain 2002. Jakab B. Szolcsanyi J. 73:23–28. Diener HC. 350:1104–1110. Edvinsson L. 129. 114. 115. 114:1001–1011. Hoskin KL. Goadsby PJ. a highly potent inhibitor of neurogenic inflammation: results of two randomized doubleblind placebo-controlled clinical trials. J Anat 1997. Roon KI. Diener H-C. Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Nemeth J. Ann Neurol 1993. et al. Husstedt I-W. Zagami AS. 121. Goadsby PJ. 101:4274–4279. Hoskin KL. In: Rose FC. Hypothalamic activation in cluster headache attacks. Goadsby PJ. Differential effects of low dose CP122. Craniovascular application of capsaicin activates nociceptive thalamic neurons in the cat. Goadsby PJ. Cephalalgia 2004. Hill RG. 67:355–359. 132. Goadsby PJ. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. Frackowiak RSJ. Evidence for postjunctional serotonin (5-HT1) receptors in the trigeminocervical complex. J Neurosci 1999. 19:3423–3429. Shields KG. Sharma RV. Lambert GA. Buchel C. Lambert GA. Goadsby PJ. Classey JD. 5-HT1Dand 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. 135. May A. 139. Zagami AS. 147. Frackowiak RSJ.96 Goadsby 130. Basbaum AI. Hoskin KL. 148. Goadsby PJ. 1991:169–171. Boers PM. Inhibition of trigeminal neurons after intravenous administration of naratriptan through an action at the serotonin (5HT1B/1D) receptors. Rizatriptan has central antinociceptive effects against durally evoked responses. Durham PL. Evidence for 5-HT1B. Cumberbatch MJ. 140. Kaube H. 82:15–22. London: Smith-Gordon and Co Ltd. Goadsby PJ. Fields HL. 953:181–188. Suppression by eletriptan of the activation of trigeminovascular sensory neurons by glyceryl trinitrate. Hoskin KL. Hoskin KL. GABA receptors modulate trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Brainstem activation specific to migraine headache. Russo AF. Russo AF. Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. Lancet 1998. Friston K. . Lancet 2001. 50:804–807. Hargreaves RJ. 141. 122:918–922. Cephalalgia 2003. Hill RG. 62:1270–1275. Goadsby PJ. Kalisch R. Matharu MS. 142. 138. Naratriptan modulates trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Akerman S. Goadsby PJ. Goadsby PJ. Durham PL. Cephalalgia 2004. Br J Pharmacol 1997. Ann Neurol 2001. Bahra A. Skinner K. Lasalandra MP.and postsynaptic 5-HT1D and 5-HT1F receptor immunoreactivity (IR) in the rat trigeminocervical complex (TCC) new therapeutic possibilities for the triptans. Electron microscopic demonstration of pre. 328:37–40. Storer RJ. 136. 24:148. 18:659–664. 23:10988–10997. Ahan AH. Zagami AS. 133. Shields KG. Cohen AS. 143. Donaldson C. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine? Pain 1996. Cumberbatch MJ. Goadsby PJ. Knight YE. Functional MRI in SUNCT shows differential hypothalamic activation with increasing pain. Hargreaves RJ. Pain 1999. 149. 150. Neuroscience 2003. 128:86–97. 144. ed. Cephalalgia 1998. 134. Bahra A. Shields KG. Arch Neurol 2005. Kaube H. Eur J Pharmacol 1997. Afridi S. Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. Zagami AS. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 2005. Neurosci Lett 1991. J Neurosci 2003. Brain Res 2002. 357:1016–1017. 122:491–498. New Advances in Headache Research: 2. Goadsby PJ. Goadsby PJ. 145. Buchel C. 17:9545–9553. 137. Cephalalgia 2004. 146. 24:1098–1099. Akerman S. Differential effects of the 5HT1B/1D receptor agonist naratriptan on trigeminal versus spinal nociceptive responses. Matharu MS. et al. J Neurosci 1997. Potrebic S. Classey JD. 23:728. A PET study in spontaneous migraine. Stimulation of the superior sagittal sinus increases metabolic activity in cat thalamus. Goadsby PJ. 131. 352:275–278. Giffin NJ. Maneesi S. 121:187–190.288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat. 24:1098. et al. 16:500–505. Welch KM. J . 74:680–682. 109:367–378.Neurol. Goadsby PJ. McGonigle DJ. Frackowiak RSJ. Lambert GA. 153. Brain stem activation in spontaneous human migraine attacks. The electrophysiology of migraine. Goadsby PJ. Lambert GA. Brain 2004. Veloso F. Cohen AS. Dopamine and migraine. Goadsby PJ. 106:793–800. Neurovascular headache and a midbrain vascular malformation— evidence for a role of the brainstem in chronic migraine. 156. Nagesh V. 1:658–660. Brain Res 1989. Lance JW. 41:629–637. Curr Opin Neurol 2002. Headache 1987. Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. 173. 162. Arne-Bes MC. Pain 2004. Matharu MS. Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Goadsby PJ. Hosobuchi Y. The mechanism of cerebrovascular vasoconstriction in response to locus coeruleus stimulation. 157. 160. et al. 336:113–116. Guell A. 38:507–515. Zagami AS. Posterior hypothalamic and brainstem activation in hemicrania continua. Kumar K. Afridi S. Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Goadsby PJ. Bartsch T. 31:365–371. New onset migraine with a brainstem cavernous angioma. Brain 2005. Neurology 1997. 46:791–793. 168. The periaqueductal gray matter modulates trigeminovascular input: a role in migraine? Neuroscience 2001. Goadsby PJ. Bulmer DCE. Bartsch T. Periaqueductal grey matter dysfunction in migraine: cause or the burden of illness? Headache 2001. 167. Lasalandra M. Buchel C. Neurosurg Psychiatr 2003. Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Posterior hypothalamic activation in paroxysmal hemicrania using PET. Goadsby PJ. Aurora S. Premonitory symptoms in migraine: an electronic diary study. May A. Giffin NJ. Neurology 2003. Jonkman A. May A. In press. 15: 303–309. Goadsby PJ. Hoskin KL. 476:71–77. Headache 1998. Toth C. 154. Benjamin L. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. Neurosci Lett 2003. Lasalandra MP. Levy MJ. 197:29–35. Knight YE. Weiner RL. Goadsby PJ. Lance JW. Lambert GA. Goadsby PJ. 165. Limmroth V. Knight YE. Bahra A. 164. et al. Trigeminal antinociception induced by bicuculline in the periaqueductal grey (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. 161. Brain Res 1985. Dopaminergic hypersensitivity in migraine: a diagnostic test? La Nouvelle Presse Medicale 1982. Cohen AS. Ruggiero L. 60:935–940. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Knight YE. Goadsby PJ. Giffin NJ. Cephalalgia 2002. 11:1475–1478. et al. J Anat 2001. Frackowiak RSJ. 49:650–656. Bartsch T.Pathophysiology of Migraine 97 151. Goadsby PJ. 169. Headache may arise from perturbation of brain. Bes A. Lee L. Low frequency stimulation of the locus coeruleus reduces regional cerebral blood flow in the spinalized cat. Headache secondary to deep brain implantation. 172. Cephalalgia. Goadsby PJ. Matharu MS. 166. Weiller C. 174. Ann Neurol 1999. 44:462–463. Gelman N. 155. Geraud A. Ward N. Matharu MS. Goadsby PJ. Frackowiak RSJ. Levy MJ. Differential modulation of nociceptive dural input to [hypocretin] Orexin A and B receptor activation in the posterior hypothalamic area. Lipton RB. 158. 249:247–254. Headache 1991. Headache 2004. Kaube H. Duckworth JW. Brain Res 1982. 171. 128:932–939. Lamb S. Matharu MS. 326:213–217. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. . Turner R. Raskin NH. Ward N. Neurobiol Dis 2004. 127:220–230. Peroutka SJ. 163. Afridi S. 22:107–111. 170. 27:416–420. 159. Nat Med 1995. 152. Schoenen J. Cephalalgia 2003. the contingent negative variation. Timsit-Berthier M. 182. Sandor PS. 257:73–76. Goadsby PJ. 178. Wang W. Synchrony: a neural mechanism for attentional selection?. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90. Olesen J. Afra J. Curr Opin Neurobiol 2002. Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. Kaube H. 17:849–854. Habituation of visual and intensity dependence of cortical auditory evoked potentials tend to normalise just before and during migraine attacks. Hsiao SS. Eur J Neurol 1995. Delwaide PJ. 2:115–122. Eppe T. Schoenen J. 5:34–35. Gerber WD. 126:241–247. Interictal potentiation of passive ‘‘oddball’’ auditory eventrelated potentials in migraine. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. J Neurol Sci 1996. Johnson KO. Birk S. Maertens de Noordhout A. et al. Wang W. 177. Schoenen J. 185. Cephalalgia 1993. Angelini L. Cephalalgia 1985. Phys Rev Lett 2004. 93:038103-1–038103-4. 180. Contingent negative variation: methods and potential interest in headache. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Cephalalgia 2000. 184. Goadsby PJ. Cephalalgia 1998. 183. 24: 1095–1096. Albert A. 23:565–566. 18:261–265. Kropp P. May A. Afra J. Schoenen J. 20:347. 181. Zomig). Limmroth V. 186. Migraine pathophysiology: the brainstem governs the cortex. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. 13:28–32. Schoenen J. Neurosci Lett 1998. Ambrosini A. Diener HC. Kruuse C. 187. Thomsen LL. Clin Neurophysiol 2003. 179. Contingent negative variation (CNV) in migraineurs before and during prophylactic treatment with beta-blockers. 114:955–972. 138:60–65. Introduction of a clinical scoring system for migraine research applied to electrophysiological studies. Niebur E. Steady-state visual evoked potentials and phase synchronization in migraine patients. Auerbach P. Cephalalgia 1997. Wosnitza G. Proietti-Cecchini A. 176. . Schoenen J. Gantenbein A. Prediction of migraine attacks using a slow cortical potential. de Tommaso M. Cephalalgia 2004. 12:190–194. Schoenen J. Timsit-Berthier M. Guido M. Maertens de Noordhout A. Sandor P. Brain 2003.98 Goadsby 175. 188. Jefferson Headache Center.S.8 Allodynia and Sensitization in Migraine William B. Avi Ashkenazi Department of Neurology. Allodynia is the abnormal experience of pain in response to normally nonpainful stimuli. Philadelphia. In theory and in practice. Thomas Jefferson University. the blood vessels. Young Department of Neurology and Inpatient Program. The first references to migraine date back to Sumerian times (1). but related. INTRODUCTION Migraine is a common disorder that has been recognized since the earliest recorded times. Thomas Jefferson University. or described only as abnormal sensitivity when combing or brushing the hair. or in second or higher order neurons within the central nervous system. Pennsylvania. types of sensory system sensitization. U. Furthermore. Even during these early times. each of these abnormal sensory responses could be due to changes in the first-order sensory neuron. less likely. U. Central sensitization occurs when central 99 . Hyperalgesia is a heightened pain response to noxious stimuli. Cutaneous allodynia accompanying a headache attack was perhaps first described by Liveing in 1873 (2). Throbbing head pain is probably due to peripheral sensitization of the first-order trigeminal neuron innervating the meninges or. and finding effective treatments have become a priority in current headache research. preventing its development. Thomas Jefferson University.A. In 1960.A.A. Oshinsky Department of Neurology and Preclinical Research. Understanding the mechanisms of allodynia. migraine symptoms were noted to include more than just pain. Selby writes: ‘‘This may be so severe as to prevent the patient from lying on the affected side. allodynia was found to be associated with acute attack refractoriness. Michael L. A number of terms are used to describe different. Pennsylvania. Jefferson Headache Center. U. Jefferson Headache Center. Selby and Lance (3) noted that 65% of their patients complained of cutaneous allodynia in the form of scalp tenderness. Philadelphia. Philadelphia.’’ Cutaneous allodynia has recently been linked to sensitization of neurons in the trigeminal nucleus caudalis (TNC) in animal models of migraine.S.S. Pennsylvania. and the dura mater.. Transitions between these three states demonstrate the functional plasticity of the nervous system. to the cerebral cortex. dorsal horn excitability can be increased. The somatosensory system can be suppressed by descending inhibition from neurons in the brain stem. vibration. These structural alterations result in lasting changes in sensory processing. localized pain. Alternatively. brief bursts of nociceptor activity sensitize dorsal horn neurons. These afferents have a nociceptive function. neurons involved in pain transmission become more readily activated by peripheral sensory stimulation. their axons may atrophy. The primary afferent input to the dorsal horn is carried by large. In this state. Central sensitization is normally initiated by C-fiber input.g. and an expansion of the receptive fields of dorsal horn neurons (6–13). peripheral inflammation. The nervous system can. however. and coolness. Pain signals from these structures are processed in second-order neurons of the caudal trigeminal nucleus and the C1/C2 dorsal horns. enabling fight-or-flight reactions in the presence of major injury. Nerve cells may die. SENSORY PROCESSING BY THE NERVOUS SYSTEM The anatomic and physiologic relationships of the trigeminovascular system underlie important aspects of migraine symptom generation. whereas a high-intensity stimulus activating a primary afferent nociceptor will result in transient. an increase in responsiveness. These sensory neurons then project rostrally to the thalamus and. a low intensity stimulus will produce an innocuous sensation. SENSITIZATION OF THE DORSAL HORN Repeated. This central sensitization causes a state shift in the sensory system. and the number and morphology of glial cells can change. Peripheral tissue injury. Sensory processing occurs at the dorsal horn and at higher levels. manifested as a reduction in threshold. the large venous sinuses. which transmit noxious and thermal information. This allows for distinction between damaging and nondamaging stimuli (5). Cutaneous allodynia is thought to be due to changes in first. In a normal state. e. finally. When this occurs.or second-order sensory neurons or in higher order sensory neurons. the pial vessels. and by smaller. more slowly conducting. undergo structural reorganization. such as touch. and unmyelinated C fibers. and damage to the central or peripheral nervous system may all cause sensitization of the dorsal horn and the transition into this state. Myelinated and unmyelinated fibers arising from the ophthalmic division of the trigeminal nerve innervate the large cerebral vessels. fast-conducting Ab-fibers. new axon terminals may sprout and form novel connections. warmth. pressure. low-intensity stimuli acting via low-threshold afferents produce the sensation of pain (cutaneous allodynia). in the thalamus. The sensitized state functions to protect injured body parts from suffering further tissue injury. Migraine pain is thought to originate from activation of nociceptors in intracranial structures combined with reduced activity of endogenous pain-control pathways (4). a high-intensity stimulus activates nociceptors but fails to cause the sensation of pain. which transmit non-noxious sensory information. which are maladaptive and pathological (5). . thinly myelinated Ad-fibers.100 Young et al. When activated. blocks prostaglandin production and has analgesic. adenosine triphosphate (ATP). supraspinal regions of the brain are implicated in maintaining sensitization in the dorsal horn. acting at a spinal NMDA receptor. anti-inflammatory. Upon recovery from the injury or inflammation. spinal nitric oxide (NO). and an extracellular signaling pathway mediated by the release of glutamate. Local neuronal transmitters (ATP.Allodynia and Sensitization in Migraine 101 This can be demonstrated by applying C-fiber irritants. there is a body of evidence that correlates increased activity in the rostral ventral medulla (RVM) with sensitization. and other mediators have been implicated in maintaining hyperalgesia (20). In particular. which directly influence neuronal activity (24). protein kinase C. the spinal cord has been the focus of many of the preclinical studies of central sensitization. Intra-RVM injection of a selective neurotensin receptor antagonist (SR48692) or NMDA receptor antagonist (2-amino5-phosphonovaleric acid) fully and dose dependently prevented mustard oil–induced facilitation of the tail-flick reflex (22). Activated astrocytes coalesce to form a microenvironment with which they modulate local neuronal hyperexcitability. PGE2. This process is sustained and regulated by astrocyte calcium waves: contiguous astrocytes become sequentially active with an increase in intracellular calcium (26). A centrally mediated. Treatment with cyclooxygenase (COX) inhibitors. they release cytokines [amino acids. Because central sensitization is considered to reflect plasticity at spinal synapses. the magnesium ion diffuses out of the channel. the N-methyl-D-aspartate (NMDA) glutamate receptor plays a central role in synaptic efficacy in the dorsal horn. this receptor contributes little to the synaptic current due to the blockage of the channel by a magnesium ion. and NO]. such as nonsteroidal anti-inflammatory drugs. in turn activating nearby astrocytes. the source of central sensitization is removed and the allodynia and hyperalgesia disappear within several hours or days. In addition to short. Nerve injury and peripheral inflammation are able to induce central sensitization through neurochemical changes in the dorsal horn. It exerts its cellular effects through four different G protein–coupled receptors encoded by separate genes. These changes allow for low-intensity stimuli to produce prolonged excitability in dorsal horn neurons (15–17). allowing calcium and sodium ions to traverse the channel. such that repeated tactile stimuli of the inflamed skin cause pain sensation of an increased intensity (18. glial and inflammatory cells have a critical role in the development and maintenance of allodynia and central sensitization in animal models of pain. glutamate. producing an Ad-fiber–mediated tactile allodynia (14). Upon membrane depolarization. Progressive activation involves a direct intercellular pathway mediated by gap junctions/connexin macromolecules and the diffusion of inosital triphosphate. termed EP1 through EP4.19). On the molecular level. carrying current with them. Another important modulator involved in sensitization is prostaglandin. Subsequent to NMDA receptor activation. Glutamate. They regulate glutamate in the neuronal junction (25). to the skin. is implicated in development of sensitization (allodynia and hyperalgia). substance P. Microglia also become activated during central sensitization. and ATP in the extracellular environment. At resting membrane potential. progressive tactile allodynia results. tumor necrosis factor (TNF) alpha. Protein kinase C or tyrosine kinase is activated at the postsynaptic NMDA receptor ion channel (21). Prostaglandin E2 (PGE2) is implicated as a key factor in the generation of exaggerated pain sensations evoked by inflammation.and long-term processes affecting neuronal activity directly. In addition to the dorsal horn of the spinal cord. such as capsaicin or mustard oil. and antipyretic effects (23). prostaglandins. and fractalkine) and circulating . He recorded the activity of the neurons in the rat trigeminal ganglion that innervate the dural venous sinuses. Both the dural and cutaneous receptive field size increased. Deleo et al. and mandibular distributions of the trigeminal nerve. NO. oxygen radical. predominantly causes cold or heat allodynia. such as capsaicin. whereas crush or nerve ligation injuries result in a more prominent mechanical allodynia (29). Toll-like receptors appear to mediate part of this response. peroxynitrite. IL1b. however. Astrocyte inhibitors. when administered before injury. Strassman modeled head pain by sensitizing the dura mater with inflammatory agents. peripheral injection of a nociceptive substance. This central sensitization may account for the extracranial tenderness and cutaneous allodynia that are often experienced during a migraine attack. These substances in turn potentiate NMDA receptor functions in neurons. suggest that microglia initiate the phase of persistent activation. As a general rule. Chemical stimulation also enabled the normally non-noxious stimuli to produce neuronal responses and blood pressure increases that were previously evoked only by noxious stimuli. but did not extend further. including histamine. but it is ineffective postinjury (27). Burstein further explored this animal model by locating neurons in the TNC that receive convergent input from the dura and from the skin. These neurons developed an increased sensitivity to mechanical stimuli (administrated using von Frey hairs) after chemical stimulation of the dura. or formalin. cutaneous receptive fields that had previously included only the periorbital regions expanded to include the maxillary and mandibular area after the chemical stimulation (31). as well as physiologic recording of neuronal activity and pathological studies. The cutaneous receptive fields of trigeminal neurons included the periorbital. mustard oil. maxillary. arachidonic acid derivatives. whereas astrocytes are more crucial for maintaining central sensitization. Chemical stimulation of the dura caused an increase in the sensitivity of the corresponding cutaneous receptive field neurons to both mechanical and thermal stimuli. suggesting that innocuous stimuli would be perceived as painful after chemical stimulation of the dura (32). Minocycline. reduces microglial and astrocytic activation. Additionally. serotonin. These drugs target peripheral nociceptors and are not known to have an effect on second. after central sensitization develops. Thus. The activated microglia in turn release TNF. IL6.102 Young et al. These data demonstrate that the noxious inputs from dural inflammation or from distended intracranial blood vessels cause sensitization of TNC neurons. bradykinin. This may explain why head pain is aggravated by physical activity during a migraine attack. Triptans. He recorded the dural receptive fields by mechanically stimulating the dura and the cutaneous receptive fields by mechanically and thermally stimulating the skin. RAT MODEL OF MIGRAINE HEADACHE AND ALLODYNIA Most studies of somatic hyperalgesic pain involved extratrigeminal injury to the rat followed by observation of rat behavior. attenuate chronic pain states (28). are commonly used in the treatment of migraine attacks. Burstein sensitized the rat dura mater . and low-molecular-weight toxins.and third-order neurons. dilation of the meningeal blood vessels by rat calcitonin gene–related peptide (CGRP) sensitized the second-order TNC neurons (33). proteolytic enzymes. lipopolysaccharides and interleukin (IL)1b signal the microglia to become activated. 5HT1B/1D agonists. and PGE2. Similarly. as well as the pulsating quality of the pain (30). these drugs are expected to have little effect. including the somatosensory cortex. defined as triptan administration at the same time as inflammatory soup administration. and cerebellum (40). hypothalamus. Positron emission tomography (PET) and functional magnetic resonance imaging (MRI) studies of BA in conditions other than migraine have demonstrated activation of a network that includes bilateral SII. followed by cold and heat allodynia (37). and midanterior and cingulate cortex. Peyron studied BA and compared responses to brush stimuli in an allodynic area and the contralateral nonallodynic area in 27 patients with neuropathic pain with a variety of causes (43). Based on experimental compression nerve blocks. Early. However. these studies demonstrate a matrix of supratentorial activation occurring during allodynic pain. thalamus. anterior cingulate cortex. insulae. Ipsilateral responses were greatly magnified in SII. However. insulae. BA is mediated by myelinated nerve fibers. Other areas activated by allodynic stimuli included motor and premotor areas. Functional neuroimaging studies have shown activation of various cortical and subcortical areas in migraine. They do not demonstrate pain processing in brainstem or trigeminal nuclei.39). Late intervention resulted in shrinkage of expanded neuronal receptive fields in the dura and normalization of neuronal response to threshold dural indentation. Similarly. Additionally. Static mechanical (pressure) allodynia (PA). SI. In the inflammatory soup model of head pain.Allodynia and Sensitization in Migraine 103 with an inflammatory soup and recorded neuronal activity in the TNC in a similar manner to that used in previous studies (34). BA can cause a variety of pain sensations and may be accompanied by emotional and vegetative reactions including nausea. He administered intravenous triptans either at the same time as the chemical stimulation (early intervention) or two to four hours after it (late intervention). is the second most common type. and insula. whereas PA utilizes unmyelinated fibers (38). HUMAN STUDIES OF ALLODYNIA IN PAIN DISORDERS OTHER THAN MIGRAINE Dynamic mechanical (brush) allodynia (BA). pain evoked by steadily applying light pressure on the skin. and contralateral SI and anterior cingulate cortex (41. though late intervention decreased the peripheral sensitization. pain evoked by gently stroking the skin. it did not reverse spontaneous TNC neuron firing or increased response to skin brushing. Cumberbatch found that a 5HT1B/1D agonist. Early intervention prevented both peripheral sensitization (expansion of dural receptive fields and sensitization of primary afferents to mechanical stimuli) and central sensitization (expansion of cutaneous receptive fields of secondary afferents and sensitization to both mechanical and thermal stimuli) (35). basal ganglia. Taken together. and sweating (37. thalamus. dizziness. it did not effect the development of central sensitization (35).42). . intervention was able to reverse central sensitization. given immediately after brainstem exposure but before location of a neuron in the TNC or dilation of meningeal blood vessels by CGRP. posterior parietal areas. blocked cutaneous sensitization (33). Burstein compared early triptan treatment. and late triptan treatment. but not late. is the most common type of allodynia in neuropathic pain patients. Increased activation volumes were found in contralateral SI and primary motor cortex. Early intervention blocked the development of all aspects of central sensitization. amygdala. defined as triptan administration two hours after administration (36). with 48% experiencing cold allodynia. Overall. Burstein examined the relationship between static mechanical allodynia.7% vs. HUMAN STUDIES OF ALLODYNIA IN MIGRAINE Migraineurs may have baseline differences in sensory processing compared with nonmigraineurs. found that migraine patients who experienced aura were more likely to have BA compared with those who did not have aura (42% vs. There was a trend for allodynic subjects to have a higher attack frequency. whereas heat and electrical stimulation pain thresholds were the same for both patients and controls (44). there was no significant difference in BA prevalence between those who had headache exacerbation when tested and those who did not (45. heat allodynia appeared ipsilaterally and contralaterally on the head.1%. warm. but attack duration was similar (46). and migraine. BA was more common in patients with TM (42. At the onset of head pain. Burstein noted that allodynic subjects were on an average 6. Allodynia of the periorbital region was interpreted as a result of central sensitization of TNC neurons. 54 patients (27%) had BA. tested with von Frey hairs. 9. Similarly. a manifestation of sensitization of peripheral nociceptors in intracranial blood vessels and meninges (intracranial hypersensitivity). Subjects with allodynia were more likely to have aura. 33. and pressure stimuli on the periorbital and ventral forearm skin bilaterally.5 years older than nonallodynic subjects. Burstein examined a single patient for the sequential spread of cutaneous allodynia during a migraine attack.0% vs. Seventy-nine percent of patients experienced allodynia on the facial skin ipsilateral to the headache. He examined 44 patients interictally to determine their thresholds to cold. Within the EM group.7%) compared with patients with EM (14. At no time did the patient experience any allodynia on the contralateral forearm. 40. the patient first experienced aggravation of his head pain by coughing or bending over. In the TM group. BA was more common in patients with migraine with aura compared to those with migraine without aura. At four hours into the attack.104 Young et al. and 64% experiencing PA (45). while allodynia continued to develop ipsilaterally. thermal allodynia. the patient experienced cold and PA ipsilateral to the head pain. Furthermore.3%).5% vs. Patients’ pain thresholds were reexamined three to four hours into a migraine attack. At two hours into the attack. 19.1% vs. whereas allodynia of the ipsilateral forearm was interpreted as resulting from sensitization of third-order trigeminovascular neurons that receive inputs from both TNC and C2–7 dorsal horn neurons (34). both in the whole study population (42. cold. and BA also developed contralateral to the head pain and cold allodynia developed on the ipsilateral forearm.9 %). migraineurs had increased temporal summation of pain to mechanical and electrical stimulation compared with controls. BA was more common in patients who had an acute headache when tested compared with those who did not (60% vs. Weisman–Fogel found that migraine patients had a lower pain threshold for mechanical stimulation compared with controls. however. There was a positive correlation (of 0. 9. studied dynamic BA in a series of 111 patients with episodic migraine (EM) and 89 with transformed migraine (TM) (47). TM: 57. After one hour of head pain. and ipsilaterally on the forearm. pressure. Ashkenazi et al. 55% experiencing heat allodynia. Extracranial hypersensitivity developed later.1%) and in the EM and TM groups separately (EM: 26. Ashkenazi et al.37) between the allodynia score (the sum of positive responses to a short list of questions describing various . 19%) (47). Cutaneous allodynia was defined as a decrease in pain threshold at one or more of the skin locations by one or more standard deviation compared with baseline.4%).7%). These subjects could have bilateral migraine. and 42% had allodynia at four sites. Because Burstein reported only on patients with unilateral headache. of these. studied allodynia location in 33 allodynic patients with unilateral headache (45). Selby and Lance showed that patients with unilateral migraine had more scalp tenderness than patients with bilateral migraine (3). There was also a correlation between the side of head pain and the side of BA. Subjects with unilateral headache were significantly more likely to have BA than those with bilateral headache. 21% had allodynia at three sites. Bove described the location of BA in 39 patients. All subjects had heat. This was not due to headache severity.2%). The illustration shows the prevalence of BA at various anatomic sites across a diverse population of headache patients. BA was not reported.Allodynia and Sensitization in Migraine 105 types of allodynia) and the headache level at testing time. BA was more common in patients with psychiatric comorbidity compared with those without it (34. 21% had allodynia at two sites. or PA ipsilateral to the headache. Four sites were assessed: the head ipsilateral and contralateral to the pain. but this was not universal (47). Similarly. The results of this study are summarized in Figure 1. these findings are not confirmed for other types of allodynia. Young et al. most of whom had EM or TM (49). and the forearm ipsilateral and contralateral to the headache. BA is generally more severe ipsilateral to the headache. In patients with unilateral headache. 19. compared the incidence of BA with unilateral and with bilateral headache among a cohort of inpatients with a variety of headache disorders (61/78 had TM) (48). cold. 15% had only ipsilateral head allodynia. Figure 1 Spatial distribution of allodynia. Burstein et al. .6% vs. which was identical in subjects with and without BA. Lopinto et al. Symptoms that are believed to reflect allodynia and central sensitization are listed in Table 1. N/A)?  Combing your hair  Pulling your hair back (e. Mathew found a positive correlation between the presence of allodynia and both duration of illness and frequency of attacks. and there was an incomplete overlap between these groups. compared BA and PA in 55 migraine patients and in a control group.. 50% had pure cephalic allodynia. it was more likely to be PA than BA. Anecdotally.. symptoms of allodynia may persist for hours after headache pain resolution. When BA was tested on the left posterior neck and left forehead. and pressure pain thresholds. 35% had both cephalic and extracephalic allodynia. Do you experience pain or unpleasant sensation on your skin during migraine attack when you engage in ANY of the following activities (Yes.g. Among patients with allodynia.106 Table 1 Allodynia Questionnaire Young et al. No. Fifty-three percent of patients reported allodynia. TIME COURSE OF SENSITIZATION IN MIGRAINE Based on a small number of patients and time points. This is roughly consistent with central sensitization studies in rats. This suggests that BA and PA may result from sensitization of different neuronal populations. Mathew interviewed 295 consecutive migraine patients for symptoms of allodynia. PA was slightly more common than BA. allodynia appears to develop within several hours of the initiation of throbbing pain in migraine (45). If a patient had allodynia to only one sensory modality. cooking and placing heating pads on your face)  Cold exposure (e. and 15% had pure extracephalic allodynia. personal communication.. ponytail)  Shaving your face  Wearing eyeglasses  Wearing contact lenses  Wearing earrings  Wearing necklaces  Wearing tight clothes  Taking a shower (when shower water hits your face)  Resting your face on a pillow on the side of pain  Heat exposure (e. They defined PA for each filament used as the pain level on the visual analog scale below which 95% of the controls responded (50). cold. reported on a patient with referred BA who had EM and right-sided headache (47). THE EFFECT OF ALLODYNIA ON TREATMENT OUTCOME Burstein studied 31 migraineurs on three separate clinic visits. pain was referred to the right forehead. although brush at this area did not produce pain or discomfort. He obtained baseline interictal data on heat. Ashkenazi et al. breathing through your nose on a cold day and placing ice packs on your face) Source: Burstein R.g.g. This report suggests that a complex pain-processing abnormality may occur in migraine. He then studied these . compared with the cervical. allodynia was present in all of the four chronic cluster headache (CH) patients. Young et al. In contrast to Burstein’s findings with temperature and PA. and their response to triptan treatment. 2004). headache level decreased in 90% of patients and allodynia decreased in all of them. both ipsilateral and contralateral to the side of GON block. whether given early or late. reported a case of migraine with allodynia in which allodynia in both the trigeminal territory and the midthoracic area was completely relieved within five minutes of GON block. COX-2 inhibitors (52) and steroids (53) were effective at decreasing allodynia. For attacks in patients who were allodynic. Twenty minutes after treatment. studied the effect of greater occipital nerve (GON) block and trigger point injections on both head pain and BA in 19 migraine patients (54). In a cohort of hospitalized headache patients. BA did not affect outcome in a group of hospitalized headache patients (48). Sumatriptan treatment also resulted in decreased heat pain thresholds in both migraine patients and controls. Because thoracic and trigeminal first-order neurons are unlikely to converge on the same neuron near the TNC or cervical complex. suggesting a descending inhibitory process (51). as opposed to only 15% of the attacks when the subjects were allodynic. one and four hours into a migraine attack. he suggested that a descending inhibitory process for allodynia may underlie the effectiveness of GON block in migraine (51). The duration of hospitalization was similar between the groups. found that sumatriptan treatment caused a transient increase in BA in migraine patients (55). to a similar degree. Ashkenazi and Young studied 10 CH patients . Ashkenazi et al. The outcome of triptan treatment was linked to the presence of allodynia. type. demonstrated that occipital nerve block could relieve migraine pain and BA within minutes of injection. The allodynia level decreased. and intensity of treatments that inpatients receive compared with treatments given to outpatients. In contrast. Young et al. not the presence of aura (46). THE EFFECT OF TREATMENT ON ALLODYNIA There is little published data on clinically effective allodynia treatments in migraine. The decrease in allodynia was more pronounced in the trigeminal. When the subjects were nonallodynic. For attacks in patients who were not allodynic. These effects were noted 20 minutes after treatment but were no longer significant 40 minutes after. Linde et al. triptan treatment was equally effective if given early (within one hour of attack onset) or late (four hours after attack onset). ALLODYNIA IN HEADACHE DISORDERS OTHER THAN MIGRAINE Migraine is not the only primary or secondary headache condition in which allodynia can develop. dermatomes. personal communication.Allodynia and Sensitization in Migraine 107 subjects. Burstein reported that ketorolac was effective in reversing allodynia in migraine (London Migraine Trust. they became headache-free after triptan treatment in 93% of attacks. The disparity between these findings and Burstein’s may be due to differences in the duration. triptan treatment was equally ineffective. Sixty-six percent of migraine patients with BA and 70% of patients without BA became headache-free by the end of hospitalization. In animal studies of inflammatory and neuropathic pain. and in one of the two posttraumatic headache patients (48). short unilateral neuralgiform headache with conjunctival injection and tearing (57). Because treatment outcomes are worse in episodic migraineurs with allodynia. REFERENCES 1. 10:2717–2726. 66:228–246. 7. Nature 1987. Pathophysiology of headache. Goadsby PJ. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. Pain 1989. Mense S. 325:151–153. Lipton RB. Liveing E. plasticity. 9.108 Young et al. 33:76–81. Rozen et al. These attacks had the same duration as her migraine attacks and resolved completely after she was treated with a beta-blocker. Nature 1983. CONCLUSION Allodynia is an important clinical feature of migraine and other primary headache disorders. J Neurophysiol 1991. not one to several hours as in migraine. 36:239–247. Dalessio DJ. Long-term changes in discharge behavior of cat dorsal horn neurones following noxious stimulation of deep tissues. Mannion R. Melzack R. In: Wall P. Of the two subjects who were studied during an attack. J Neurosci 1990. 5. In: Silberstein SD. for the occurrence of BA (56). 306:686–688. Pain 1992. 10. Hoheisel U. eds. suggesting that allodynia in CH may be a timedependent process. Textbook of Pain. Discontinuing the beta-blocker led to recurrence of the migraine and ESBA. 4th ed. Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brainstem neurones. and the generation of pain. Piovesan et al. . Allodynia started half an hour into the attack. Evidence for a central component of postinjury pain hypersensitivity. et al. Doubell T. have noted transient allodynia in attacks of SUNCT. 2001:57–72. 11. Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord. New York: Oxford University Press. 1873. eds. 3. Sometimes Jello helps: perceptions of headache etiology. Woolf CJ. Simone D. 2. 6. Cook AJ et al. triggers and treatment in literature. Sick Headache. Median disease duration was longer in patients with BA (22 years) compared with those without BA (12 years). Observation on 500 cases of migraine and allied vascular headaches. and Some Allied Disorders: A Contribution to the Pathology of Nerve-Storms. The dorsal horn: state-dependent sensory processing. developing treatments for migraine with allodynia is now a priority. Sorkins L. King AE. described a patient with a migraine-related disorder in which allodynia appeared to be a cardinal feature (58). treating migraine before allodynia develops will improve treatment outcome. In the meantime. This is especially interesting because the allodynia here began in seconds. London: Churchill. 8. Wolff’s Headache Other Head Pain. 23:23–32. Lance JW. Selby G. This patient developed attacks of extracranial stabbing and burning pain associated with allodynia (ESBA) independent of her migraine attacks. Woolf CJ. Woolf C. On Megrim. 4. Patterson SM. 48:53–60. Silberstein SD. London: Churchill Livingstone. Hu JW et al. one had BA that resolved after treatment. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C primary afferent input. Headache 1993. 7th ed. Oh U. J Neurol Neurosurg Psychiatr 1960. 1999:165–181. They found that four patients had BA. Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine. . J Neurophysiol 1993. Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. 26. Morphine. Yu XM. Schaible HG. Raymond SA. Ahmadi S. Basbaum A. J Neurosci 1997. Traub R. Fukuoka T. Reinold H. 67:97–106. Woolf C. Leslie T. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Ma Q. 23. Pain 1996. 20. Gebhart GF. Exp Brain Res 2001. Yamamura H. Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn mechanisms. Mantyh P. 116:407–420. Substance P induced by peripheral nerve injury in primary afferent sensory neurons and its affect on dorsal column nucleus neurons. Ma QP. 21. Trafton J. Nature 1996:360–364. Glowinski J. 37:239–243. Gebhart GF. Murphy S. Doubell T. Nature 1996. Giaume C. Pain 1992. Pain 1989. Nature 1992. 15:7633–7643. Huang YH. Grzybycki D. McBurney DL. Neuropharmacology 1994. Woolf CJ. Hu JW. Meller ST. 25. Chamberlin NL. Neuropathic pain in aged rats: behavioral responses and astrocytic activation. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. 28. the NMDA receptor antagonist MK901 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inflammation-induced progressive tactile hypersensitivity. 16. deLeo JA. Huang L. 384:560–564. Torebjork HE. 32. Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and nonnoxious stimulation. Supraspinal contributions to hyperalgesia. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brainstem trigeminal neurons. Progressive tactile hypersensitivity: an inflammation-induced incremental increase in the excitability of the spinal cord. Miki K. J Neurophysiol 1999. Abbadie C. 64:299–311. Burstein R. Stuesse SL. Gebhart GF. Evidence for a central component in the sensitization of spinal neurons with joint input during development of acute arthritis in cat’s knee. 27. PNAS 1999. Schechter JB. Burstein R. Koltzenburg M. 137:219–227. Malick A. J Clin Invest 2005. Nahin R. Strassman AM. Senba E. 70:1704–1707. 17:8049–8060. Sessle BJ. 19. Liu H. 51:207–219. Differential effects of cutaneous and deep application of inflammatory irritant on mechanoreceptive field properties of trigeminal brain stem nociceptive neurons. Prog Brain Res 1998. 14. Lovell JA. 14:346–352. J Neurophysiol 1998. Hylden J. Kawai Y. Tanga FY. J Cell Biol 2000. Protein kinase C reduces Mg2þ block of NMDA-receptor channels as a mechanism of modulation. 24. Tawfik VL. Crisp T. Sensitization of meningeal sensory neurons and the origin of headaches. 33:1471–1478. Cruce WL. 77:49–57. Burstein R. 17. Neugebauer V. 10:40–52. Bergles DE. Rouach N. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. Pain 1998. 30. Chen L. 356:521–523. Neuroscientist 2004. 13. Neumann L. Activity-dependent neuronal control of gap-junctional communication in astrocytes. 81:479–493. Noguchi K. Malick A.Allodynia and Sensitization in Migraine 109 12. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. The glutamate synapse: a target in the pharmacological management of hyperalgesic pain states. Strassman AM. 29. 31. Yamamura H. Lundberg LE. Urban MO. 18. 96:7687–7692. Glutamate transporters bring competition to the synapse. et al. 22. 79:964–982. Dykstra C. Urban MO. Curr Opin Neurobiol 2004. J Neurophysiol 1990. Depner UB. 15. Woolf C. 149:1513–1526. J Neurosci 1995. Dubner R. 104:693–700. Yarnitsky D. Headache 2002. Richardson ES. Lopinto C. et al. and Pain in Health and Disease: Mechanisms and Assessments. Anesthesiology 2004. An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. 62:A336 (Abstract). Anjum MW. 36. Pain 2003. Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons. 49. Ashkenazi A. Brain 2000. Hanaoka K. Brush (dynamic mechanical) allodynia in headache: the mapping study. Prevalence of mechanical (brush) allodynia in migraine. Temperature. 62:A83-A84 (Abstract). Unmasking mechanisms of peripheral neuropathic pain in a clinical perspective. 42. Ann Neurol 2004. et al. Burstein R. Lancet Neurol 2004. Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Peyron R. Nozaki-Taguchi N. Neurology 2004. Collins B. Takeda K. Occipital nerve block rapidly eliminates allodynia far from the site of headache: a case report. Garcia-Larrea L. 47:614–624. Collins B. Neurology 2004. 100:1249–1257. Antiallodynic effects of oral COX-2 selective inhibitor on postoperative pain in the rat. 47. Mason G. 34. Faillenot I. Petrovic P. 33:465–472. Triptan therapy can abort migraine attacks if given before the establishment or in the absence of cutaneous allodynia and central sensitization: clinical and preclinical evidence. Young WB. Williamson D. Defeating migraine pain with triptans: a race against the developing allodynia. Ashkenazi A. Ochoa JL. Sholtzow M. 126:1478–1486. A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Cephalalgia 2004.110 Young et al. Hansson P. In: Bovie J. Burstein R. Sawamura S. Sprecher E. Bajwa Z. 35. Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Sekiyama H. 46. 33. Possibilities and potentials pitfalls of combined bedside and quantitative somatosensory analysis in pain patients. 40. 1994:113–132. Yamamoto T. 53. Ashkenazi A. Br J Pharmacol 1999. Bajwa ZH. Hansson P. 42:390–391 (Abstract). Burstein R. Effect of methylprednisolone on neuropathic pain and spinal glial activation in rats. Burstein R. 43. 83:459–470. Bove ME. 3:272–292. Ashkenazi A. 51. Cumberbatch M. Seattle: IASP Press. Can J Anesth 2000. 55:19–26. 38. Yarnitsky D. 37. Brush allodynia in hospitalized headache patients. Young WB. Hansson P. Peyron R. Comparison of dynamic (brush) and static (pressure) mechanical allodynia in migraine. Ann Neurol 2004. 3:645–651. 45:999–1003. Touch. Cutrer MF. Tamai H. Headache 2005. Schneider F. 63:1838–1846. Mechanical hyperalgesias in neuropathic pain patients: dynamic and static subtypes. Pain Rev 1996. Yarnitsky D. Stone-Elander S. 50. Goor-Aryeh I. Gregoire MC. 39. Young WB. Jakubowski M. An association between migraine and cutaneous allodynia. Shukla P. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. 41. Alvarez LJ. Burstein R. Functional neuroimaging of headaches. Pain 1999. Kinnman E. Jakubowski M. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case. Ransil BJ. 24:1093 (Abstract). Petersson KM. Granovsky Y. 52. Sanchez Del Rio M. Weissman-Fogel I. Young WB. Pain 2000. Mateos V. Lindblom U. Hargreaves RJ. 24:906–907. Ann Neurol 1993. 48. eds. 47:354–360. Neurology 2004. Ingvar M. 55:27–36. 123(Pt 8):1703–1709. 45. Young WB. Yarnitsky D. 44. 84:77–87. Parietal and cingulate processes in central pain. . Cephalalgia 2004. Ann Neurol 2000. Hansson P. Sakashita Y. 57. Linde M. In press. Ashkenazi A. Dahlof CG. Silberstein SD. Abrupt onset and termination of cutaneous allodynia (central sensitization) during attacks of SUNCT. Ashkenazi A. Sumatriptan (5-HT1B/ 1D-agonist) causes a transient allodynia. Headache 2003. Young BW. 24:1057–1066. Headache. The effects of occipital nerve block and trigger point injection on brush allodynia and pain in migraine. 56. . 55. Cephalalgia 2003.Allodynia and Sensitization in Migraine 111 54. Piovesan EJ. Cephalalgia 2004. Brush allodynia in cluster headache. Young WB. Recurrent extratrigeminal stabbing and burning sensation with allodynia in a migraine patient. Werneck LC. Headache 2005. 58. Olausson H. Young WB. Saper JR. Haynes GV. Lundblad L. Rozen TD. 23:231–234. 45:153–155. Sheftell FD. Elam M. Oshinsky ML. Kowacs PA. 43:543 (Abstract). . Migraine without aura (MO) and migraine with aura (MA). The Netherlands INTRODUCTION—GENETIC STUDIES ON HEADACHE While genetic research in primary headaches has mainly focused on migraine. more recently. Leiden. FHM attacks often resemble those of basilar migraine (1). J. the identification of migraine genes was facilitated. van den Maagdenberg Department of Neurology and Human Genetics. Leiden. Leiden. are genetically complex. Some patients have atypical attacks. M. The Netherlands Michel D. Leiderdorp. Vanmolkot and Rune R. fever.9 Genetics of Migraine and Other Primary Headaches Gisela M. Ferrari Department of Neurology. The Netherlands Joost Haan Department of Neurology. and the headache and aura symptoms. either with a prolonged aura lasting up to five days or with signs of diffuse encephalopathy. and Department of Neurology. the two most common subtypes of migraine. apart from the hemiparesis. are identical to those of MA (2). aura consists of hemiparesis. genetic susceptibility in cluster headache (CH) and tension-type headache are also receiving attention. Leiden. preceding the headache phase. Leiden University Medical Center. Rijnland Hospital. Kors Department of Neurology. Very often an initial diagnosis of epilepsy is made. There must be at least one family member with identical attacks. J. The Netherlands Kaate R. Leiden University Medical Center. Leiden University Medical Center. but not 113 . and sometimes epileptic seizures. By investigating familial hemiplegic migraine (FHM). In FHM. Terwindt and Esther E. Leiden University Medical Center. Leiden University Medical Center. with an autosomal dominant mode of inheritance. Frants Department of Human Genetics. a rare subtype of MA. The Netherlands Arn M. Patients with FHM and their relatives are at increased risk for ‘‘nonhemiplegic’’ typical MA. due to the combination of genes and environmental factors involved. expressed as confusion or coma. Leiden. Attacks may be triggered by head trauma. in addition to typical (visual) aura symptoms. The T666M mutation has been found in 20 families worldwide (5. Most patients have hemiplegic attacks with interictal ataxia. The proband of one of the families had—after a mild head trauma—a symptom-free period of several hours before she went into a coma. CACNA1A.22). often triggered by trivial head trauma.18–20. but two mutations occur more frequently. With the identification of the second FHM (FHM2) gene (ATP1A2. THE CLINICAL SPECTRUM OF THE CACNA1A GENE MUTATIONS The chromosome 19-linked CACNA1A gene encodes the Cav2. Mutations in the CACNA1A gene cause FHM1 and also two other neurological disorders with an autosomal dominant inheritance pattern. Patients with this mutation have a high frequency of hemiplegic migraine (98%). Affected members of FHM1 families with the S218L mutation (17) had recurrent atypical attacks. was identified in 1996 on the short arm of chromosome 19 (5).10. suggesting a reduced penetrance for migraine attacks. These channels are expressed throughout the brain and are also present at motor nerve terminals in the neuromuscular junction (NMJ).114 Terwindt et al. unlike some family members who had FHM. The still-expanding clinical spectrum of CACNA1A mutations has a very complex genotype–phenotype correlation.12–14. atypical attacks with coma (50%). identified in 2003) (6) and the results of several genome screens in MO and MA patients.20). Patients with the T666M mutation can also show mental retardation (18). exclusively missense mutations are found in FHM (Fig.1 protein. important progress has been made toward elucidating the genetic causes of migraine. 1) (5. and aphasic) (4). Pseudomigraine with lymphocytic pleocytosis is characterized by episodic neurologic dysfunction associated with headache and cerebrospinal fluid lymphocytic pleocytosis. It seems that the S218L (and possibly other) CACNA1A mutations may put persons at risk for cerebral edema and fatal coma after minor head trauma. Another recurrent mutation is R583Q described in six families (8. She died 10 days later because of severe cerebral edema. MO attacks (3). have been linked to CACNA1A mutations. Sporadic cases with FHM symptomatology [sporadic hemiplegic migraine (SHM)] exist. which is the pore-forming subunit of P/Q-type calcium channels (5). FHM. So far. She had never experienced attacks of (hemiplegic) migraine. and nystagmus (86%) (12).8–22). but some members of a large Portuguese family showed cerebellar ataxia only (8). EA-2 and SCA6 have considerably overlapping phenotypes. including all families with additional cerebellar ataxia. virtually always with other aura symptoms as well (visual.13. or attacks resembling acute confusional migraine. sensory. One T666M patient was diagnosed as EA-2 because of ataxic symptoms during the attacks (16). although the initial symptoms seem to be present at a much younger age. namely episodic ataxia type 2 (EA-2) and spinocerebellar ataxia type 6 (SCA6). Most mutations have been identified in one or two families only. on the long arm of chromosome 1. As cerebrospinal fluid lymphocytic pleocytosis can occur in . Their main function is to mediate transmitter release from synaptic nerve terminals (7). CACNA1A: FHM Over 50% of all FHM families. The ataxic features are similar to those seen in SCA6. The first gene for FHM (FHM1). which was almost exclusively derived from sibling pairs affected with MA (25).: Genbank Ac. where an excess allele sharing of markers in the CACNA1A region was found in affected sib-pairs. no mutations were found in eight patients. This study suggests that the CACNA1A gene might be involved in MO and MA. suggesting a role of CACNA1A in the more frequent types of migraine (13. using DNA markers adjacent to or within the CACNA1A gene. the CACNA1A gene was studied as a candidate gene (23). . X99897). but no mutation was found in this family either (26–30). The Cav2. Each domain includes six membrane-spanning segments and a so-called P-loop between the fifth and sixth segments. atypical FHM attacks and both pseudomigraine and FHM can be triggered by angiography. but none showed evidence of linkage to MA either under locus homogeneity or under locus heterogeneity.1 pore-forming subunit of P/Q-type voltage-gated calcium channels is located in the neuron membrane and contains four repeated domains. however.24). Polymorphic microsatellite markers surrounding the CACNA1A gene were genotyped on 757 individuals. In the study conducted by Chapman and colleagues. A recent Finnish study aimed to clarify the role of the CACNA1A locus in MA by analyzing 72 multigenerational Finnish MA families. the largest family sample so far (35). A large Australian family showed linkage to the D19S1150 marker that is located in the CACNA1A gene. seq. This is supported by a study with sibling pairs with MA and/or MO. nr. Other studies found no positive linkage results in migraine families. Positions of mutations identified in this gene are given (CACNA1A ref.Genetics of Migraine and Other Primary Headaches 115 Figure 1 The CACNA1A gene with mutations. but the contribution to MA seems larger than to MO. No FHM mutations were found in unselected groups of patients with MO and/or MA (26–28).31–34). CACNA1A: MA and MO Some mutation carriers in FHM1 families have attacks of MA or MO only. confirming genetic heterogeneity (29. 116 Terwindt et al. a new family with absence epilepsy and EA-2 was found with a novel CACNA1A mutation (40). 1) (5. and dysarthria (57). The presence of (childhood) seizures next to attacks of EA-2 and in a CACNA1A mutation carrier further supports a role for CACNA1A in epilepsy (41). suggesting that mutations can be missed or that other genes causing a similar symptomatology exist (54–56). A follow-up study showed that two SNPs in the immediate vicinity of exon 8 were responsible for the association with epilepsy (61). kinetics. mild upper limb ataxia.59). including physical exercise or emotional stress. SCA6 is caused by moderate. . a family was shown with a (novel) CACNA1A mutation. Recently. more than 30 missense mutations or mutations resulting in premature stop or affecting alternative splicing have been identified in patients with EA-2 (Fig. and expression. There are considerable interfamilial differences. The most consistent change found with FHM mutations seems to be a hyperpolarizing shift of about 10 mV of the activation voltage. In some cases. SCA6 is characterized by the late onset of a slowly progressive cerebellar ataxia with oculomotor abnormalities. in other patients. CACNA1A: EA-2 and SCA6 EA-2 patients present with early onset attacks of imbalance and/or vertigo. Some patients have ataxia combined with episodic headache or nausea. FHM mutations cause different effects on channel conductance. CACNA1A: Functional Studies Several FHM mutations have been analyzed with electrophysiological techniques in neuronal and non-neuronal cells (40.16. gait ataxia.41. but not investigated further. Eye-movement abnormalities such as saccadic intrusions during smooth pursuit and nystagmus are prominent and consistent early manifestations (58). The first association was reported in a group of patients with idiopathic generalized epilepsy (60). The attacks can be provoked by a number of triggers. patients with EA-2 can have interictal permanent cerebellar ataxia. one SNP in exon 8 showed a significant association. The permanent signs can be preceded by episodic manifestations (58). In some families with symptoms indistinguishable from EA-2. An effect on expression or alternative splicing of the protein was suggested. causing childhood epilepsy. that occurred independently of FHM attacks (64).39–53). Like FHM1.62. episodic weakness can precede the attacks of ataxia (38. no CACNA1A mutation was identified. Of four single-nucleotide polymorphisms (SNPs) and one microsatellite marker located within CACNA1A. and can be prevented by acetazolamide. While EA-2 truncating and missense mutations all show a dramatic decrease or even complete loss of Ca2þ channel electric current.39).65–69). Recently. Although this effect in theory will lead to easier opening of the channels in neurons. generalized weakness is reported during ataxic spells.63). lasting hours to days (36). Three patients with EA-2 had generalized epilepsy (40–42). stabile expansions of a CAG repeat in the CACNA1A gene. CACNA1A: Epilepsy The involvement of the CACNA1A locus in epilepsy in humans is of interest in view of the epileptic phenotype observed in Cacna1a mutant mice (57. and the attacks can be associated with symptoms of (basilar-type) migraine (37). The association was not limited to a specific epileptic syndrome or subgroup. Epileptic seizures or status epilepticus in association with FHM attacks have been described in patients with CACNA1A mutations (21. So far. Interestingly. . because motor nerve terminals contain P-type calcium channels responsible for acetylcholine release. Transmitter release in tottering NMJs in vitro was decreased during high-rate nerve stimulation (78). in parallel with a reduced release of cortical glutamate (80). Some phenomena might contribute to the episodic nature of symptoms.and L-type currents. Aura symptoms in some FHM patients could be abolished by the glutamate receptor antagonist ketamine (77).75). carrying the human pure FHM1 R192Q mutation (81). Two Cacna1a-null-mutant (knock-out) mice show a lethal phenotype at a young age (74. accumulation of inactivated channels was observed during repetitive stimulation. and an altered glutamate was reported in tottering and Cacna1a knock-out mice (75. It is now generally accepted that migraine aura is caused by cortical spreading depression (CSD). leaner. R192Q mice exhibit no overt phenotype. Multiple gain-of-function effects were found. Total calcium current density in cerebellar cells was found decreased. a reduced threshold and increased velocity of CSD. because P/Q-type calcium channels mediate glutamate release. Indeed. a depolarization wave associated with temporary disturbance of ion balances (76). Unlike the other mouse models. P/Q-type currents were abolished and partly compensated for by N. The main effect of tottering. in the intact animal. a knock-in mouse model was generated. CACNA1A: The NMJ The neuromuscular junction (NMJ) is a suitable synapse model to study Cacna1a mutations. the R192Q knock-in mice show enhanced neurotransmission at the NMJ. spontaneous quantal transmitter release was doubled. Neuromuscular transmission in vivo in patients may be compromised as well. For other FHM mutations. Recently. Furthermore. Experimentally induced CSD in tottering and leaner mice was found altered. It seems that whole-animal studies are necessary to dissect the effects of mutations and understand the integrated physiology of a disease. such as R583Q and D715E. because calcium influx will be altered. especially during high neuronal activity. recent clinical electrophysiological studies showed NMJ malfunction in three EA-2 patients with CACNA1A missense and truncation mutations: single-fiber electromyography (SFEMG) demonstrated increased jitter and the occurrence of blockings in these patients (39). SFEMG recordings in FHM patients and patients with SCA6 were unremarkable (39.78. In comparison. CACNA1A: Mouse Models Several mouse Cacna1a mutants with symptoms of ataxia and epilepsy are available.Genetics of Migraine and Other Primary Headaches 117 the overall change in calcium influx is difficult to predict because it will be determined by a delicate interplay of effects of a particular mutation on the different channel properties and the cellular environment. including increased Cav2. and rolling Nagoya mutated P/Q-type channels appears to be reduction of calcium current density (70–73). CACNA1A mutations might very well influence CSD. While similar findings were observed in patients with MA (82).79). Cerebellar granule cells of heterozygous mice from one of the two null-mutants displayed a 50% reduction in P/Q-type current density whereas no reduction was observed in the other model (74.83).1 current density in cerebellar neurons and.75). Mutant T666M and V714A channels have a low conductance mode that sometimes switches to the wild type state. leaner and rolling Nagoya channel kinetics are changed (70–72). NM_000702). the phenotypic spectrum of FHM2 expands beyond migraine. . however. nr.118 Terwindt et al. So. Another Italian group found a G301R mutation in a family with FHM. Since then. seizures. like that of FHM1. Positions of mutations identified in this gene are given (ATP1A2 ref. Kþ-ATPase a2 subunit. revealed six novel ATP1A2 mutations (87). which is located in the plasma membrane and contains 10 transmembrane segments. Three other novel mutations (and another three possible mutations) were found in German FHM families (88). and a T345A mutation caused FHM attacks and coma in a Scandinavian family (86). A screening in 27 FHM families. Figure 2 Predicted transmembrane model of the Naþ. 2). in which CACNA1A mutations were excluded. and sensory deficits. seq. it took another six years to identify mutations in the ATP1A2 gene. but—importantly—also transient and permanent cerebellar signs (90). missense mutations were identified in two Italian families with pure FHM (without ataxia) (6). THE CLINICAL SPECTRUM OF THE ATP1A2 GENE In 1997 linkage studies identified the FHM2 locus on chromosome 1. A novel M731T mutation was identified in a small Dutch family with pure FHM (85). encoding the alpha2 subunit of sodium–potassium pumps (6. but basilar migraine or migraine with (visual) aura (89). coma. several other FHM families with similar mutations have been described (Fig.: Genbank Ac. patients with an R548H mutation did not have FHM attacks. In a small family from Italy. ATP1A2: FHM First.84). dyspnea. In both studies. . occurring during hemiplegic attacks or in isolation. A further association between an ATP1A2 mutation (G301R) and epilepsy was found by an Italian group. but some of its aspects are clearly distinct. The true contribution of the ATP1A2 gene to MO and MA is still unclear. sensory deficits. including choreoathetosis. (ii) episodes of bilateral hemiplegia or quadriplegia. all BFIC persons tested had the missense mutation. strabismus. Two separate groups found ATP1A2 mutations in (presumed) cases of AHC (94.Genetics of Migraine and Other Primary Headaches 119 ATP1A2: MA and MO In a recent study. It seems that. nystagmus. In the family. in this family. and autonomic phenomena. because they expand the number of families with ATP1A2 mutations (AHC or not). and a progressive course associated with mental deterioration. characterized by (i) repeated periods of hemiplegia involving either side of the body. (iv) immediate disappearance of all symptoms on going to sleep. at least in some attacks. which causes FHM and benign familial infantile convulsions (BFIC) in a large family (85. ATP1A2: Epilepsy Three subjects in the Italian families of the first publication on ATP1A2 (6) reported a history of epileptic seizures resembling the migraine-triggered seizures observed in FHM1 patients. The association of ATP1A2 mutations and epilepsy was confirmed by the finding of the R689Q mutation. including tonic/dystonic attacks. the Italian families described in the first publication (6)].. AHC has often been regarded as being related to migraine. and permanent neurologic abnormalities. benign form of epilepsy.97). So. there are.92). however. and (v) evidence of developmental delay.g. dystonia. Epileptic seizures were also present in German D719N and P979L mutation carriers (88). seizures. migraine and epilepsy have partially overlapping mechanisms related to dysfunction of ion transport. these findings are of importance. and transient and permanent cerebellar signs (90). in our two previous studies. In several of the published families with ATP1A2 mutations. However. (iii) other paroxysmal phenomena. In general age at onset is before 18 months (93). no ATP1A2 mutations were found in probands of families with common types of migraine (MO and MA) (91). with strictly partial. no CACNA1A or ATP1A2 mutations were found in sporadic AHC patients (96. coma. because AHC is generally considered a sporadic disease. including choreoathetosis and dystonic posturing. but only the discovery of ATP1A2 mutations in sporadic AHC patients could confirm the importance of this gene in AHC. mental retardation. mutation carriers with ‘‘nonhemiplegic’’ migraine [e. but BFIC and FHM only partially cosegregated. with recurrence 10 to 20 minutes after awakening in longlasting attacks. starting either as generalization of a hemiplegic episode or present bilaterally from the start. ATP1A2: AHC Alternating hemiplegia of childhood (AHC) is a rare brain disorder. it was remarkable that familial cases were studied. BFIC is a rare. or ataxia. choreoathetotic movements. in a family with FHM. The clinical description of the patients in both studies could also lead to the diagnosis of FHM. nonfebrile convulsions that begin between 3 and 12 months of age and disappear after the first year in all. autosomal dominant.95). as sporadic patients. However. because of severe motor deficits that also abolish respiration (100. whereas first-degree relatives of probands with exclusively SHM had no increased risk of MO but an increased risk of typical MA. which resulted in the inclusion of SHM as a separate diagnostic entity in the second edition of the diagnostic criteria. in line with the observed epilepsy in patients. and utilizes ATP hydrolysis to extrude Naþ ions.101). defining SHM as a heterogeneous disease of unknown (genetic) origin. Interestingly. This was confirmed by the observation that first-degree relatives of SHM probands had an increased risk of both MO and typical MA. heterozygous Atp1a2þ/– mice revealed enhanced fear/anxiety behaviors after conditioned fear stimuli. either because of Naþ.98). apart from migraine with typical aura (4. Some of the sporadic patients are the first ‘‘FHM patient’’ in the family. Atp1a2null mice died immediately after birth. resulting in increased susceptibility to CSD (99). clearance of synaptic glutamate and Kþ is slowed. probably due to the observed neuronal hyperactivity in the amygdala and piriform cortex (100). ATP1A2: Mouse Models Several transgenic mouse Atp1a2-null mutants have been generated (100. and ATP. GENETIC SUSCEPTIBILITY IN MIGRAINE Family and Twin Studies in Migraine Two recent twin studies confirmed the presence of genetic and environmental factors in migraine. Both functional phenotypes fit nicely the current concepts of (hemiplegic) migraine pathophysiology. The gene is predominantly expressed in neurons at the neonatal age and in glial cells at the adult age. without affected family members. Heterozygous Atp1a2þ/– mice are viable. ATP1A2: Functional Studies The ATP1A2 gene encodes the alpha2 subunit of an Naþ.101). Kþ. Svensson et al. SPORADIC HEMIPLEGIC MIGRAINE Hemiplegic migraine patients are not always clustered in families. It was shown that the clinical symptoms of patients with SHM were more similar to FHM than MA. Atp1a2-null mice on 129sv genetic background display frequent and generalized seizures. as was shown by the identification of CACNA1A mutations in 2 out of 27 patients undergoing mutation analysis (20). including a . studied a cohort of twins aged 42 to 81 years. are often seen. the majority seem to have no mutation in any of the known FHM genes. Kþ pump ATPase. Naþ pumping provides the steep Naþ gradient essential for the transport of glutamate and Ca2þ.103). but die within 24 hours after birth (102). SHM probands had a highly increased risk of typical MA only (104). Kþ ATPase haploin sufficiency or reduced Kþ affinity.120 Terwindt et al. Functional analysis of mutated proteins revealed inhibition of pump activity and decreased affinity for Kþ(6. and the heart showed a hypercontractile state with positive inotropic response and resembles what is typically seen after the administration of cardiac glycosides (101). Selective neuronal apoptosis in the amygdala and piriform cortex in response to neural hyperactivity was revealed in 18.5-day-old Atp1a2-null fetuses (100).94. In addition. This catalytic subunit binds Naþ. Compared to the general population. among monozygotic twins reared apart.7-fold higher in the three-generation compared with the two-generation MA families and 4. and this was especially true for women. by comparing sibling risk. respectively. Previous family studies have found an increased relative risk of first-degree family members of patients with MO and MA of approximately 2 and 4. To further investigate the ‘‘migraine-spectrum. age at onset. and one generation. those separated at three years of age or earlier were more similar for lifetime migraine than those separated later. They found no significant shared rearing environmental influences on migraine. estimated the genetic load in familial MA. Mulder et al. and by the modest contribution to disease of individual susceptibility mutations (109). and aura type in 54-MA probands categorized by family history of MA (108). Linkage Studies in Migraine The identification of genes responsible for the frequent forms of migraine is a challenging task. belonging to a continuous migraine spectrum.8-fold higher in the three-generation compared with the one-generation MA families. studied the prevalence of MO and MA in probands with FHM and in their first-degree relatives (3). Svensson et al.6 times in FHM-affected first-degree relatives and 2. including a total of 29. Thus. but a significantly increased risk of almost eight times of MA. The prevalence of migraine ranged from 10% to 13% in Finland to 32% to 34% in Danish and Dutch females. The heritability of migraine was estimated at 38% for men and 48% for women. as compared to the general population. whereas environmental influences make family members different. whereas the risk of MA was significantly increased—7. A similar pattern was seen among their first-degree relatives. Linkage analysis in multifactorial diseases such as migraine is limited by the lack of clear genetic segregation of any DNA variants in multigenerational family material.717 twin pairs. . the genetic variance or heritability was the same between sexes. FHM probands had virtually no increased risk of MO. Families with an MA proband were divided into families with MA in three generations (n ¼ 15). FHM and MA seem to be part of the same spectrum. MA probands from the three-generation families were significantly younger than probands with no affected family members. A small family study of MA probands and their first-degree family members in a southern Italian town found a similar risk (107). only the proband being affected (n ¼ 19). (105).’’ Thomsen et al. Interestingly. These results suggest that the genetic abnormality resulting in FHM may also cause attacks with the symptomatology of MA. One of the presumptions in the scientific investigations of the genetics of migraine is that the rare autosomal dominant disease FHM is an extreme form of migraine. not similar. (105) concluded that family ‘‘resistance’’ in migraine is mainly due to genetic factors. and that study of this rare variant can provide insight into the more common forms.Genetics of Migraine and Other Primary Headaches 121 subsample of 314 pairs reared apart and 364-matched control pairs reared together (105). ranging from 34% to 57% in the different cohorts.4 times in non–FHM-affected first-degree relatives. (106) compared the prevalence and heritability of migraine across six of the countries that participated in the GenomEUtwin project. Noble-Topham et al. The recurrence risk to siblings of probands was 2. who had no increased risk of MO. The significant difference in genetic load and the earlier age at onset in the three-generation families is further evidence for a genetic basis for MA. two generations (n ¼ 20). Unlike the results of Svensson et al. In a Canadian linkage study. according to the researchers. population admixture. selected because of an apparent autosomal dominant pattern of transmission (114).1 (116). which shows overlap with the Finnish locus. and homocysteine-related genes were studied frequently. Associations between migraine polymorphisms in genes such as the glutathione S-transferase gene (126). 1q31. the low-density lipoprotein receptor gene (127).1 (117). and mutation analysis showed no mutation in two migraine families previously reported to be linked to this region (125). Potential publication bias. the LOD score increased when the sample set was reanalyzed using affected females only. and Xq24-28 (30. showed linkage to chromosome 4q21 in Finnish MA families (34). Recently. additional studies should investigate the contribution of these loci to migraine. a genome-wide screen was conducted in 43 families with MA. Other Studies on Headache Genetics Migraine and Mitochondria Inherited mitochondrial abnormalities are frequently claimed to be important in migraine (131). located on chromosome X. In a large Swedish family with MO and MA. power problems. The causative gene has not been identified in any of the above-mentioned loci. a locus in the 15q11-q13 region was found (115).2-p21.122 Terwindt et al.110–112). and associations between migraine and dopamine receptor genes and the MTHFR gene have been reported (118–124). A large Italian MO pedigree revealed significant evidence of linkage on chromosome 14q22. linkage was obtained for a locus on chromosome 6p12. Linkage studies in large Australian families with MO and MA revealed linkage on 19p13. Interestingly. In addition to linkage analysis in multifamily studies. the endothelin type A receptor gene. Based on this presumption. two mapping studies were reported in single families. the INSR gene (128). they allowed a relaxed definition of MO in about half of the MO patients. The serotonin 5-HT-2C receptor gene. This might be explained. Like the Icelandic study. but mtDNA mutations have never been found in groups of migraine . serotonin-. and (129) the tumor necrosis factor–a gene (130) need confirmation. A susceptibility locus was identified on chromosome 11q24. In 10 Italian MA families with autosomal dominant inheritance. dopamine-. which was recently confirmed in 103 Icelandic families with 289 MO patients (113). Association Studies in Migraine A widely used method to assess the genetic background of complex disorders such as migraine is to study possible associations between migraine patients and polymorphisms in genes with hypothesized function in the migraine pathway. Genome-wide scanning revealed a locus on chromosome 4q21. and allowing a relaxed definition of MO. These results await confirmation. revealed no significant association in a group of 275 migraineurs and 275 controls. One should keep in mind that association studies are difficult to perform in a comprehensive and meaningful manner. several successful genome-wide linkage studies have been conducted. and the issue of linkage disequilibrium within a gene make individual studies of limited importance. by the higher preponderance in females. Wessman et al. Further studies are needed to confirm the involvement of the hypocretin receptor 2 gene or other genes in this chromosomal region. myopathy. Recent clinical investigations gave further evidence of a genetic background of CH. A lower mean age at onset in women with familial CH was found. The 1246 G > A polymorphism of the hypocretin receptor 2 gene was significantly different between cases and controls (138).1-fold increased risk of chronic tension-type headache (CTTH). and 14 (MO). recently included in the second edition of the international classification of headache disorders (103) as one of the childhood periodic syndromes that are commonly precursors of migraine. Torelli et al. and migraine appears to be part of the phenotype (134). based on the assumption that FHM is part of the migraine spectrum. Hyporcretin neurons play an important role in regulating the sleep–wake cycle and CH attacks often during the night. and dysautonomia-like symptoms were far more common in matrilineal versus nonmatrilineal relatives (133). first-degree relatives had a 3. on the presence of a migrainous infarct or on other clinical grounds. This is now supported by several family studies. without any attempt to map or identify a putative CH gene (135–137). TENSION-TYPE HEADACHE In a genetic epidemiological study. evaluated several polymorphisms of the hypocretin/orexin system genes in 109 CH patients and 211 controls. New loci for the common forms of migraine were reported on chromosome 6 (MO and MA). even if they were selected based on matrilinear inheritance. CLUSTER HEADACHE Since the 1990s. compared familial and nonfamilial CH cases (137). The identification of the second FHM gene. ATP1A2. 11 (MA). familial occurrence of CH has been repeatedly recognized. accompanying symptoms. and active periods. An interesting observation was made in the so-called cyclic vomiting syndrome (CVS). confirmed that dysfunction in ion transport is a key factor in the pathophysiology of (familial hemiplegic) migraine. The origin is thought to be mitochondrial. duration and frequency of attacks. Compared with the general population.Genetics of Migraine and Other Primary Headaches 123 patients. mtDNA sequence variants are probable risk factors in most children at this ‘‘severe’’ end of the CVS spectrum. seizures. Rainero et al. A survey of parents of 62 children with a severe form of CVS showed that migraine. A complex segregation analysis further emphasized the result by suggesting that chronic tension-type headache has multifactorial inheritance (139). and the . There were no significant differences between the two CH groups in pain location. the familial aggregation of chronic tension-type headache was investigated. CONCLUDING REMARKS Investigation of FHM is an important part of migraine genetics research. A recent description of segregation of familiar cases of migraine in a family with the Leber T14484C mutation (132) adds to a number of previous clinical observations of migraine in patients with various mtDNA mutations. et al. et al. Olesen J. Ostergaard E. Tuna A. 7. Kim GW. Is familial hemiplegic migraine a hereditary form of basilar migraine? Cephalalgia 1995. Alonso I. Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. 60(4):595–601. 10. Clin Genet 2004. Clinical spectrum of episodic ataxia type 2. Genetic heterogeneity in Italian families with familial hemiplegic migraine. A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and hemiplegic migraine. et al. Denier C. A new CACNA1A gene mutation in acetazolamideresponsive familial hemiplegic migraine and ataxia. 64:89–98. 49(6):753–760. Joutel A. Piatti M. 12. Friend KL. et al. Piatti M. 8. Stenirri S. Joutel A. 52(suppl 2): A115–A116. Baloh RW. Thomsen LL. Alonso I. Eriksen MK. Russell MB. Ophoff RA. 4. A new mutation in the Chr19p calcium channel gene CACNL1A4 causing hemiplegic migraine with ataxia. Hum Genet 1999. Increased risk of migraine with typical aura in probands with familial hemiplegic migraine and their relatives. . Haploinsufficiency of ATP1A2 encoding the Naþ/Kþ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Russell MB. Thomsen LL. Bos PL. 62(1):17–22. Olesen J. et al. Brain 2002. 5. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. 87:543–552. Terwindt GM. Ferrari MD. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Finally. 13. 17. 3. associations between migraine and polymorphisms in the dopamine receptor D4 gene and the MTHFR gene show that these genes and the corresponding metabolic pathways are likely part of the genetic susceptibility in migraine. Ducros A. Neurology 1999. Haan J. previously reported MA locus on chromosome 4 seems to be important in MO as well. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. 53:38–43. De Fusco M. 2. REFERENCES 1. Gardner K. Structure and function of neuronal Ca2þ channels and their role in neurotransmitter release. et al. et al.124 Terwindt et al. 105(3):261–265. Keegan M. Barros J. 9. et al. Am J Hum Genet 1999. 24(5–6):307–323. Jen J. et al. Tuna A. Russell MB. Thomsen LL. et al. 345(1):17–24. N Engl J Med 2001. et al. Cell 1996. 33(2):192–196. 53(1):26–33. Phan TG. Vergouwe MN. Cell Calcium 1998. 15:477–481. 10(4):421–427. Nat Genet 2003. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Neurology 1999. Vermeulen FL. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 1999. 60(4):610–614. 16. 11. Olesen J. Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Ducros A. Carrera P. Andersen I. Neurology 2004. Terwindt GM. Kors EE. Battistini S. Silvestri L. Stenirri S. Crimmins D. 125(Pt 6):1379–1391. Ophoff RA. 6. Marconi R. Catterall WA. Roemer SF. Denier C. 65(1):70–72. Barros J. Ann Neurol 2001. Frants RR. Bernal O. 14. Terwindt GM. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. 15. Eur J Neurol 2003. Neurology 2003. These findings underline the complex genetic nature of MO and MA. Arch Neurol 2003. Takahashi Y. CACNA1A gene de novo mutation causing hemiplegic migraine. Vahedi K. Pseudomigraine with lymphocytic pleocytosis: a calcium channelopathy? Clinical description of 10 cases and genetic analysis of the familial hemiplegic migraine gene CACNA1A. 30. et al. 25. 70(3):652–662. Griffiths LR. coma. 23. Kallela M. Neurology 2000. Pediatr Neurol 2002. Terwindt G. et al. Haan J. Igarashi S. 72(5):676–677. Kors E. Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine. Nelson SF. Familial migraine: exclusion of the ¨ ¨ susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. et al. 21. Headache 2003. Chapman KM. Rigamonti A. Wieser T. et al. Takahashi T. Brimage PJ. Am J Med Genet 1998. Familial migraine with vertigo: no mutations found in CACNA1A. van Eijk R. Hutchins RP. 29. Lea RA. Ophoff RA. Dyment DA. Ophoff RA. Saitoh S. 27. Watanabe T. Kaunisto MA. Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene. 37. 55(7):1040–1042. Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Nyholt DR. 23(1):1–5. Hons BSc. and cerebellar atrophy [In Process Citation]. Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity. Pericak-Vance MA. Deufel T. Am J Hum Genet 2002. Am J Med Genet B Neuropsychiatr Genet 2004. 23:707–709. 56(8):1028–1032. J Neurol Neurosurg Psychiatr 2002. Brimage PJ. Yue Q. 59(6):1016–1018. et al. Farkkila M. Baloh RW. 41(3):272–275. Boyd PR. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Nelson SF. Kimura T. Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. 19. Cader MZ. Ann Neurol 1997. Jones KW. Clin Chem Lab Med 2003. Brugnoni R. Haines JL. 59(7):1099–1101. 36.Genetics of Migraine and Other Primary Headaches 125 18. and progressive ataxia. Griffiths LR. et al. 33. Kim JS. 32. Ehm MG. Neurology 2002. et al. Kobayashi N. Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine. 132B(1):85–89. Goadsby PJ. 60(5):684–688. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. coma. 20. . Szczygielski BI. Kaunisto MA. Mueller C. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Chromosome 19p13 loci in Finnish migraine with aura families. 43(8):892–895. Wada T. Hovatta I. Neurology 1998. Tikka PJ. Wessman M. Brandt T. Audiol Neurotol 1997. 28. 79:148–151. Noble-Topham SE. Furman JM. Terwindt GM. 22. Evers S. Giffin NJ. Peltonen L. Haan J. 31. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. 35. Peroutka SJ. Yue Q. Am J Med Genet 2001. Strupp M. et al. Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). 41(1):8–16. 2(6):373–383. et al. Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region. Kors EE. Ducros A. Neurology 2001. 26. Denier C. 105:707–712. Lea RA. 24. on chromosome 4q24. 50:1105–1110. Kallela M. et al. Zierz S. Curtain RP. Leone M. Arch Neurol 2002. Aoki T. Terwindt GM. Kallela M. Genomics 1994. 50:1428–1432. 78(3):150–154. 19p13. Haan J. et al. A susceptibility locus for migraine with aura. 26(1):47–50. Arch Neurol 2003. Genomics 2001. Is the CACNA1A gene involved in familial migraine with aura? Neurol Sci 2002. Toth C. Baloh RW. Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility. 34. Neurology 1998. 59. 77:298–301. Glasauer S. Am J Hum Genet 2001. Neurology 1999. Diepstraten CM. 56. 210(1–2):91–93. 54(6):725–731. Clusters of non-truncating mutations of P/Q type Ca2þ channel subunit Ca(v)2. Episodic ataxia type 2. Nelson SF. 2(9):1250–1260. Neurology 1999. 62(9):1623–1625. Eunson LH. Isawa M. Bonnen P. 52:1816–1821.126 Terwindt et al. 358(9284):801–807. Nelson R. Am J Med Genet 1998. Jaffe SL. Thwe MM. Yue Q. Durr A. Brandt T. 108(4):345–349. Mantuano E. Frants RR. 58(2):292–295. Tournier-Lasserve E. et al. 57(10):1843–1848. Denier C. Ducros A. Denier C. A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene. Jen JC. Wan J. 68(3):759–764. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. et al. Freilinger T. Kors EE. Plomp JJ. Arch Neurol 2001. Brunt ER. 39. et al. Graves M. 249(11):1515–1519. Jen J. Sasaki O. Bailey J. Lancet 2001. Nagao Y. Spadaro M. Neurology 2001. et al. Sinke RJ. Acta Neuropathol (Berl) 2004. Neurotological findings in a family with episodic ataxia. 44. Novel splice site CACNA1A mutation causing episodic ataxia type 2. 45. Raike RS. Mochizuki Y. Molenaar PC. et al. 52. J Neurol 2002. Baloh RW. Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. et al. Dichgans M. Ducros A. Takita J. Hayashi Y. A novel insertion mutation of acetazolamideresponsive episodic ataxia in a Japanese family.1 in absence epilepsy and episodic ataxia. 11(2):187–189. Kaunisto MA.1 causing episodic ataxia 2. Am J Hum Genet 1997. Van den Maagdenberg AM. Mutant P/Q-type calcium channel electrophysiology and migraine. 47. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the 1A-voltage-dependent calcium channel. Int J Mol Med 2003. Dysfunction of the brain calcium channel CaV2. Guida S. Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Trettel F. Kallela M. 250(3):373–375. Arch Neurol 2001. Kawata A. Curr Opin Investig Drugs 2001. Progressive ataxia due to a missense mutation in a calcium-channel gene. Matsuyama Z. Ann Neurol 2003. 41(6):e82. De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia. Pagnutti S. 42. J Med Genet 2004. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. Nelson SF. 58. Chandra T. Spauschus A. 58(11): 1839–1844. Hereditary paroxysmal ataxia with mental retardation: a clinicopathological study in relation to episodic ataxia type 2. Jouvenceau A. Kalla R. et al. 61(5):1078–1087. 50. Brain 2004. Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. . Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families. et al. et al. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Scoggan KA. Baloh RW. Eunson LH. Chassande B. 54. Zhuchenko O. 38. 51. J Neurol Sci 2003. 53. Complete loss of p/q calcium channel activity caused by a cacna1a missense mutation carried by patients with episodic ataxia type 2. Yue Q. Murase M. Ippel EF. 127(Pt 12):2682–2692. Arayama T. 55. Imbrici P. Subramony SH. Nat Genet 1997:62–69. Van den Maagdenberg AM. J Neurol 2003. Jen JC. et al. Harno H. Schott K. et al. Usami S. A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. et al. Missense CACNA1A mutation causing episodic ataxia type 2. et al. 57. Strupp M. 43. Kim GW. 48. Baloh RW. Mizutani T. Veneziano L. Ferrari MD. 53:34–37. Hahn AF. et al. Jen J. Nelson SF. Neurogenetics 2004. 49. Shimizu H. Igarashi T. 38(4):249–253. Neurology 2004. Yue Q. 41. 46. Vahedi K. Hirose H. Jen JC. 40. 5(1):69–73. Eymard B. Bulman DE. J Med Genet 2001. Chen G. Brain 1994. The spreading depression theory. Abbott LC. Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2þ) channel kinetics. 18(12): 4482–4489. Fletcher CF. 43(3):387–400. Osei-Lah A. Striessnig J. Chioza B. J Biol Chem 1998. familial hemiplegic migraine. Neurology 2000. Herzog J. Nashef L. Furby A. and a new CACNA1A mutation. Frankel WN. 77. Eur J Paediatr Neurol 1997. 20(15):5654–5662. 74. Dichgans M. Kors EE.Genetics of Migraine and Other Primary Headaches 127 60. et al. Cave-Riant F. Kaufer T. Dove LS. Frants RR. Yamazaki K. Wakamori M. Nashef L. Neurology 2001. 56(9):1245–1246. New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus. 273(10): 5586–5590. Neuron 2004. Koschak A. Tournier-Lasserve E. 15(7):1288–1290.1 current density in neurons. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. 52(1):58–61. 68. Tsien RW. 64. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. 63. 65. Heringt S. Presynaptic Ca2þ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2þ channelopathy. 117(Pt 1):199–210. FASEB J 2001. Diener HC. Matsunodaira H. et al. 273(52):34857–34867. et al. 75. Van den Maagdenberg AM. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2þ) channel mutation. 1(1):35–38. 63(6):1136. J Biol Chem 2000. Margalith D. Glossmann H. 70. Oda S. 123(Pt 3): 463–471. Proc Natl Acad Sci USA 1999. 72. Sinnegger MJ. Piedras-Renteria ES. Cao YQ. 18(19):7687–7699. Lennon VA. Hans M. Vanmolkot KRJ. et al. Eur J Hum Genet 2002. Harata NC. 62. Mori Y. Wakamori M. 78. Williams M. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. 61. et al. Tardieu M. altered synaptic transmission. 76. J Neurosci 1998. 71. . Jun K. Plomp JJ. Lorenzon NM. Smith SM. and progressive ataxia in mice lacking the alpha(1A)-subunit. Chioza B. Beauvais K. Ablation of P/Q-type Ca(2þ) channel currents. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Childhood epilepsy. 10(12):857–864. 55(1):139–141. Vergouwe MN. Beam KG. et al. Melberg A. Familial hemiplegic migraine mutations change alpha 1A Ca2þ channel kinetics. Brain 2000. J Neurosci 2000. Eur Neurol 2004. Familial hemiplegic migraine mutations increase Ca(2þ) influx through single human CaV2. 67. Lerman-Sagi T. Lauritzen M. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. Lutz CM. et al. J Neurosci 1998. Wilkie H. Reduced voltage sensitivity of activation of P/Qtype Ca2þ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)). Functional consequences of mutations in the human 1A calcium channel subunit linked to familial hemiplegic migraine. cerebellar ataxia. A family with hemiplegic migraine and focal seizures.1 channels and decrease maximal CaV2. Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy. et al. De Barace C. Tottene A. Neurology 2004. Pathophysiology of the migraine aura. 96(26):15245–15250. Kaube H. 99(20):13284–13289. Kraus RL. 66. Molenaar PC. Kraus RL. Proc Natl Acad Sci USA 2002. 69. Smith GB. Fellin T. Harel S. Ferrari MD. Pagnutti S. Griffith WH. 19(5):1610–1619. 275(13): 9239–9243. J Neurosci 1999. et al. Sinnegger MJ. 73. et al. Luvisetto S. Piedras-Renteria ES. Kramer U. Tottene A. J Biol Chem 1998. 9Mb region on chromosome 1q23. 92. Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene. 96. 89. Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Neurology 2004. 54(3):360–366. et al. Maertens DN. Neuroscience 2000. Neurology 2001. Tonelli A. 95(3):639–645. Shimizu-Sasamata M. Ambrosini A. Ann Neurol 2004. Ursu S. 279(42):43692–43696. 122(5 Pt 1):673–679. Ann Neurol 2003. Scanzano R. Goutieres F.128 Terwindt et al. et al. Bolay H. et al. a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex.324. 55(6): 884–887. Neuropediatrics 2004. Grieco GS. Obrenovitch TP. J Med Genet 2004. Ferrari MD. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. 81. Epilepsia 1998. Bresolin N. Spadaro M. Vanmolkot KR. 93. Zilkha E. 55(2):276–280. Kors EE. Eur J Neurol 2004. 117(5):931–937. Lehmann-Horn F. De Fusco M. D’Onofrio M. 85. Ducros A. 97. Neurology 2004. Single-fiber EMG in familial hemiplegic migraine. Kors EE. 90. Kþ-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. 53(3):376–381. Pizzorusso T. Familial hemiplegic migraine type 2 is linked to 0. Vanmolkot KR. 35(5):293–296. ATP1A2 screening in 27 families with hemiplegic migraine. Moskowitz MA. J Pediatr 1993. 83. Ploton C. Ambrosini A. et al. 84. Lo EH. Moskowitz MA. 80. J Biol Chem 2004. Cephalalgia 2000. Br J Pharmacol 1996. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Alternating hemiplegia of childhood. Ayata C. Bassi MT. et al. Haan J. Neuromuscular transmission in migraine: a single-fiber EMG study in clinical subgroups. et al. et al. Jen JC. 99. 87. 5(3):177–185. Neurogenetics 2004. No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. 11(suppl 2):292. 98. Aridon P. Kaunisto MA. 62(10):1857–1861. Van den Maagdenberg AM. Ophoff RA. 65:1826–1828. Freilinger T. Jurkat-Rott K. K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2. 95. et al. et al. Bourgeois M. Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2. Swoboda KJ. Dalkara T. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Xaidara A. Kanavakis E. Variability of familial hemiplegic migraine with novel A1A2 Naþ/Kþ-ATPase variants. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Harno H. Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome. Dudding KA. 94. et al. Marconi R. et al. Arch Neurol 2004. et al. Riant F. Ann Neurol 2004. Terwindt GM. Baloh RW. Vanmolkot KR. 41(8):621–628. Schoenen J. Vein AA. Kinetic alterations due to a missense mutation in the Na. Kors EE. 86. . Neurology 2005. A G301R Na(þ)/K(þ)-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. 20(8): 696–700. Kim GW. Pietrobon D. 56(8):1038–1043. Terwindt GM. Lindhout D. Terwindt GM. Haan J. Dreier JP. Inhibition of cortical spreading depression by L-701. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. 63(10):1942–1943. Segall L. 38(9):915–921. Aicardi J. Neurogenetics 2004. 88. 79. 41(5):701–710. A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. Van Dijk JG. Neuron 2004. Noebels JL. 61(6):926–928. Ann Neurol 2003. Kors EE. Hottenga JJ. 82. et al. Novel mutations in the Naþ. 5(2): 141–146. Kaunisto MA. 91. Mol Cell 1999. 112. Svensson DA. 73(6):986–993. 106. Kþ-ATPase alpha2 subunit-deficient mice is attributable to abnormal Cl-homeostasis in brainstem neurons. 23(9):921–928. A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes. Cortelli P. Vettori A. et al. Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice. dopamine transporter and dopamine-beta-hydroxylase genes. Hum Mol Genet 2003. 103. J Neurosci 2003. Cevoli S. 101. Griffiths LR. 74(8):1128– 1130. Neurogenetics 2002. Genetic and environmental influences on migraine: a twin study across six countries. Brown JD. Mol Med 1998. Hum Mol Genet 1998. 43(3):235–244. 3(5): 555–563. . 2(2):91–99. Significant linkage to migraine with aura on chromosome 11q24. Waldenlind E. Russo L. Genetic loading in familial migraine with aura. Neurol Sci 2003. Association study designs for complex diseases. Dyment DA. Nyholt DR. 116. 110. 118. et al. Neurology 1998. 109. Forsgren L. Ostergaard E. Headache 2003. 107(1):18–23. Yamakado M.Genetics of Migraine and Other Primary Headaches 129 100. et al. Headache 2003. Palmas MA. Brimage PJ. 104. Cephalalgia 2004. et al. Bell JI. Bjornsson A. Sangiorgi E. van Baal C. Nylander PO. Am J Hum Genet 2004. et al. Nicholson GA. Headache Classification Subcommittee of the International Headache Society. Malfunction of respiratory-related neuronal activity in Naþ. et al. 6(5):422–431. Am J Hum Genet 2003. Soragna D. 24(suppl 1): 1–160. Romer SF. et al. 113. J Neurosci 2004. Onaka T. Cologno D. Cephalalgia 2003. Manzoni GC. Gaistz D. Hum Genet 2000. 117. et al. 107. Mariotti P. Goadsby PJ. De Pascale A. 102. 76(2). 43(3):231–234. Wilhoit TL. Ikeda K. Dawkins JL. Identification of a susceptibility locus for migraine with and without aura on 6p12. Ebers GC. Thomsen LL. 4(1):17–22. Rice GPA. Mochi M. et al. Lea RA.3. Shepherd AG. A genetic association study of migraine with dopamine receptor 4. Neurology 2002. 108. Noble-Topham S. Nat Rev Genet 2001. Shared rearing environment in migraine: results from twins reared apart and twins reared together. The International Classification of Headache Disorders. 59(11):1804–1807. Association between dopamine receptor genes and migraine without aura in a Sardinian sample. 120. A typical migraine susceptibility region localizes to chromosome 1q31. Localization of a gene for migraine without aura to chromosome 4q21. Cader ZM. anxiety and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Cardon LR. Yamada J. Evidence for an x-linked genetic component in familial typical migraine. Gudmundsson G. Curtain RP. 105. Pedersen NL.1. Price SC. Mulder EJ. Peroutka SJ. 23(11):4667–4676. 12(19):2511–2517. 115. et al. James PF. 24(47):10693–10701. Larsson B. Identification of a specific role for the Na. Carlsson A. Noble-Topham SE. 111. et al. 7(3):459–463. J Neurol Neurosurg Psychiatr 2003. Griffiths LR. Grupp IL. K-ATPase alpha2 isoform as a regulator of calcium in the heart. A locus for migraine without aura maps on chromosome 14q21. 2nd ed. Cader MZ.2-p21. Nyholt DR. Cherchi A. Del Zompo M. et al. Jones KW. Am J Hum Genet 2003. 72(1):161–167. Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder. Comorbid migraine with aura. Carraro G. Gudfinnsson E.2-q22. et al. 114. Grupp G. 23(6):301–305. Familial occurrence of migraine with aura in a population-based study. Twin Res 2003. 51:781–786. Ikeda K. Onimaru H. 4:14–21. Familial typical migraine: significant linkage and localization of a gene to Xq24–28. Dyment DA. 119. Curtain RP. Kowa H. 121. et al. 60(11):1864–1865. Tzourio C. Kowa H. Neurology 2004. Genomics 2001. Clinical observations on familial cluster headache. 136. Migraine and MTHFR C677T genotype in a population-based sample. 24(2):61–64. 96(6):762–764. Sakai F. An investigation of the 5-HT2C receptor gene as a migraine candidate gene. 137. Torelli P. Salani G. Svensson D. Lea RA. Ostergaard S. Arnold G. Macmillan J. Poirier O. Ovcaric M. J Neurol Sci 2003.2) in susceptibility to migraine without aura. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. May A. Rainero I. Lea RA. et al. Neurol Sci 2003. Pediatr Res 2004. BMC Med 2004. Glutathione S-transferase polymorphisms: susceptibility to migraine without aura. Ishizaki K. . 49(4):218–222. Traff H. Urakami K. 134. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. 23(5):376–380. 59(2):372–375. Johnson MP. Sundholm J. 60(4):717–719. Neurology 2004. 132. Massa R. Reichmann H. Mochi M. Takeshima T. Eur Neurol 2003. Waldenlind E.10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Cupini LM. Mitochondrial DNA in migraine with aura. Meisel A. Hosford DA. 117B(1):86–89. 130. 135. Schuh-Hofer S. MacMillan JC. Riley JH. Association of the C677T and A1298C polymorphisms in the 5. 125. Ergul E. Ann Neurol 2006. Pedersen NL. 133. 63(7):1286–1288. Migraine-like disorder segregating with mtDNA 14484 Leber hereditary optic neuropathy mutation. 213(1–2):7–10. 126. Association between the tumor necrosis factoralpha-308 G/A gene polymorphism and migraine. Li BUK. 78(3):135–149. Verschuren WM. Nakashima K. et al. 122. Maternal inheritance in cyclic vomiting syndrome. Neurology 2001. Seibel P. Alperovitch A. 123. Cupini LM. Calabresi P. 127. 56(10):1273–1277. 46(6):1735–1738. Investigation of an LDLR gene polymorphism (19p13. Neurology 1996. Cephalalgia 2003. Kilic G. Cevoli S. Kara I. 62(1):141–143. Gallone S. Comparison of first degree relatives and spouses of people with chronic tension headache. et al. Monozygotic twin sisters suffering from cluster headache and migraine without aura. Am J Med Genet 2000. Santorelli FM. Am J Med Genet 2003. Association between migraine and endothelin type A receptor (ETA-231 A/G) gene polymorphism. BMJ 1998. Brain Res Mol Brain Res 2003. Olesen J. Cortelli P. Neurology 2003. Neurology 2003. Floris R. Reuter U. Curtain RP. Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine. Kaya G. Griffiths LR. Papagiannuli E. 128. Rainero I. 139. Diener HC. McCarthy LC. 138. Russell MB. Adams K. et al. Iani C. Nicaud V. Valfre W. Grimaldi LM. Manzoni GC. Boles RG.130 Terwindt et al. 129. Berndtsen L. Kusumi M. Klopstock T. Ekbom K. El Amrani M. Scher AI. 111(1–2):84–90. Sazci A. Bousser MG. Terwindt GM. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. 314:1092–1093. A note on cluster headache in a population-based twin register. 55(4):273A–274A. 124. Fariello G. 2(1):3. Yasui K. et al. Griffiths LR. 131. It is important to have an approach to headache and to exclude red flags.A. the only way to truly identify or exclude secondary headaches is to investigate.10 Identification or Exclusion of Secondary Headaches Randolph W. For the most part this chapter will deal with neuroimaging. judicious use of testing is essential to distinguish primary from secondary headaches. New York. This chapter reviews in detail the following topics: general indications for neuroimaging. Neuroimaging is at best however. Nonneurological testing such as laboratory testing and imaging outside the nervous system still have a role to play. evaluation of the acute severe new-onset headache (‘‘first or worst headaches’’). Texas. and Queen Elizabeth II Health Sciences Centre. The other strategies for subsidiary investigation will be discussed when appropriate. which includes over 300 different types and causes of headache. Nova Scotia. 131 . Canada INTRODUCTION Clinical assessment still has a significant role to play in identifying and excluding secondary headaches. Halifax. and evaluation of new daily headaches. neuroimaging for headaches with a normal neurological examination. U. Houston. any of the secondary headache disorders can mimic primary headaches. and Baylor College of Medicine. a good history and careful neurological and general physical examination remains the basis of such an assessment and. headaches over the age of 50. Weill Medical College of Cornell University. becoming the actual standard to identify and exclude secondary headache etiologies. Department of Neurology. Notwithstanding the instances listed above. Therefore. Evans Department of Neurology and Neuroscience. but frequently there are signs and symptoms of a nonneurological etiology. However. neuroimaging for migraine. Dalhousie University. R. New York. it is now a surrogate for good clinical assessment. in large part. works best for primary headache disorders.S. Allan Purdy Division of Neurology. neuroimaging is the most relevant investigative tool for yielding primary neurological etiologies. This has been dealt with in previous reviews (1). The Methodist Hospital. In essence. The ‘‘first or worst’’ headache 2. Chronic daily headache 5. Patients with headaches and seizures C. Headaches other than migraine with aura associated with focal neurologic symptoms or signs 12. or personality change Source: From Ref. and medicolegal issues (2). Based on associated symptoms and signs 10. Sempere et al. Subacute headaches with increasing frequency or severity 3. cognitive impairment. with a mean age of 38 years. faulty cognitive reasoning. 2. recently reported a study of 1876 consecutive patients aged 15 years or older. concluded that there was not sufficient information to estimate the probability of important intracranial pathology among patients with nonmigrainous headache and a normal neurological examination.7%). A progressive or new daily-persistent headache 4. NEUROIMAGING FOR HEADACHES WITH A NORMAL NEUROLOGICAL EXAMINATION The yield of computed tomography (CT) scan or magnetic resonance imaging (MRI) in patients with any headache and a normal neurologic examination is about 2% (3). post-traumatic (3. Headache Consortium. with accessibility to testing being a problem in other countries. cluster (1. Headaches associated with papilledema. Based on the temporal and headache features 1. particularly in the United States. New-onset headaches in patients who have cancer or who test positive for HIV infection 8. Lack of funds and underinsurance continue to be barriers for appropriate diagnostic testing for many patients. stiff neck. and recommended comparative studies between MRI and CT (4).132 Evans and Purdy GENERAL INDICATIONS FOR NEUROIMAGING FOR HEADACHES There are many reasons why physicians recommend diagnostic testing for headaches: aiming for diagnostic certainty. . In the era of managed care. Based on the demographics 7. Table 1 provides reasons to consider neuroimaging for headaches. The types of headaches were the following: migraine (49%).1%). Headaches always on the same side 6. the medical decision rule that holds that it is better to impute disease than to risk overlooking it.4%). New-onset headaches after age 50 9. The U. tension-type (35. and vomiting 11.S. Headaches not responding to treatment B. patient and family expectations. equally compelling reasons for not ordering diagnostic studies include physician fears of deselection and at-risk capitation. Headaches associated with symptoms and signs such as fever. busy practice conditions in which tests are ordered as shortcuts. financial incentives. nausea. who presented to a neurology clinic in Spain with nonacute headache (5). which published an evidence-based guideline. and Table 1 Reasons to Consider Neuroimaging for Headaches A. large arachnoid cyst (2). meningioma (2).S. brain stem glioma. However. while the other two-thirds reported headaches for more than one year.2% of patients. one can miss significant pathology at the patient’s peril and one’s own medicolegal risk (Table 2). a small meningioma that was not treated surgically. spontaneous low cerebrospinal fluid (CSF) pressure syndrome mimicking primary cough headache (which would have been missed without the administration of gadolinium) (7). but that we suspect many experienced neurologists will have similar cases. study is outstanding and provides valuable information about neuroimaging in a large consecutive series of patients referred to a neurology clinic. arteriovenous malformation (AVM). MRI is the preferred study for the evaluation of headaches with the exception of patients with head trauma. Questions still remain about the value of MRI versus CT and MRI. and posterior fossa papilloma (1). Headache Consortium reported that a meta-analysis of patients with migraine and a normal neurological examination found a rate of significant intracranial lesions of 0. and selection of use of magnetic resonance angiography (MRA) and magnetic resonance venography (MRV). Evans has found occasional incidental saccular aneurysms on MRI scans in his own practice (7) as contrasted to the 0% reported by Sempere. ischemic stroke.9%. Chiari type I malformation. Among 118 patients with normal neurological examinations and normal CT scans. All patients underwent either a MRI or a CT scan. 8 were treated surgically. and a pilocytic astrocytoma of the cerebellar hemisphere with mass effect mimicking migraine status (8). The low overall detection rate for significant pathology corresponds to our experience.18% (3).’’ Table 3 provides some reasons to consider neuroimaging in patients with migraine. Of these 17 patients. low-grade astrocytoma.8% of adults (9). cavernous angioma. and contraindications to MRI. detected on MRI. ‘‘Neuroimaging is not usually indicated for patients with migraine and normal neurological examination. Severe. MRA may detect incidental saccular aneurysms in 2. When available. and new-onset headaches were not associated with higher rates of significant intracranial lesions. 17 patients).2%. progressive. without contrast versus with and without contrast. For example.8%). The consortium concluded. that would have been missed on CT: a hemorrhagic pituitary adenoma mimicking migraine (6).Identification or Exclusion of Secondary Headaches 133 indeterminate (10. The Sempere et al. In addition. NEUROIMAGING FOR MIGRAINE The U. Significant intracranial abnormalities were detected in those with headaches and a normal neurological examination (0. . There were no saccular aneurysms detected among the 580 patients who underwent MRI scans and there was only one patient with a greater than or equal to 5 mm tonsillar descent. ‘‘Crash’’ migraines are considered in the next section. if one concludes that CT is as sensitive as MRI for the evaluation of headache. MRI disclosed only one significant lesion. colloid cyst. The point is not that Evans is so astute. acute headache to rule out subarachnoid hemorrhage (SAH). One-third of the patients had new-onset headache. Neuroimaging studies detected significant lesions in 1. Neurological examination was normal in 99. hydrocephalus (2). Evans has reported three types of pathology from his own general neurology practice. a Chiari I malformation that was asymptomatic. The diagnoses in these 17 patients were pituitary adenoma (3). prolonged. especially those in the occipital lobe. Bruyn reported the following features in Table 3 Reasons to Consider Neuroimaging in Migraineurs Unusual. or persistent aura Increasing frequency. Vascular disease Saccular aneurysms Arteriovenous malformations (especially in the posterior fossa) Subarachnoid hemorrhage Carotid or vertebral artery dissections Infarcts Cerebral venous thrombosis Vasculitis (white matter abnormalities) Subdural and epidural hematomas B. Migraine-like headaches with and without visual symptoms can be associated with AVMs. Source: From Ref. However. severity. or change in clinical features First or worst migraine Basilar Confusional Hemiplegic Late-life migraine accompaniments Aura without headache Headaches always on the same side Posttraumatic Request of patient or family and friends Source: From Ref. . which is the predominant location of about 20% of parenchymal AVMs (13). One potential migraine mimic is an AVM malformation where side-locked headaches are present in up to 95% of cases (12). There is a question mark after ‘‘Headaches always on the same side. 2.14). Neoplastic disease Neoplasms (especially in the posterior fossa) Meningeal carcinomatosis Pituitary tumor and hemorrhage C.134 Evans and Purdy Table 2 Causes of Headache That Can Be Missed on CT Scan of the Head A.’’ because 17% of patients with migraine without aura and 15% of those with migraine with aura always have headaches on the same side (side-locked headaches) (11). 10. Infections Paranasal sinusitis Meningoencephalitis Cerebritis and brain abscess E. Cervicomedullary lesions Chiari malformations Foramen magnum meningioma D. computed tomography. Low cerebrospinal fluid pressure syndrome Abbreviation: CT. a typical migraine due to an AVM is the exception because there are usually distinguishing features (12. Based upon a meta-analysis.Identification or Exclusion of Secondary Headaches 135 patients with migraine-like symptoms and AVM: unusual associated signs (papilledema. 20%. spread of symptoms within a modality with a gradual march of paresthesias from limb to face or an enlargement of a scotoma and from one modality to another. Table 4 provides the extensive list of possible causes of the acute severe new-onset headache (the ‘‘first or worst’’). 24%. Internal carotid artery dissection can also cause a scintillating scotoma alone resembling the migraine aura (17). A severe headache with nausea and vomiting can accompany or follow the other symptoms. brief scintillating scotoma. 50%. atypical sequence of aura. and prolonged course (16). EVALUATION OF THE ACUTE SEVERE NEW-ONSET HEADACHE (‘‘FIRST OR WORST HEADACHES’’) There are numerous secondary headaches that have to be excluded as the cause of primary headaches which can present with an acute and severe onset such as crash migraine (maximum intensity shortly after the onset). Over 30. no neurologic deficit other than cranial nerve palsy). In about 50% of these arteriogram-negative cases. 65%. Vertebral artery dissection can also rarely mimic migraine (18). and seizures. In about 15% of cases. and bruit). primary exertional headache (including weightlifting headache). Perhaps 50% of SAHs will present with a Hunt and Hess grade I (no symptoms or minimal headache. perimesencephalic hemorrhage that may be caused by a ruptured prepontine or interpeduncular cistern dilated vein or venous malformation. Most patients with headache due to SAH will have the worst headache of their life with maximum intensity within five minutes and a duration of at least one hour (23. Distal internal carotid artery dissection is another rare migraine mimic that may be of concern in patients with either new-onset migraine aura or those with a change in the aura or unusual features. A prospective study of 148 patients with acute severe headaches seen by general practitioners in the Netherlands found SAH to be the cause in 25% (20). an arteriogram does not demonstrate the cause of the bleeding. About 85% of SAH are due to ruptured intracranial aneurysms (21) and 5% are due to rupture of intracranial AVMs. first migraine. 19% (23). short duration of headache attacks.24).000 people per year in the United States have an SAH from a ruptured saccular aneurysm.’’ The headaches were of . resulting in over 18. the onset of headache was as follows: almost instantaneous. Migrainous features may include positive symptoms such as monocular visual scintillations or paresthesias. 25% (11). In a series of 42 patients with aneurysmal SAH. and vomiting.1% had a history of migraine in one study) (15). There are many causes of SAH (Table 5). SAH can present with identical symptoms to these primary headaches. The diagnosis can be more challenging because carotid dissection is more common in migraineurs (49. field cut. 10%. CT angiography (CTA). Twelve percent had a feeling of a ‘‘burst. carotid ultrasound (less sensitive than the other tests). absent family history. and 1 to 5 minutes. slight nuchal rigidity) or II (moderate to severe headache. MRA. the CT scan reveals blood confined to the cisterns around the midbrain. 15%. and primary headache associated with sexual activity. primary thunderclap headache. Other causes of arteriogram-negative SAH are listed in Table 5 (20). 2 to 60 seconds. or catheter angiography can detect the dissection. headache. 10%. the prevalence of saccular aneurysms in the general population is about 2% with 93% of aneurysms 10 mm or less in size (22). Multiple episodes can occur.000 deaths. SAH can be easily overlooked (25). Cephalic infection Meningoencephalitis Acute sinusitis H. Associated with nonvascular intracranial disorders Intermittent hydrocephalus Benign intracranial hypertension Post–lumbar puncture Spontaneous intracranial hypotension Related to intrathecal injections Intracranial neoplasm Pituitary apoplexy E. Acute intoxications F. Cervicogenic Greater occipital neuralgia Cervical myositis K. Acute mountain sickness I. gradually increasing headache (26). . Nineteen percent had a prior headache resembling the acute headache. Primary headache disorders Migraine Cluster Primary exertional headache Primary thunderclap headache Primary headache associated with sexual activity B.136 Table 4 Differential Diagnosis of the Acute Severe New-Onset Headache (‘‘First or Worst’’) A. Evans and Purdy moderate-to-severe intensity. Trigeminal neuralgia Source: From Ref. Associated with noncephalic infection Acute febrile illness Acute pyelonephritis G. Transient loss of consciousness lasting for 1 to 10 minutes was reported by 26%. 53. Disorders of eyes Acute optic neuritis Acute glaucoma J. Posttraumatic C. Associated with vascular disorders Acute ischemic cerebrovascular disease Subdural and epidural hematomas Parenchymal hemorrhage Unruptured saccular aneurysm Subarachnoid hemorrhage Systemic lupus erythematosis Temporal arteritis Internal carotid and vertebral artery dissection Cerebral venous thrombosis Acute hypertension Pressor response Pheochromocytoma Preeclampsia D. Ten percent of patients have no headache at onset and 8% describe a mild. When first primary orgasmic and exertional headaches occur. A lumbar puncture should be considered in all patients with a new-onset headache suspicious for SAH. 2. defecation. Unfortunately.Identification or Exclusion of Secondary Headaches Table 5 Causes of Nontraumatic Subarachnoid Hemorrhage 80% Intracranial saccular aneurysm 5% Intracranial arteriovenous malformation 15% Negative arteriogram 50% Benign perimesencephalic hemorrhage 50% Other causes Occult aneurysm Mycotic aneurysm Vertebral or carotid artery dissection Dural arteriovenous malformation Spinal arteriovenous malformation Sickle cell anemia Coagulation disorders Drug abuse (especially cocaine) Primary or metastatic intracranial tumors Primary or metastatic cervical tumors CNS infection CNS vasculitides Abbreviation: CNS. Red blood cells (RBCs) are present in virtually all cases of SAH and variably clear in about 6 to 30 days. aneurysmal SAH is present on 95% of scans but decreases to 50% by the end of the first week. and over 40% after four weeks (29). intracranial ferromagnetic clips. there is additional risk from the intravenous contrast in patients with renal insufficiency. During the first 24 hours. Using spectrophotometry to detect xanthochromia. Although oxyhemoglobin can be detected as early as two hours after the entry of RBCs into CSF. When the CSF obtained from the first lumbar puncture is bloody. and almost 0% by the end of the third week (28). Some centers are using CTA . dehydration. and severe claustrophobia. Spiral (helical) CTA can detect 93% to 100% (31. CTA can be very useful instead of or as an alternative to MRA for patients with contraindications to MRI. central nervous system. such as those with pacemakers. or sexual intercourse. From more than 3 to 14 days after the hemorrhage.3% of hospital laboratories in the United States. In practice. the probability of detection is 100% through the first two weeks after the SAH. 30% by the end of the second week. lifting. Source: From Ref. 137 A stiff neck is absent in 36% of patients (27). over 70% after three weeks. However. MRA and CTA are both limited. in addition to contrast allergy.32) of intracranial saccular aneurysms. spectrophotometry is available in only about 0. of course. xanthochromia is not present in all cases until after 12 hours. SAH has to be excluded because one-third of SAHs occur during activities such as bending. who have normal CT or MRI scans. A CT scan of the brain is the initial imaging study of choice to detect SAH. the only certain way to distinguish SAH from a traumatic tap is the presence of a xanthochromia. and diabetes (when used as a screening study instead of MRA). MRI using the fluid-attenuated inversion recovery sequence is more sensitive than CT scan in the identification and delineation of SAH. MRA can detect about 90% of saccular aneurysms with a size of 5 mm or larger (30). by the quality of the images and the ability of the interpreting physician. Although 90% of headaches in younger patients are of the primary type. is present in 40% of patients with brain tumors. in females and males. . 92% and 74%. 66% and 53%. Only one patient met the migraine criteria. the prevalence of headaches is as follows: 21 to 34 years. Table 6 New-Onset Headaches Occurring Over 50 Years of Age A. hypnic headache. When new-onset tension-type headaches occur. compared with younger patients. As examples. Secondary headaches Neoplasms Subdural and epidural hematomas Head trauma Cerebrovascular disease Temporal arteritis Trigeminal neuralgia Postherpetic neuralgia Medication related Systemic disease Diseases of the cranium. Eight percent of patients with headaches and brain tumors have a normal neurologic examination.138 Evans and Purdy alone preoperatively for most cases. Primary headaches Migraine Tension Cluster Hypnic B. neck. although patients may complain of pain in other locations of the head as well as the neck. and headache of Parkinson’s disease are secondary headaches occurring with much greater frequency in this population. ears. the most frequent diagnoses were tension-type (43%) and trigeminal neuralgia (19%) (37). Fifteen percent had secondary headaches due to conditions such as stroke. The most common location of headaches is bifrontal. HEADACHES OVER THE AGE OF 50 YEARS The prevalence of headache decreases with older age. Papilledema. eyes. and over 75 years. Temporal arteritis. Primary and metastatic brain tumors should be considered (39). temporal arteritis. or intracranial neoplasm. only 66% of those in the elderly are primary (34). Although the quality of the headache is usually similar to that of the tension type. The risk of serious disorders causing headache increased 10 times after the age of 65. About 10% of those with tension-type headaches have an onset after 50 years of age (38). 55 to 74 years. which is usually associated with headaches. In a study of 193 patients 65 years of age and older with new-onset seen by a neurology service. Unilateral headaches are usually on the same side as the neoplasm. There are numerous causes of new-onset headaches in those over 50 years of age (Table 6) (36). 35. respectively. the diagnosis is one of exclusion. (31) whereas others still consider digital subtraction angiography the gold standard. at the following ages. and nose Parkinson’s disease Exertional headache due to angina Source: From Ref. 55% and 22% (33). Cluster headache has an onset over the age of 50 years in only a minority of cases. Late-life migrainous accompaniments are transient visual. motor. and blood studies) for transient ischemic attacks (TIAs) or seizures is performed. A history of similar episodes associated with a more severe headache 5. Table 7 Features of Late-Life Migrainous Accompaniments 1. Diagnosis facilitated with the occurrence of two or more identical episodes 7.7% of females and 8. an onset over the age of 50 was reported by 16. or a heavy feeling of an extremity). Serial progression from one accompaniment to another (e. brain stem and cerebellar dysfunction (ataxia. The following features help to distinguish migraine from TIAs: a gradual buildup of sensory symptoms. aneurysm of the anterior communicating. to exclude the rare secondary causes of cluster. especially if atypical features are present. Most of the headaches are intermittent with moderate-to-severe intensity. 35. sensory. pseudoaneurysm of intracavernous carotid artery. and rarely migraine with aura and cluster headaches. Headache is associated with only 50% of cases and may be mild. and associated with nausea and vomiting—occurs in a minority of patients with brain tumors. and multiple stereotypical episodes. worse in the morning. and flashing or bright lights 4. In a study of 554 episodic and chronic cluster patients. especially when the patient is seen after the first episode or if there are unusual aspects.7% of males (42).. The usual diagnostic evaluation (such as CT scan. hearing loss. from most to least common: visual symptoms (transient blindness. cardiac evaluation. carotid. including the following: internal carotid artery dissection.g. homonymous hemianopsia. or dysphasia) 6. Positive visual symptoms such as scintillating scotoma. a march of sensory paresthesias. or basilar artery. carotid ultrasound. Only 2% of migraineurs have a new onset after 50 years of age. A usually benign natural history. MRI and MRA of the brain. Headache is only present in 50% of cases and may be mild 3. Other causes of transient cerebral ischemia should be considered. A duration of 15–25 min 8. Another cause not shown by diagnostic testing that is performed when indicated Source: From Ref. Consideration might be given to obtaining an MRI scan in late-onset cluster. Gradual appearance of focal neurologic symptoms with spread or worsening over a period of minutes 2. from flashing lights to paresthesias. paresthesias (numbness. without permanent sequelae 10. The ‘‘classic’’ brain tumor headache—severe. Table 7 provides the features of late-life migrainous accompaniments. and disturbances of speech (dysarthria or dysphasia). pins-and-needles sensation.41). clumsiness. or behavioral neurologic manifestations that are similar or identical to the auras of migraine with aura (40. and blurring of vision). paresis. but a significant minority report only mild headaches relieved by simple analgesics. tingling. These accompaniments occur more often in men than in women. tinnitus. and syncope).Identification or Exclusion of Secondary Headaches 139 occasional patients have headaches similar to migraine without aura. The complaints occur as follows. longer duration (90% of TIAs last for less than 15 minutes). vertigo. with a prevalence of about 1%. serial progression from one accompaniment to another. . A characteristic ‘‘flurry’’ of accompaniments 9. electroencephalography. A few additional examples will be discussed.140 Evans and Purdy AVM of the middle cerebral territory or occipital lobe. particularly when seen within the first two months after onset. phonophobia. and not aggravated by routine physical activity such as walking or climbing. temporal arteritis. orbitosphenoidal aspergillosis. When the headaches have been present for more than three months with a normal neurological examination. within three days of onset. New-onset daily headaches with a normal neurological examination could also be due to various other causes. the yield of testing is low. high cervical meningioma. the criteria for new daily-persistent headache (NDPH) are a headache that. and hypertension. and neither moderate or severe nausea nor vomiting. brain tumors. including postmeningitis headache. is daily and unremitting for more than three months and has at least two of the following characteristics: bilateral location. maxillary sinus foreign body. chronic meningitis. pressing/tightening (nonpulsating) quality. NEW DAILY HEADACHES Table 8 lists some primary and secondary causes of new daily headaches (44). leptomeningeal metastasis. and orbital myositis (43). or mild nausea. the headache is not attributed to another disorder (45). Finally. According to the IHS second edition. The criteria require both of the following: no more than one of photophobia. pituitary adenoma. unilateral cervical cord or lateral medullary infarction. Table 8 Differential Diagnosis of New Daily Headaches Primary headaches New daily-persistent headache Chronic migraine Chronic tension type Combined features (new daily-persistent headaches with frequent migraine features) Primary thunderclap headache Secondary headaches (new daily-persistent headache mimics) Postmeningitis headache Chronic meningitis Primary with medication rebound Neoplasms Temporal arteritis Chronic subdural hematoma Posttraumatic headaches Sphenoid sinusitis Hypertension Subarachnoid hemorrhage Low cerebrospinal fluid pressure syndrome Cervical artery dissections Pseudotumor cerebri Cerebral venous thrombosis . posttraumatic headaches. chronic subdural hematomas. sphenoid sinusitis. mild or moderate intensity. meningioma of the lesser wing of the sphenoid. Some of these secondary disorders may have a thunderclap or sudden onset of severe headache whereas others may develop gradually over one to three days and meet the onset period criteria for NDPH. Neurology 1994. 4%. Diagnostic Testing in Neurology. and cerebellar signs. the legs are flexed. 1999:1–18. Rosenberg JH. American Academy of Neurology. Purdy RA. CVT can be a mimic of PTC. Cerebral venous thrombosis (CVT) can also be misdiagnosed as PTC when the appropriate neuroimaging study is not obtained. Cervical artery dissections can be a rare cause of new daily headaches (47). In: Evans RW. Philadelphia: WB Saunders. and the abdominal muscles are contracted. the pressure can be fictitiously elevated if the patient is not relaxed. 3. 2. bilateral cortical signs. 42%. Evans RW. Computed tomography only diagnoses about 20% of cases of CVT when demonstrating the hyperdensity of the thrombosed sinus on plain images and the delta sign seen with superior sagittal sinus thrombosis after contrast administration. Helical CT venography is a very sensitive diagnostic method. http:// www. Occasionally. 3% (53). resolve even though the intracranial pressure is still elevated (51). Pseudotumor cerebri (PTC) or idiopathic intracranial hypertension can be a cause of new daily headaches and is easily suspected when papilledema is present. 4. Conversely. multiple cranial nerve palsies. Frishberg BM. MRI abnormalities are usually (perhaps 90% of cases) but not always present. The headache can be unilateral or bilateral in any location. on conventional angiography. Evidenced-based guidelines in the primary care setting: neuroimaging in patients with nonacute headache. focal deficits. 85(4):847–863. Clinical evaluation of a patient presenting with headache. Although the CSF opening pressure can be up to 25 cm of water in obese people. Matchar DB. . Neuroimaging studies have variable sensitivities in diagnosing CVT. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations.com. encephalopathy. As noted. pseudo-PTC (52). MRV increases the sensitivity of MR especially within the first five days of onset or after six weeks. In over 95% of cases. rarely. PTC without papilledema (49) can rarely occur and should be considered as the cause of NDPH especially in obese females who account for 90% of the cases of pseudotumor.Identification or Exclusion of Secondary Headaches 141 Spontaneous intracranial hypotension can be a difficult clinical diagnosis especially when the orthostatic component is minimal or absent (46).aan. REFERENCES 1. 44:1353–1354. and can lead to a pattern of chronic daily headaches especially after cervical carotid artery dissection (48). CVT can also be demonstrated. Papilledema can initially be present in PTC and then. 39%. Med Clin North Am 2001. et al. of course. and intermittent or constant. mild to severe. 31%. The orthostatic worsening can be absent both early in the clinical course and chronically. The evaluation of headaches. However. seizures. the headache is associated with a variety of neurological signs in the following percentages of patients: papilledema. 11%. Caution is advisable to avoid misdiagnosis. 51%. The onset is usually subacute but can be sudden or thunderclap. the headaches can persist intermittently for months and even years. Headache is present in up to 90% of cases of CVT and is often the initial symptom. ed. PTC can be present with papilledema and normal CSF opening pressure (50). CVT may be missed on routine MRI imaging of the brain although echo-planar T2à -weighted MRI may increase the sensitivity (54). Prevalence and risk of rupture of intracranial aneurysms. 14. Johnston SD. Available at www. van der Wee N. 74:743–748. Robinson TJ . Neurology 1996. 13(59):435–437. J Neurol Neurosurg Psychiat 1989. Migrainelike headaches associated with pituitary hemorrhage. van Gijn J. Medlink Neurology. Jane JA. 2002. ed. 21. Subarachnoid hemorrhage. 13. 42(3):105–112. In: Purdy RA.142 Evans and Purdy 5. 18. Headache 1993. Welch KM. ON: BC Decker. van Gijn J. 24. 26. 14:79–87. Cephalalgia 1984. Yamagata Z. Bartelds AIM. J Neurol Neurosurg Psychiat 1998. Benslamia L. Occipital arteriovenous malformations: visual disturbances and presentation. Linn FHH. Kongable GL. Torner JC. Kupersmith MJ.com. Guillon B. 12. 41:1084–1107. Chyatte D. Djibuti M. Evans RW. Haley EC. 20. 344:590–593. eds. 2d ed. Blijenberg BG. Retrospective analysis of the prevalence of asymptomatic cerebral aneurysm in 4518 patients undergoing magnetic resonance angiography—when does cerebral aneurysm develop? Neurol Med Chir (Tokyo) 2002. Cephalalgia 1994. Porta-Etessam J. 45:374–377. Leone M. Algra A. Kassell NF. Evans RW. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after a negative scan? J Neurol Neurosurg Psychiat 1995. Young G. 33:381–384.1111/j. 19. Intracranial arteriovenous malformation and migraine. Rinkel GJE. Van Gijn J. 7. Spontaneous low cerebrospinal fluid pressure syndrome can mimic primary cough headache. 27. Lancet 1994. Hijdra A. 100(2):116–120. et al. 9. Neurology. et al. Headache 1997. Rinkel GJE. van der Graaf Y. Headaches from aneurysms. Characteristics of headache associated with cerebral arteriovenous malformations. Wityk RJ. 4:191–207. van Gijn J. Adams HP. 17. Acute headache in the emergency department. 23. Nukui H. Wijdicks EFM. Cephalalgia OnlineEarly doi:10. 37:455–456. Tzourio C. San Diego: MedLink Corporation. Scintillating scotomata associated with internal carotid artery dissection: report of three cases. D’Amico D. Clinical considerations on side-locked unilaterality in long lasting primary headaches. Boes C. In: Gilman S. Tepper S. Vermeulen M. Weir B. 8. et al. Stroke 1998. Postgrad Med 1998. J Neurol Neurosurg Psychiat 2002. Vertebral artery dissection mimicking migraine. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Ramadan NM. J Neurol Neurosurg Psychiat 1995. et al. Frediani F. Medrano V. 73:18–36. Sempere AP. J Neurosurg 1990. 25. 59:340–341. 29:251–256. The international cooperative study on the timing of aneurysm surgery. Part I: Overall management results. Sheftell F. 72(suppl 2):ii33–ii37. Hasan D. Subarchnoid haemorrhage: difficulties in diagnosis and treatment. 52:826–828. 46:953–957. A systematic review. Hamilton. Headache 2005. Migraine and the risk of cervical artery dissection: a case-control study. Tietjen GE. Cephalalgia 2005. Clin Neurol Neurosurg 1998. et al. Bruyn GW. 2005. Davenport R. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. Weerdesteyn-van Viiet FAC. 2006. Advanced Therapy of Headache. 15. Evans RW. Vargas ME. 16. 58:357–359. Ghossoub M. Neurology 1991. Transient migraine-like symptoms with internal carotid artery dissection. Rinkel GJE.1468–2982. Levine SR. 47:177–183. Nataf F. Algra A. . Yashar A. Linn FHH. 25:30–35. Khajavi K. 65:791–793. 11. 10. van Gijn J. 22. Rapoport A. Xanthochromia after subarachnoid haemorrhage needs no revisitation. Humphrey P. Merienne L. Silverman IE.medlink. Medico-legal headaches: trials and tribulations. Horikoshi T. Neuroimaging in the evaluation of patients with non-acute headache. 6. Akiyama I. Neurochirurgie 2001. Hasan D. Sanin LC. 54. MedLink Neurology. 22:94–100. First or worst headaches. Headache 2001. 41. Nemeroff CB. Geriatric headache. 45:1517–1522. Piovesan LdoR. Piovesan EJ. Purdy RA. The International Classification of Headache Disorders. Adults and children with headache: evidencebased diagnostic evaluation. Karamessini MT. New York: Oxford. Selim M. Fink J. 2d ed. 2006. 22:39–53. et al. Mathew NT. 30:273–276. 43. Low cerebrospinal fluid pressure syndromes. In: Evans RW. 49. Green JP. Demographics of headache in elderly patients. Long-term evolution of papilledema in idiopathic intracranial hypertension: observations concerning two cases. In: Silberstein SD. Stowe ZN. New daily persistent headache. 33. Purdy RA. Silbert PJ.medlink. Neurosurgery 2004. Available at www. The Pontypridd headache survey. eds. Evans RW. Handbook of Headache. Mokri B. 49:212–223. Kagadis GC. 22:55–74. Pascual J. 2d ed. J Neuroophthalmol 1996. Experience in the diagnosis of headaches that start in elderly people. Headache in cervical artery dissections. Handbook of Headache. Curr Pain Headache Rep 2003. Evans RW. Diagnosis of headaches and medico-legal aspects. In: Evans RW. 59(6):1021–1026. Philadelphia: Lippincott-Williams&Wilkins. San Diego: Arbor. Evans RW. Goadsby PJ. 7:303–307. Frame J. Handbook of Headache. 51.Identification or Exclusion of Secondary Headaches 143 28. Neuroimaging Clin N Am 2003. 42. Goadsby PJ. 53. Newman NJ.com. Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. 41(4):416–418. 14:81–90. 2001:349–392. Kirby S. Mathew NT. 2d ed. Kittner SJ. Eur J Radiol 2004. 2d ed. Wolff’s Headache Other Head Pain.com. 45. 8). 17:1033–1042. CT angiography with three-dimensional techniques for the early diagnosis of intracranial aneurysms. Linfante I. 2d ed. 47. 2005 (Chap. Lipton RB. Cheung AC. Headache in clinical practice. Neurol Clin N Am 2004. Lange MC. Headache 1974. Arq Neuropsiquiatr 2002. MedLink Neurology. 12). Cephalalgia 2004. 34. Ravishankar K. 46:1226–1230. 31. Comparison with intraarterial DSA and the surgical findings. Waters WE. Petsas T. Evans RW. Ekbom K. 2006. 21:774–777. Philadelphia: Lippincott-Williams&Wilkins. Fisher CM. In: Gilman S. Traff H. et al. ed. Dulli D.medlink. ‘‘Normal pressure’’ pseudotumor cerebri. Headache associated with vascular disorders. ed. Results of a prospective protocol of computed tomographic angiography in place of catheter angiography as the only diagnostic and pretreatment planning study for cerebral aneurysms by a combined neurovascular team. Age at onset and sex ratio in cluster headache: observations over three decades. Berciano J. 2002:269–283. London: Martin Dunitz. In: Silberstein SD. Mokri B. Neurol Clin 2004. 46. 37. Curr Pain Headache Rep 2002. 30. Silberstein SD. Vasconcellos E. 32. 38. Hoh BL. 6: 209–216. 24(suppl 1):1–232. 60(2–B):453–457. 50. Headaches over the age of 50. Arch Neurol 2002. Cephalalgia 2002. San Diego: Arbor. Solomon GD. et al. 2005 (Chap. Pseudo-pseudotumor cerebri. Waldenlind E. . 57:1255–1257. 13(2):225–235. Coexistence of migraine and idiopathic intracranial hypertension without papilledema. D’Souza B. In: Gilman S. Neurology 1996. Kunkel RS. Late-life migraine accompaniments: further experience. Epidemiology of headache. 16(4):241–246. 48. Mathew NT. 44. Rasmussen BK. Cluster headache. 35. Good J. Mathew NT. 1). In: Evans RW. Headache 1990. Stroke 1986. Available at www. Neurology 1995. 54:1329–1340. 29. Evans RW. Mokri B. J Neurol Neurosurg Psychiat 1994. Cephalalgia 2001. et al. Schievink WI. Svensson DA. Headache Classification Subcommittee of the International Headache Society. Lipton RB. Bousser MG. 7th ed. Medina LS. 39. Late-life migrainous accompaniments. Philadelphia: Lippincott-Williams&Wilkins. 52. Dalessio DJ. 2005 (Chap. 40. Headaches and brain tumors. eds. 36. Rabinov JD. Diagnosis of cerebral venous thrombosis with echoplanar T2à -weighted magnetic resonance imaging. . Epidemiology and Population Health. New York. Connecticut. Bigal Department of Neurology. INTRODUCTION Headache is one of the most common types of recurrent pain (1. Albert Einstein College of Medicine. APPROACHING A PATIENT WITH HEADACHE Step 1—Distinguishing Primary from Secondary Headaches An important first step in headache diagnosis is to distinguish primary from secondary headaches.S. If the headache is atypical or difficult to classify. Lipton Departments of Neurology. U. New York.A. New York. Diagnosis of headache disorders is challenging and is complicated by the fact that one individual may have more than one disorder. and The New England Center for Headache. there are well-defined headache disorders that vary in incidence. New York. Crucial elements include a thorough history taking. Although virtually everyone gets occasional headaches.S. supplemented by general medical and neurological examinations. In brief. as well as laboratory testing and neuroimaging in selected patients. The Montefiore Headache Center. If multiple headache disorders occur concurrently. the physician must conduct the workup indicated by the red flag (Table 1) and thereby diagnose or exclude any secondary headache disorder that may be present. U. Albert Einstein College of Medicine.11 Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach Richard B. the conceptual process needs to be repeated for each headache.2). Marcelo E. An orderly approach is required for the proper diagnosis. and duration (1–4). The strategies to identify or exclude secondary headaches are discussed in Chapter 10. as well as one of the most frequent reasons for medical consultation (3.A. In the absence of secondary headaches. and The Montefiore Headache Center.’’ the features that suggest the possibility of a secondary headache (Fig. 1). Once these features are identified. the 145 . Stamford. prevalence. the clinician proceeds to diagnosing a primary headache disorder. the approach is to spot or exclude ‘‘red flags.4). possibility of a secondary headache should be reconsidered.146 Lipton and Bigal Figure 1 Algorithm for headache diagnosis. 2). Short-duration headaches are divided into those that have specific provocative factors and those that do not (Fig. nonpulsating quality. Source: Adapted from Ref. Step 2—Divide Primary Headaches into Four Syndrome Categories Based on Duration and Frequency In a patient for which secondary headache syndromes were excluded. after excluding secondary disorders. Step 3—Assign a Specific Diagnosis Within the Syndrome Category Low-to-Moderate Frequency Headaches of Long Duration Low-to-moderate frequency headaches of long duration include migraine and episodic tension-type headache (TTH). Long-duration headaches are classified on the basis of frequency as those with low-to-moderate frequency (<15 headache days per month) or those with high frequency (!15 headache days per month). In contrast to migraine. The objective of this section is to propose a strategy to approach primary headaches. and lack of aggravation by routine physical activity. either by clinical history or by appropriate investigation. mild-to-moderate intensity. although the modifying effect of any treatment being taken should be kept in mind. 5. the main pain features of TTH are bilateral location. though either photophobia or phonophobia (but not both) does not exclude . The diagnostic criteria of primary headaches are discussed in Chapter 1. The pain is not accompanied by nausea or vomiting. the next step is to divide the primary headaches based on the average duration of the attacks as short-duration headache (<4 hours a day) or long-duration headache (!4 hours) (6). patients may be prostrated and pale. encephalitis. High-Frequency Headaches of Long Duration High-frequency headaches of long duration include transformed migraine (TM). New daily persistent headache is characterized by a new onset of a CDH (14). Migraines are frequently of severe intensity. Migraine attacks may be unilateral or bilateral. mass lesion (especially posterior fossa) Mass lesion. collagen vascular disease 147 Possible investigation(s) Neuroimaging Lumbar puncture (after neuroimaging evaluation) Neuroimaging Worsening-pattern headache Headache with cancer. Lyme disease. When a clear history of TM is obtained. subdural hematoma. first seeking care with this syndrome. meningitis Subarachnoid hemorrhage. it is not a frequent cause of medical visits (Fig. sometimes vomiting. it is present in more than 80% of TM patients in subspecialty clinics (11. AVM. or phonophobia (8).Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach Table 1 Red Flags in the Diagnosis of Headache Red flag Sudden-onset headache Consider Subarachnoid hemorrhage. photophobia. medication overuse Meningitis. Source: Adapted from Ref. and associated with nausea (or vomiting). neck stiffness. or Valsalva Headache during pregnancy or postpartum Abbreviation: AVM. investigation is necessary to exclude secondary disorders. It is a primary headache disorder. However. In patients with acute headache. 4). Medication overuse is common. or symptoms other than typical visual or sensory aura Papilloedema Neuroimaging Lumbar puncture Biopsy Blood tests Neuroimaging Collagen vascular evaluation Neuroimaging Lumbar puncture (after neuroimaging evaluation) Neuroimaging Considerer lumbar puncture Neuroimaging Mass lesion. systemic infection. or other systemic illness (fever. new daily persistent headache. .8). mass lesion Cortical vein/cranial sinus thrombosis Carotid dissection Pituitary apoplexy Triggered by cough. 5. HIV. investigation is not required (Fig. encephalitis. Even though episodic TTH is the most prevalent primary headache disorder in the population. cutaneous rash) Focal neurologic signs. Because the attack may be very severe. and hemicrania continua (HC) (10).12) but in only 30% of chronic headache sufferers in population studies (13). migraine-like attacks not responsive to treatment and requiring prolonged hospitalization (>12 hours) should be investigated. pseudotumor. collagen vascular disease. arteritis Mass lesion. Migraines are more common in the clinic setting. chronic TTH. and investigation in a typical attack is not necessary. throbbing. bleed into a mass or AVM. exertion. arterio venous malformation. the diagnosis (7. 3) (9). straining or Valsalva maneuver. If the headaches are longstanding. exertion. and phonophobia. photophobia. . lacrimation.148 Lipton and Bigal Figure 2 Classification of primary headaches based on frequency and duration. it does not usually have the morning and end-of-dosing interval pattern of exacerbations typical of TM. Shorter-Duration Headaches For shorter-duration headache of low or high frequency. patients with HC usually do not have antecedent history of episodic migraine.16). the patient may not remember how they began. and ptosis. it must be considered whether the headache is triggered by coughing. In HC. In addition. Although pain fluctuates in HC. unilateral pain. 5). In TM. Figure 3 Long-duration headaches with low-to-moderate frequency. Both disorders are characterized by chronic unilateral pain with superimposed painful exacerbations. commonly mistaken for TM (15. It is advisable to offer to patients with unilateral chronic daily headache a therapeutic trial with indomethacin prior to other intervention (doses of up to 225 mg/day for 3 to 4 days). the painful exacerbations are often associated with ipsilateral autonomic features such as conjunctival injection. attacks increase in frequency over time. HC is probably the most frequently unrecognized primary headache. or sexual activity (Fig. In TM. HC is a chronic. exacerbations are more typically accompanied by nausea. Figure 5 Short-duration headaches.Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach 149 Figure 4 Long-duration headaches with high frequency of attacks. High-frequency. episodic and chronic cluster headache (CH). short-duration headaches not triggered by these factors include the trigeminal autonomic cephalgias (TAC). episodic and chronic paroxysmal hemicrania. short unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome. and hypnic headache. . is a very rare primary headache. However. It does not occur outside sleep (22. It usually peaks in 10 to 15 minutes but remains excruciatingly intense for an average of one hour within a duration range of 15 to 180 minutes. The most common disorder in this family is CH. supraorbital. in contrast to the pulsating pain of migraine. the patient remains exhausted for some time. exertion. SUNCT. characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain. with moderately severe pain peaking in intensity within three seconds and prominent tearing (20. piercing. (ii) of a short duration (2–30 minutes). In contrast with CH. the paroxysmal hemicranias are characterized by unilateral attacks of trigeminal pain and autonomic features. or stabbing. Hypnic headache is a primary headache disorder of the elderly. in many cases on more nights than not. with ipsilateral autonomic features (17–20). The third TAC. drilling. Like CH. These headaches may just be diagnosed after exhaustive and methodic search for secondary causes (Table 2) (24–28). often < 1 min Frequent for complex partial seizures ‘‘Butterflies’’—rising epigastric sensation Complicated visual phenomenon Common (seconds to minutes) Sometimes More common Common Common . or temporal stabbing or pulsating pain. knifelike. it is usually not necessary to repeat the investigation and the patient should be treated. The attacks are characteristically dramatic. lasting 5 to 240 seconds and accompanied by ipsilateral conjunctival injection and lacrimation. the paroxysmal hemicranias have three main features: It is (i) more frequent (more than five per day). They are rare (19. Autonomic features are absent. After an attack. Headaches triggered by cough. patients find it difficult to lie still. Table 2 The Aura in Migraine and Epilepsy Symptom Duration of aura Automatisms Gastrointestinal aura Visual disturbances Paresthesias Altered consciousness Olfactory Aphasia ´ ` Deja vu Source: Adapted from Ref. During this pain. very different from the unilateral orbital or periorbital knife-like intense pain of CH. 35. The pain of CH is described variously as sharp. which awaken the patient at a constant time each night.21). and autonomic features are usually obvious. and sexual activity include the disorders named for these triggers. nausea (common) Positive/negative Common (5–60 min) No Very uncommon Not rare Rare Epilepsy Brief. in a patient previously investigated or previously diagnosed. boring.20). The diagnostic criteria require at least 20 high-frequency attacks (3–200 per day) of unilateral orbital. Migraine 15–60 min Unusual Abdominal pain (rare). Hypnic headache is usually bilateral (though unilaterality does not exclude the diagnosis) and usually mild to moderate.150 Lipton and Bigal The TACs are characterized by unilateral pain in the trigeminal distribution. exhibiting often marked agitation and restlessness. and (iii) has an absolute response to therapeutic doses of indomethacin.23). obtain additional laboratory tests (particularly neuroimaging). Thus. It is also important to remember that patients with one headache disorder sometimes develop another superimposed primary or secondary headache. This is a good reason to reconsider diagnosis. . Figure 6 Summary algorithm.Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach 151 Step 4—Reconsider Diagnosis It is sometimes difficult to assign a specific headache diagnosis if atypical features are present. the diagnostic process remains part of the ongoing management. or refer to a specialist. If the patient does not respond as expected. Specific diagnosis provides a foundation for treatment. the diagnosis should be revisited. Classification and diagnostic criteria for headache disorders. Stewart WF. Epidemiology of Pain. Silberstein SD. 2002. Lipton RB. The precise criteria for each disorder are presented in the specific chapters of this book. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. ‘‘Hemicrania continua’’: a clinical review. Washington: IASP Press. 7:40–46. 22:432–438. Distribution of headache by diagnosis as the reason for neurologic consultation. cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. ed. Bigal ME. 2. Celentano DD. Chronic daily headache in a tertiary care population. New daily persistent headache. Berciano J. Epidemiology of headache. 4. Risk factors for chronic daily headache. Lipton RB. 15:45–68. Transformed or evolutional migraine. Spierings EL. 8(suppl 7):1–96. Lipton RB. Curr Pain Headache Rep 2002. including new cases. Polo JM. Sliwinski M. Linet MS. Mathew NT. et al. Schrader H. 4:65–70. 17. Figure 6 is a summary algorithm that integrates the information discussed in this chapter. Headache Classification Committee of the International Headache Society. Brain 1997. 31:20–26. 6. Headache characteristics associated with physician consultation: a population-based survey. Rebollo M. Lipton RB. Lipton RB. In: Crombie IK. 27:305–306. Cephalalgia 2002. Lipton RB. 14. Headache in clinical practice. Rozen TD. Cephalalgia 2004. It is clear that there is some overlap. 13. Combarros O. Stovner LJ. London: Martin Dunitz (Taylor Francis). 120:193–209. A review of paroxysmal hemicranias.152 Lipton and Bigal CONCLUSIONS The differential diagnosis of the primary headaches requires a systematic approach. Sheftell FD. These algorithms should help physicians to move forward quickly and safely. Olesen J. Am J Prev Med 1991. 5. 9. The International Classification of Headache Disorders. Silberstein SD. 15. Silberstein SD. Curr Pain Headache Rep 2003. Leno C. Classification of daily and near-daily headaches: field trial of revised IHS criteria. attacks may last just around 30 minutes. Tepper SJ. 8. 24:1–160. Med Clin (Barc) 1995. Correlation between the International Headache Society Diagnostic Criteria and proposed revisions of criteria for chronic daily headache. Sjaastad O. when assessing patients with headaches. 44(9):856–864. 47(4):871–875. Dahlof CG. 1999: 159–170. 7(3):218–223. SUNCT syndrome and other short-lasting headaches with autonomic features. Rapoport AM. 11. Hemicrania continua: another headache absolutely responsive to indomethacin. Neurology 1996. Pascual J. For example. 16. Rasmussen BK. Lipton RB. REFERENCES 1. Bigal ME. Goadsby PJ. although TTH is usually a headache of long duration. Tepper SJ. Dowson A. Headache 2004. Sjaastad O. Steiner TJ. Scher AI. Headache 1987. Neurology 2004. Goadsby PJ. Herein. Scher AI. 12. Cephalalgia 1984. Antonaci F. 104(5):161–164. Seattle. 6:486–491. Bordini C. Cephalalgia 1995. 3. 7. The classification of primary headaches. Headache 1991. we have presented an orderly approach to differential diagnosis. 10. 63(3):427–435. Stewart WF. Migraine and headache: a meta-analytic approach. Cephalalgia 1988. . 40(12):1904–1905. exertional. Berciano J. Migraine with aura triggered by orgasm. Dodick DW. Jelencsik I. Headache 1996. Green MW. Cephalalgia 2002. Silberstein SD. 14:105–108. Calandre L. Cluster headache. 24. Goadsby PJ. 36:251–253. Cephalalgia 2000. Iglesias F. Sjaastad O. 23. Oterino A. Mosek AC. A spectrum of exertional headaches. 20:518–520. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. 26. D’Andrea G. . Cephalalgia 2000. Pareja JA. Sjaastad O. 18:152–156. Cephalalgia 1998. Rozen TD. Ertsey C. 22:485–486. and sexual headaches: an analysis of 72 benign and symptomatic cases. 37:195–202. Newman LC. Neurology 1996. SUNCT syndrome. Granella F. The hypnic (‘‘alarm clock’’) headache syndrome. Dale I. Lipton RB. Cough. Evidence for a new (?) treatable headache entity. A clinical review. Pascual J. 29:648–656. Verdelli F. Antonaci F. Neurology 1990. 19. 4:1085–1092. Sjaastad O. 28. Headache 1974. 20. 21. 46:1520–1524. 22. Solomon S. 25. Headache 1989. Headache 1997. Dodick DW. Benign Valsalva’s maneuver-related headache: an MRI study of six cases. Vazquez-Barquero A. Headache 2001. 27. Hernandez-Lain A. The hypnic headache syndrome: a benign headache disorder of the elderly. Lopez-Valdes E. 20:787–803.Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach 153 18. Cough headache associated with Chiari type-I malformation: responsiveness to indomethacin. Campbell IK. . (iv) failure to initiate appropriate therapy among all who are diagnosed.12 Diagnostic and Severity Tools for Migraine Marcelo E. INTRODUCTION Migraine remains a substantially underdiagnosed and undertreated condition in the United States (1). and facilitate appropriate care (3). Richard B. We recognize 155 . U. disability tools may help identify those in need of more aggressive treatment approaches. Albert Einstein College of Medicine. Prior reports have identified the following barriers to migraine diagnosis and treatment: (i) under-recognition of migraine by headache sufferers themselves. Finally. and The Montefiore Headache Center.S. Headache Consortium (the Consortium) provided a multispecialty consensus on the diagnosis and treatment of migraine (4). Albert Einstein College of Medicine. and The New England Center for Headache. might also improve patient outcomes. The Montefiore Headache Center. In the primary care setting. (iii) failure to diagnose all who consult. Bigal Department of Neurology. screening tools might increase the speed and efficiency of headache diagnosis and help target patients who need treatment. such as depression and anxiety. we present in-depth discussions of the tools we use and recommend to screen for assessing migraine disability and comorbid illnesses. New York. encourage consultation. the U. (ii) underconsultation among migraine sufferers who need medical care.A. In this chapter. New York. and (v) lack of ongoing assessment of the benefits of treatment (2). Recently. providing a basis for stratified care. Connecticut. Stamford.A.S. Lipton Departments of Neurology.S. Effective application of diagnostic screeners within the population should increase recognition of migraine. U. New York. Tools that screen for migraine and assess disability have been proposed as strategies for surmounting some of these barriers. Screening for conditions comorbid with migraine. The Consortium also recommends that clinicians assess the severity of the patient’s migraine using measures of headacherelated disability as a prelude to selecting treatment. One approach recommended by the Consortium to improving primary care diagnosis is to employ screening or case-finding instruments. New York. In primary and specialty care. tools that directly assess the adequacy of acute or preventive treatments might help to improve satisfaction with treatment. Epidemiology and Population Health. The test must be acceptable to patients and health-care providers.S. the goal is to detect individuals who have established undiagnosed disease. detection. The Task Force also made recommendations regarding screening policies for a large number of disorders (Table 1). validating. We then discuss the importance of screening comorbid diseases using a validated screener for this purpose. the U. to manage the problem and to refer to specialists when necessary. 8. 6. screening programs may also alter future pain and disability and impact disease progression. Task Force on Preventive Health Services (The Task Force) proposed criteria for evaluating policy decisions about screening programs (7). but discussed few neurologic diseases. 4. The disease must have a recognizable latent phase or early symptomatic stage (or must be undetected by the health-care system when fully symptomatic)b. good alternatives are available and provide references for the options.. a b U. Because migraine progresses in some individuals. The screening and treatment program must be cost effective. In migraine screening. A. sensitivity. It has significant prevalence in the population at risk B. 7. We then assess migraine to determine how well it meets the criteria for screening. Effective treatment for the disease must be available and cost effective. It has significant short-term or long-term morbidity or mortality A population at risk for the disease must be defined. This parenthetical statement is a modification of traditional criteria for screening programs. Table 1 Criteria for Screening Programsa 1.S. . Preventive Services Task Force 7. so that current pain and disability can be treated. the Chronic Disease Commission issued a formal and widely influential policy statement on screening (7). The main recommendations from the Task Force are discussed below.7). the PRIME-MD. Resources must be available for developing. 5. An effective screening test must be available with appropriate specificity.e.156 Bigal and Lipton that in many cases. The primary goal is to alter the natural history of disease through early screening. the ID-migraine. Criteria for Screening Although screening tests have long been an informal part of medical practice. and reliability for the disease and health-care context. We start by reviewing the criteria for screening diseases. it must be effective. and relatively safe.6). 2. The condition must be a public health problem. Migraine exemplifies the issues in primary care screening. 3. affordable. and describe a well-validated migraine-screening test. More recently. i. We close with a discussion of tools for assessing satisfaction with treatment. and distributing the test. and treatment (6. SCREENING FOR MIGRAINE Medical screening programs survey a population at risk to identify individuals with asymptomatic or early symptomatic disease (5. in 1957. We discuss the assessment of disability and the use of the migraine disability assessment (MIDAS) questionnaire as a prelude for treatment. Primary care providers are called upon to screen for a range of medical problems. the condition first must be a significant public health problem in a specified population at risk for disease. In addition. That is. Effective ‘‘Screening’’ Tools (Criteria 5) Effective screening programs require appropriate screening tests. For disorders that affect quality more than quantity of life. decreased morbidity. such as migraine. the major benefits of screening are decreased risk of death. Cost-effective. . therefore. Thus. disability at work. One compares disease classification based on the results of the screening test. and improving health-related quality of life (9–12). the indirect costs (missed work. workable (i. For migraine with a peak prevalence in early and mid-adult life. its potential for producing widespread morbidity and mortality also rises. It produces 113 million lost work-day equivalents per year.) often predominate (13–15). preferably at an early stage. The public health significance of any disorder is determined by its prevalence. costing American employers more than 13 billion dollars per year (13–15). For cancer. the condition should affect either the quantity of life (mortality) or the quality of life (morbidity) for some identifiable group. migraine meets the criteria discussed. Although migraine is prevalent at all ages. the goals of screening may include decreasing disability or symptoms. the aggregate benefits of detecting and treating the disorder must outweigh the aggregate risks and costs of screening and treatment (Table 1). etc. Finally.20). Migraine is a highly prevalent disorder. A Recognizable Latent or Early Symptomatic Stage (or a Disease Undetected by the Health Care System)(Criterion 3) In the United States. with disease classification based on the results of the gold-standard assessment. and mortality (8). as well as by the opportunity to interfere and alter natural history. The argument for screening. As the prevalence of a disorder increases.18). affecting 18% of American women and 6% of American men (1). is supported by the low rates of diagnosis and treatment. For a disorder diagnosed largely based on symptoms. Many studies demonstrate that migraine treatment is cost effective (Table 1) (19. the condition must be detectable and treatable. it is most common in women and in persons between the ages of 25 and 55 (1). sufficiently sensitive and specific) screening tests must be available. and decreased health-care costs. for any screening program. This provides the foundation for effective medical intervention once migraine cases are found (Table 1). questionnaire-based screening is an attractive approach.Diagnostic and Severity Tools for Migraine 157 A Public Health Problem in a Population at Risk (Criteria 1 and 2) According to the Task Force. Migraine may have an early symptomatic stage that progresses to chronic daily headache in some patients. morbidity. about half of migraine sufferers report that they never received a medical diagnosis of migraine (16). One advantage of questionnaire-based screening is that it is safe and relatively inexpensive (Table 1). maintaining functional independence. Screening tests are evaluated using a series of statistics based on a 2  2 table (Table 2)..e. Effective Treatment for the Disease Must Be Available and Cost Effective (Criterion 4) There is abundant evidence that supports the effectiveness of numerous acute and preventive treatments for migraine (see Chapters 20–24) (17. and the extent to which the headaches resulted in disability. Abbreviation: PPV. Efficient screening requires a high PPV. PPV ¼ A/AþB. 1). and anxiety of the more definitive diagnostic procedures. people with the disease will be missed. For these reasons. .158 Table 2 Statistics Used in the Evaluation of Screening Tests Gold-standard assessment þ Screening assessment þ Screening assessment – A C AþC Gold-standard assessment – B D BþD Bigal and Lipton AþB CþD Note: Sensitivity (true positives) ¼ A/A þ C. PPV also rises. Eligible subjects were those reporting the occurrence of at least two headaches in the previous three months. Based on the specialists’ clinical judgment (that were oriented to follow the criteria proposed by the International Classification of Headache Disorders). the specificity of the test. For this reason. who are correctly classified by the screening test as being free of disease. At a given level of sensitivity and specificity. Study subjects then underwent independent diagnostic evaluations performed by headache specialists. Specificity (true negatives) refers to the proportion of people without the disease. Each subject completed a selfadministered screening questionnaire that consisted of nine questions referring to the severity and nature of headache pain. people without disease will be unnecessarily subjected to the risk. a gold-standard diagnosis of migraine was made. The positive predictive value (PPV) is the proportion of people actually having the disease of those who screen positive for it. Specificity (true negatives) ¼ B/B þ D. The PPV is determined by three factors: the sensitivity of the test. The sensitivity (true positives) is the proportion of people with the disease correctly detected by the screening test. discomfort. people who are disease free will be classified into the diseased group. If the sensitivity is low. as disease prevalence rises in the population being screened. Three questions were identified (Fig. The first phase of development of ID-migraine involved 563 patients presenting for routine appointments at 26 primary care practice sites—the intended setting for the use of ID-migraine. a 3-item migraine screener (Fig. positive predictive value. based on the gold-standard assessment. Herein we focus on ID-migraine. and opportunities for early treatment will be lost.22). and the prevalence of the condition in the population being tested. the presence of associated migraine symptoms. screening tests should have both high sensitivity and high specificity. 1): temporary disability (missing one or more days in the previous three months due to headache). and the diagnostic sensitivity and specificity of each item was computed. If the specificity is low. Results of the gold-standard diagnostic evaluation were then compared with those of a 9-item screener. which is a valid and reliable screening instrument for migraine headaches in the primary care (23). nausea. The ID-Migraine A number of screening tests for migraine have been proposed (21. Logistic regression was used to identify those screener items that were most strongly associated with a gold-standard migraine diagnosis. and photophobia. As a consequence. it is more efficient to screen populations at a relatively high risk for the disease. 68). Distribution is inexpensive because the test is available on the Internet and costs almost nothing (Table 1). the next step is to assess ‘‘disability’’ as a prelude to developing treatment. Resources must be available for developing and validating the test (criterion 7)—a step that has been accomplished (23). After this. and a PPV of 93% versus a headache-expert migraine diagnosis. a test–retest reliability was assessed in a study involving 121 patients. affordable. ID-migraine is effective. In addition. and safe. Table 3 summarizes how migraine fits in the overall criteria for screening.Diagnostic and Severity Tools for Migraine 159 Figure 1 The ID-migraine. Good test–retest reliability was demonstrated (kappa coefficient of 0. and therefore meets these criteria. the clinician should exclude secondary headaches. ASSESSING MIGRAINE-RELATED DISABILITY If a patient screens positive. Other Criteria (Criteria 6. The excellent performance characteristics of the three-item ID-migraine suggest it to be a simple method for increasing the recognition of migraine in the primary care setting (23). Individuals who indicated that they had at least two of three of these features were said to screen positive for migraine. Measuring migraine severity is challenging because of the episodic occurrence of attacks and variation in impact of attacks both within and among individuals. and then confirm the migraine diagnosis. . a specificity of 75%. The final criterion—screening and treatment must be cost effective—is the only one that had not been studied for screening. either clinically or using subsidiary tests. 7.20). 8) Screening tests must be acceptable to patients and health-care providers (criterion 6). though migraine treatment is cost effective in diagnosed cases (19. The ID-migraine has a sensitivity of 81%. In more than 70% of the headache sufferers in this survey. including inability to do things as well as reduced effectiveness. and Japan consistently show that about 75% of migraine sufferers have a reduced ability to function during attacks (25– 27). Disability is the major determinant of the cost of illness (13. the day is considered missed.g. and family. Other studies have measured disability by estimating lost time due to migraine. Effectiveness of screening has not been demonstrated The World Health Organization (WHO) defines disability in terms of the consequences of illness on ability to work and function in other roles. social. All questions ask about either days of missed activity or days where productivity was reduced by at least half. If productivity is decreased to 50% or below. Europe. A population survey of migraine found that half of migraine sufferers discontinued normal activities during their attacks and almost one-third required bed rest (16). social. interpersonal relationships were impaired. such as household work and nonwork activities (e. 2) (30). The MIDAS score is derived as the sum of missed days due to a headache over a three-month period in the three domains. household work or chores. and family) (24). Females 25–55 at highest risk (1) No Appropriate screening test available ‘‘Gold-standard’’ diagnosis Effective treatment available Benefit of screening diagnosis and treatment outweigh the costs One-third of people with migraine are medically diagnosed. and leisure activities (31). The MIDAS questionnaire consists of five questions that focus on lost time in three domains: school work or work for pay. The four-point grading system for the MIDAS questionnaire is as follows:  Grade I (scores ranging from 0 to 5) ¼ little or no disability  Grade II (scores ranging from 6 to 10) ¼ mild disability . recreation. Studies conducted in North America.160 Table 3 Does Migraine Meet the Criteria for Screening? Disease characteristics Significant public health problems Defined population at risk Recognizable latent or early symptomatic phase Or Undetected by the health-care system Bigal and Lipton Migraine (Reference) 14 million Americans had migraine with significant disability in 2001 (1) Risk broadly distributed.29). Two additional questions on the MIDAS questionnaire are not included in MIDAS score—those assessing frequency and intensity of pain. Goal of treatment is to prevent current disability and pain (9) High societal cost of disease (24). The MIDAS Questionnaire The most frequently used disability instrument in migraine clinical care and research is the MIDAS questionnaire (Fig. 80% of people with undiagnosed migraine experience disability (13) Self-administered screening developed (23) Clinical assessment using International Headache Society criteria with a semistructured questionnaire and laboratory tests as indicated (23) Yes.28.. Diagnostic and Severity Tools for Migraine 161 Figure 2 The MIDAS questionnaire.7 is acceptable. A population-based sample of migraine sufferers recorded the occurrence and consequence of their headaches. The Cronbach alpha was 0. Abbreviation: MIDAS.76 in the United States and 0. .  Grade III (scores ranging from 11 to 20) ¼ moderate disability  Grade IV (21 or greater) ¼ severe disability The Disability Strategies of Care (DISC) study proved that MIDAS is useful for stratifying patients to therapy (32).8.82 in the United Kingdom. The gold standard for assessing validity of the MIDAS questions and the MIDAS score were equivalent measures derived from the 90-day diary data.8 or more indicates that the internal consistency is excellent.54 to 0. Study participants were examined by a physician to confirm migraine diagnosis and were then trained in the use of the daily diary.52 to 0.73 in the United Kingdom.31) performed in the United Kingdom and the United States. Attributes of the MIDAS Questionnaire The accuracy of the MIDAS score was evaluated using a 90-day daily headache disability diary as the gold standard (31). The test–retest Pearson correlation coefficient for individual items ranged from 0. migraine disability assessment. This index ranges from 0 to 1. A score of 0. the coefficient was 0.68 in the United States and from 0. Considering the total score. Internal consistency of the MIDAS score was assessed in two population-based surveys (30. and 0. The results show that MIDAS can accurately measure the headache-related disability. Stratifying Treatment by Headache Disability The U. reliability. a concept also supported by the DISC study (32). and good construct validity (35). Figure 3 provides a schematic view of how the MIDAS questionnaire might be used to provide appropriate treatment. moderate. Of course. At the time of consultation and diagnosis. These results indicate that the overall MIDAS score is highly reliable. Other Disability Tools Other disability measures include the Headache Disability Inventory and the Headache Impact Test. or severe). The physicians’ perceptions of the need for medical care based on medical histories correlated with the MIDAS score (r ¼ 0. mild. level of disability (none. or severe). and assessed whether the MIDAS questionnaire is meaningful and relevant to patients and easy to use (34).g. any specific sequence of treatment recommendation requires empirical testing. If simple analgesics are unsuccessful.S. especially if you consider that there was a three-week interval between both MIDAS assessments. the migraine patient completes a MIDAS questionnaire and is categorized into a MIDAS Grade (I–IV). If these treatments fail. moderate. Headache Consortium Guidelines recommend stratified care based on the level of disability to help physicians target patients who require careful assessment and treatment (4).69). A MIDAS score of 11 or over (MIDAS Grade III/IV) indicates high medical need. An interactive version of HIT-6 is available over the Internet.. Estimates of pain and disability by physicians were directly correlated with increasing MIDAS scores (33). A study was conducted to determine whether MIDAS scores were associated with physician’s clinical judgment of pain. and need for medical care [from 0 (lowest) to 100 (highest)]. The Headache Disability Inventory is a 25-item questionnaire with good internal consistency. All patients require a specific diagnosis. further escalation and triptan medication may be necessary. various combination treatments (e. The Headache Impact Test is a 6-item (HIT-6) paper questionnaire that was recently developed and validated (36). and education about their disorder and self-management strategies. and ratings of its perceived value increased significantly as the MIDAS grade increased. disability. together with prophylaxis where necessary. A MIDAS score of 0 to 5 (MIDAS Grade I) or 6 to 10 (MIDAS Grade II) indicates relatively low medical need. Physicians graded each patient for pain level (mild. aspirin plus metoclopramide) may be needed. robust long-term test–retest stability.162 Bigal and Lipton overall. Twelve histories from patients with migraine were presented to 49 primary and specialty care physicians unaware of the MIDAS scores. Satisfaction with current therapy decreased significantly with increasing MIDAS grade. and need for medical care (33). . Simple analgesics are appropriate for first-line acute treatments for these patients. Specific acute therapies such as the triptans may be needed by these patients. Physicians also identified MIDAS scores they associated with different degrees of disability and with the urgency to prescribe an effective treatment during the first consultation. The MIDAS Perceptions Study investigated whether MIDAS scores reflect headache severity and the need for medical care. based on the patient’s level of headacherelated disability. The MIDAS questionnaire was rated as easy to use by the vast majority of respondents. and anxiety (from 1. anxiety. An optional fourth page on recent psychosocial stressors and a section for women on problems with menstruation. Herein we describe the PRIME-MD questionnaire. Originally coined by Feinstein (37). and eating disorders and takes approximately five minutes for the patient to complete. depression. depression (odds ration ranging from 2. pregnancy. a more sophisticated approach toward the diagnosis and treatment of migraine requires the assessment of comorbid psychiatric diseases. ASSESSING PSYCHOLOGICAL COMORBIDITY It is clear that comorbid factors are significant in the development and maintenance of headaches. It was also reported to be more efficient to use (Appendix). The association between migraine. The original PRIME-MD was developed by Spitzer et al. Therefore. ASSESSING ONGOING TREATMENT A large gap continues to exist between evidence-based treatment guidelines and clinical practice. migraine disability assessment. The current version is a single. alcohol.Diagnostic and Severity Tools for Migraine 163 Figure 3 Potential utility of the MIDAS Questionnaire in relating migraine severity to treatment choice. Optimal migraine management would be enhanced if physicians had available a simple decision tool to assist them in determining which patients .3) is consistently reported (38. the Patient Health Questionnaire (PHQ). Additionally.0). and childbirth were also added. the term ‘‘comorbidity’’ is used to refer to the greater than coincidental association of two conditions in the same individual. In validation and utility studies of the self-administered PHQ among 3000 primary care patients (40). Abbreviation: MIDAS. the authors found that the diagnostic validity of the instrument was comparable to that of the original clinician-administered instrument.39). comorbid disorders are often associated to refractoriness to migraine treatment. (40).9 to 5. It consists of three pages of questions on somatoform disorders. with a sensitivity of 75% and a specificity of 90%.1 to 3. self-administered instrument. Because satisfaction with therapy is driven in part by patient expectations. in the majority of your attacks?  Global assessment of relief: Does the headache pain disappear within two hours?  Impact: Are you able to function normally within two hours? Figure 4 Summary algorithm. where the duration of a patient visit is brief (41). The systematic evaluation of efficacy and tolerability employed in clinical trials is excessively cumbersome for use in clinical practice settings.164 Bigal and Lipton are likely to benefit from a change in their acute migraine therapy. satisfaction alone may not fully inform a decision regarding the value of a change in treatment. A French group (44) and a collaborative English and American group have developed questionnaires designed to assess satisfaction with acute treatment. A validated tool that helped doctors determine whether a change in treatment was necessary would provide broad use. The migraine assessment of current therapy (Migraine-ACT) questionnaire assesses four domains with one question for each domain:  Consistency of response: Does your migraine medication work consistently. . 17:511–538.aan. Figures 3 and 4 summarize how the tools discussed in this chapter can be used in the rational assessment of migraine. 7. Potential of the Migraine Disability Assessment (MIDAS) Questionnaire as a public health initiative and in clinical practice. we anticipate that over the next several years. Di Guiseppi CG. et al. Neurology 2001. The guidelines recommend that treatment be individualized for each patient based on disability. Migraine now meets all criteria except the demonstration that screening and intervention improves outcomes in a cost-effective manner. According to the consortium guidelines (4). an approach that captures the economic burden of migraine on society. Stewart WF. The individual questions. Although still in its infancy. Ferrari MD. 4. Reed M.pdf. the physician should assess the severity of the patient’s migraine based on headache-related disability. Atkins D. Prevalence and burden of migraine in the United States: data from the American United States: data from the American Migraine Study II. .54:www. treatment satisfaction will become an important part of medical practice and that the use of well-validated measures will be incorporated into treatment guidelines. Edmeads J. Brandes JL. Amatniek JC.S. Lipton RB. Freitag F. including those related to (7) (i) significant prevalence/ disability. The U. 44(suppl 4):63–68. 41:646–657. Young WB.com/public/practiceguidelines/03. Developing evidence-based clinical practice guidelines: lessons learned by the US Preventive Services Task Force. Task Force on Preventive Health Services has established criteria for recommending screening for specific disorders. Lainez JM. Lipton RB. Woolf SH. Neurology 1994.82). Rosenerg J. Headache 2001. 5. 16:102–108. REFERENCES 1. 3. 2. 56(Suppl 1):29–34. after diagnosing migraine. et al. Multispecialty consensus on diagnosis and treatment of headache: pharmacological management of acute attacks. Matchar DB. A multinational group has developed another Treatment Satisfaction Questionnaire and has recently completed a large multinational study. Identifying and removing barriers to care. 6. 28:273–278. Gross M. Schoenen J. Active screening and the use of disability assessment with MIDAS may help address the under-recognition and undertreatment of migraine. Epidemiol Rev 1994. Clin Perinatol 2001. based on the WHO’s global burden of disease survey (44). Migraine. Diamond S. (ii) effective treatment. CONCLUSION Overall. (iii) safe and effective screening tools.Diagnostic and Severity Tools for Migraine 165  Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities? The 4-item Migraine-ACT was shown to be highly reliable (Spearman/Pearson measure r ¼ 0. Krivchenia EL. Diamond ML. The Task Force recently added depression in the list of disorders to be screened. Neurology 2000. Evans MI. and the total 4-item Migraine-ACT score. Weiss NS. Application of the case-control method in the evaluation of screening. migraine has been found to rank in the top 20 of the world’s most disabling medical illnesses. Annu Rev Public Health 1996. Principles of screening. and (iv) improving outcomes in a cost-effective manner. showed good correlation with items of the SF-36 and MIDAS. Loss of productivity and quality of life in migraine sufferers among French workers: results from the GAZEL cohort. Neurology 2003 Aug 12. Von Korff M. Cephalalgia 1997. Berger M. Stewart WF. Hettiarachchi J. 159:813–818. Ferrari MD. Lipton RB. Lipton RB. Edmeads J. National Cholesterol Education Program. 16. Hu X.aan. Morganstein D. 28. Disability and economic costs of migraine in the United States: a population-based approach. Hu X. Lipton RB. Impact of migraine and tension-type headache on life-style. J Am Board Fam Pract 1993. Arch Intern Med 1998. 14. Harrison W. Work and productivity loss in the rizatriptan multiple attack study. . Henry P. Burden of disease—implications for future research. Silberstein SD. Multispecialty consensus on diagnosis and treatment of headache: pharmacological management for prevention of migraine. Diamond S. Sadovsky R. Reed M. 13. 48(Suppl 3):S4–S9. et al. Stewart WF. Can J Neurol Sci 1993. Available at: http://www. 11. 15. Benefits and costs of screening and treatment for early breast cancer. Liberati A. 6:66–73. Headache 2004 Apr. Kattlove H. Headache 2001. Berger M. Sheftell FD. et al. 290(18):2443–2454. Krahn MD. 18. 25. Prev Med 1985.166 Bigal and Lipton 8. 17. 272:773–780. Lipton RB. Hart CC. JAMA 2001. 9. Screening for prostate cancer. Keil U. Cephalalgia 2000 Nov. Burchette R. Von Korff M. Pait DG. Stewart WF. Carides GW. Screening for hypertension: results of the Munich Blood Pressure Program. 61(3):375–82. Arch Int Med 1999. Ryan R. Keeler E. Kolodner K. Spalding W. Burden of migraine: societal costs and therapeutic opportunities.pdf Accessed March 20. O’Quinn S. Lipton RB. Igarashi H. Simple and efficient recognition of migraine with 3-question headache screen. Eckman MH. 158:1013–1018. Kramer. Ramadan NM. Stewart WF. Dasbach EJ. 43(5):441–50. Neurology 1997. Headache 1997. Stieber J. Dodick D. Mass screening program for prostatic cancer in Japan. 29. Maizels M. Krista RI. Brook RH. placebo-controlled trial. Freitag FG. Chee E. Markson L. Lipton RB. 17:15–22. Oral triptans (serotonin 5-HT1b/1d agonists) in acute migraine treatment: a meta-analysis of 53 trials. 37:71–78. 21. 27. Lindousli A. 20:131–137. Epidemiology of migraine in Japan. 10. Santanello NC. Arch Int Med 1999. Murray CJ. Int J Clin Oncol 2001. Pigeon JG. Lancet 2001: 3581668–1775. Sumatriptan injection reduces productivity loss during a migraine attack: results of a double-blind. Goadsby PJ. 2002. 285:535–539. Stewart WF. Findlay H. A self-administered screener for migraine in primary care: The ID Migraine(TM) validation study. 159:813–818. Headache 2003 May. Bloom BR. Cady RK. 44(4):323–327. 24. Michaud CM. Jhingran P. Neurology 1997. Tugwell P. Frame PS. Work-related cost of common pain conditions in the US workforce. Burden of migraine: societal costs and therapeutic opportunities. Michel P. Endicott J. JAMA 1995. Sakai F. JAMA 2003. Screening and management of cholesterol levels in children and adolescents. Watanabe H. 6:582–587. Disability and economic costs of migraine in the United States: a population-based approach. consulting behavior.com/professionals/practice/pdfs/gl0090. 22. Lipton RB. Gerth WC. Lipton RB. 14:519–531. Hense HW. Ricci JA. 26. 20. and medication use: a Canadian population survey. 19. Markson L. Diamond ML. A decision analytic view JAMA 1994. Migraine diagnosis and treatment: results from the American Migraine Study II. 23. Dartigues JF. 48(Suppl 3):S4–S9. 12. Rapid and sensitive paradigm for screening patients with headache in primary care settings. Mahoney JE. 41:638–645. et al. 273:142–148. Stewart WF. 20(9):830–4. Borchert LD. Cady RC. Neurology [serial online] 2000. Sawyer J. 42. legs. Murray CJ. 37. Can J Neurol Sci 2002. 44. Baos V. Comorbidity of migraine and psychiatric disorders. 35. 36. physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Health Serv Res Policy 1998. Pain 2000. Lipton RB. APPENDIX: THE PRIME-MD QUESTIONNAIRE Instructions and Items: 1.15(1):115–23. Evaluating migraine disability: the headache impact test instrument in context.3:207. 45. or joints (knees. Dowson AJ. 290(18):2443–54. Patient Health Questionnaire. b. 34. 159:S5–15. Kolodner K. Recommendations for clinical practice. 31. Breslau N. Headache 1995. Stewart WF. Kilminster S. Reliability of the migraine disability assessment score in a population-based sample of headache sufferers. Professional recommendations and references: economic evaluation service.) Menstrual cramps or other problems with your periods . Sawyer JPC. The pretherapeutic classification of comorbidity in chronic disease. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. D’Amico D. 41(9):854–61. Ricci JA. Sawyer J. CNS drugs 2002. Need for care and perceptions of MIDAS among headache sufferers study. During the last 4 weeks. how much have you been bothered by any of the following problems? (Scale: Not bothered. Carr-Hill R. d. Davis GC. Primary Care Evaluation of Mental Disorders. Newman CW. 88:41–52. 27:211–221. 284:2599–2605. Feinstein AR. Identifying patients who require a change in their current acute migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire. Tepper SJ. Headache disability inventory (HDI): short-term test-retest reliability and spouse perceptions. Stevens DE. Kolodner K. Dixon P. 39. Sawyer J. Baudet F. ANAES. 41. Lipton RB. 43. Chee E. Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers. Review of diagnosis and treatment of migraine in the adult and child October 2002.282(18):1737–44. Stratified care vs step care strategies for migraine: results of the Disability in Strategies of Care (DISC) Study. Stewart WF. Cephalalgia 1999. 33. Liberman J. Stomach pain Back pain Pain in your arms. 40. Ramadan NM. Alternative projections of mortality and disability by cause 1990– 2020: Global Burden of Disease Study. 29(suppl 2):11–15. 23:455–468. Do minutes count? Consultationlengths in general practice. J Psychiatr Res 1993. Lipton RB. Bothered a little. Stewart WF. 25 Suppl 3:S276–8. Williams JB. JAMA 1999 Nov 10. 16(Suppl 1):5–11. 19:107–113. hips. Headache 2001 Oct. Edmeads JG. Work-related cost of common pain conditions in the US workforce. Lipton RB. J Chron Dis 1970. Lopez AD. Norris L. c.Diagnostic and Severity Tools for Migraine 167 30. Lipton RB. 38. Neurol Sci 2004 Oct. Morganstein D. Rev Neurol (Paris) 2003. JAMA 2003 Nov 12. Stewart WF. Stone AM Lainez MJA. etc. Liberman JN. Stewart WF. 32. 35:534–549. Jacobson GP. Lee C. 349:1498–1504. Jenkins-Clarke S. Lancet 1997. Pryse-Phillips W. et al. Stewart WF. Spitzer RL. Bothered a lot) a. Kroenke K. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Migraine. Lipton RB. JAMA 2000. Neurol Clin 1997 Feb. Merikangas KR. Several days. Questions about anxiety. k. f. h. b. Do these attacks bother you a lot. f.’’ go to question #5. m. such as reading the newspaper or watching television h. In the last 4 weeks. f. in situations where you don’t expect to be nervous or uncomfortable? d. how often have you been bothered by any of the following problems? (Scale: Not at all. unsteady. or indigestion 2. g.168 Bigal and Lipton e. Over the last 2 weeks. or faint? Did you have tingling or numbness in parts of your body? Did you tremble or shake? Were you afraid you were dying? . b. depressed. j. (No or Yes) a. Do some of these attacks come suddenly out of the blue—that is. or hopeless Trouble falling or staying asleep. pound. d. Thoughts that you would be better off dead or of hurting yourself in some way 3. k. Nearly every day) a. h. or are you worried about having another attack? 4. Moving or speaking so slowly that other people could have noticed or the opposite—being so fidgety or restless that you have been moving around a lot more than usual i. Think about your last bad anxiety attack. i. Little interest or pleasure in doing things Feeling down. e. g. loose bowels. or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself or that you are a failure or have let yourself or your family down g. j. have you had an anxiety attack—suddenly feeling fear or panic? If you checked ‘‘No. Has this ever happened before? c. (No or Yes) a. l. Were you short of breath? Did your heart race. Trouble concentrating on things. More than half the days. or diarrhea Nausea. b. e. Pain or problems during sexual intercourse Headaches Chest pain Dizziness Fainting spells Feeling your heart pound or race Shortness of breath Constipation. or sip? Did you have chest pain or pressure? Did you sweat? Did you feel as if you were choking? Did you have hot flashes or chills? Did you have nausea or an upset stomach or the feeling that you were going to have diarrhea? Did you feel dizzy. i. c. gas. d. c. anxious. Trouble falling asleep or staying asleep f. c. on average? (Yes or No) 9. Feeling restless so that it is hard to sit still c. Do you ever drink alcohol (including beer or wine)? (No or Yes) If you checked ‘‘No. how often have you been bothered by any of the following problems? (Scale: Not at all. go to question #9. You drove a car after having several drinks or after drinking too much. going to school. Made yourself vomit? Took more than twice the recommended dose of laxatives? Fasted—not eaten anything at all for at least 24 hours? Exercised for more than an hour specifically to avoid gaining weight after binge eating? 8. c. Getting tired very easily d. or were hungover while you were working. Muscle tension. take care of things at home. how difficult have these problems made it for you to do your work. were any as often as twice a week. or worrying a lot about different things If you checked ‘‘Not at all. d. You had a problem getting along with other people while you were drinking. school. You drank alcohol. Feeling nervous. or other activities because you were drinking or hungover. In the last 3 months have you often done any of the following in order to avoid gaining weight? (No or Yes) a. On average.’’ go to question #6. 10. or taking care of children or other responsibilities. If you checked ‘‘Yes’’ to any of these ways of avoiding gaining weight. Somewhat difficult. More than half the days) a. Extremely difficult) . Have any of the following happened to you more than once in the last 6 months? (No or Yes) a. You drank alcohol even though a doctor suggested that you stop drinking because of a problem with your health. were high from alcohol. Becoming easily annoyed or irritable 6. what most people would regard as an unusually large amount of food? If you checked ‘‘No’’ to either a or b. (No or Yes) a. b. d. If you checked off any problems on this questionnaire. aches. Do you often feel that you can’t control what or how much you eat? b.Diagnostic and Severity Tools for Migraine 169 5. Very difficult. on edge. or get along with other people? (Scale: Not difficult at all. You missed or were late for work. Several days. c. 11. Do you often eat. Questions about eating. b. Over the last 4 weeks. e.’’ go to question #11. has this been as often as twice a week for the last 3 months? 7. b. within any 2-hour period. or soreness e. h. In the last 4 weeks. f. a. a severe accident. Yes) c. Does not apply. at least ‘‘More than half the days’’ AND  Of the 9 items. Depression items: Major depressive syndrome is suggested if  Either item #1 or #2 is positive—that is. kicked. If ‘‘Yes’’: Do these problems go away by the end of your period? (No. FOR WOMEN ONLY: Questions about menstruation. Worrying about your health Your weight or how you look Little or no sexual desire or pleasure during sex Difficulties with husband/wife. e. or has anyone forced you to have an unwanted sexual act? (No or Yes) 14. No periods for at least a year. how much have you been bothered by any of the following problems? (Scale: Not bothered.’’ (Count #9 if present at all) Other depressive syndrome is suggested if  Either item #1 or #2 is positive—that is. Yes) e. or other family members Stress at work outside of the home or at school Financial problems or worries Having no one to turn to when you have a problem Something bad that happened recently Thinking or dreaming about something terrible that happened to you in the past—like your house being destroyed. anxiety. Yes) Scoring. Does not apply. In the last year. Are you taking any medicine for anxiety. What is the most stressful thing in your life right now? 15. depression. b. or being forced to commit a sexual act 13. slapped. parents. Have you given birth within the last six months? (No. d. During the week before your period starts. i. or otherwise physically hurt by someone. do you have a serious problem with your mood—like depression. Which best describes your menstrual periods? [Scale: Periods are unchanged. or mood swings? (No. pregnancy. at least ‘‘More than half the days’’ AND . or amount. anger. Does not apply. j. c. Yes) d. No periods because pregnant or recently gave birth. or stress? (No or Yes) 16. duration.170 Bigal and Lipton 12. Have you had a miscarriage within the last six months? (No. Does not apply. g. being hit or assaulted.] b. Bothered a lot) a. Yes) f. have you been hit. Having periods because taking hormone replacement (estrogen) therapy or oral contraceptive. partner/lover. 5 or more are checked as at least ‘‘More than half the days. Does not apply. Are you having difficulty getting pregnant? (No. Bothered a little. or boyfriend/girlfriend The stress of taking care of children. and childbirth. irritability. Periods have become irregular or changed in frequency. ’’ (Count #9 if present at all) Note that item #2 (the suicide item) should always be a red flag that further investigation is necessary. 2. 3. .Diagnostic and Severity Tools for Migraine 171  Of the 9 items. or 4 of them are checked as at least ‘‘More than half the days. . migraine remains surprisingly underdiagnosed and under-recognized throughout the world (1–4). 50% or more of sufferers with migraine in the population do not receive proper diagnosis. INTRODUCTION—MIGRAINE WITHOUT AURA: AN UNDERDIAGNOSED AND UNDERTREATED DISORDER Given its prevalence.’’ has emerged as a valid neurobiological disorder. Often. or are easily self-treated.7). Over the last two decades. Springfield. sufferers are undertreated as well (5). Other. In direct-to-consumer advertising. migraine is portrayed as sinus in origin (6. Patients and physicians often regard headaches as ‘‘sinus’’ in origin if autonomic symptoms (such as congestion and running nostrils) occur.9). Connecticut. However. with unilateral throbbing pain and disability with rapid resolution. U.S. once viewed as ‘‘a disease of women that resulted from excessive stress and vascular fragility. Stamford.’’ allergy-. Eross et al. migraine. the American Academy of Otolaryngology 173 . Migraine is both a disease and an episodic disruption of nervous system function. U. Because the hallmark of successful treatment is proper diagnosis. Primary Care Network. showed that one of the most frequent reasons for physicians misidentifying migraine as sinus in origin is the location of the pain (8. the overdiagnosis of ‘‘sinus’’ headache is a myth continually perpetuated by media in the United States. Roger Cady Headache Care Center.A. and associated disability. Some of the reasons for under-recognition relates to the uniqueness of migraine itself. impact. Missouri. or stress-related. If episodes occur infrequently.13 Migraine Without Aura Fred Sheftell The New England Center for Headache. In the United States. migraine may not warrant a medical diagnosis and treatment. Through this time period. are not severe. This rapid advance in scientific knowledge of migraine has yet to displace the many myths and misconceptions that surround this important medical condition. there has been an explosion in the scientific and medical understanding of migraine. patients direct their own diagnosis by suggesting to a medical provider that their headaches are ‘‘sinus-. For example.A.S. or if the headache is related to changes in weather. more ‘‘sinister’’ factors may also be partially responsible for the underrecognition and diagnostic confusion that surrounds migraine. which further trivializes the disorder. Migraine without aura is an idiopathic. and are associated with nausea. Figure 1 presents red flags that are of concern for the diagnosis of migraine. and phonophobia.. we review the diagnostic criteria for migraine without aura according to the ICHD-2 and then move on to other instruments that may be more practical and less time consuming especially in the primary-care environment or to the nonheadache specialist. Unilateral location 2. Nausea and/or vomiting 2. recurring headache disorder manifesting in attacks lasting 4 to 72 hours if not treated.e. There are few.and inaccurate diagnosis associated with migraine. delaying diagnosis and appropriate therapy. A history of five previous attacks without sequelae and a normal physical and neurological examination should begin to provide a reasonable level of comfort with a primary-headache diagnosis.174 Sheftell and Cady states that headache is a minor criterion for the diagnosis of acute sinusitis (10). family history. Typical attacks reach moderate or severe intensity. and postdrome) (12). Pulsating quality 3. photophobia. . walking or climbing stairs) During headache. Kaniecki showed that the vast majority of patients with migraine have neck pain at some point during the attack process (prodrome. etc. and headache associated with stroke (16). arteriovenous malformations (AVM) (14). We close by presenting an illustrative case that summarizes our discussion on the classification and clinical features of migraine without aura. Photophobia and phonophobia Not attributed to another disorder D. and in fact the Second Edition of the International Classification of Headache Disorders (ICHD-2) does not recognize the ‘‘sinus’’ headache diagnosis (11). Although. In this chapter. Box 1 ICHD-2 Criteria for Migraine Without Aura A.’’ such as the triptans (17). Other issues such as neck involvement may lead to a diagnosis of tension-type headache.. the differential diagnosis of migraine and other acute headaches is described in detail in Chapter 11. other common medical complaints that present the magnitude of under. alcohol or other triggers. occurrence of at least one of the following 1. the attack. are aggravated by routine physical activity. including menstrual association. are presented in Figure 2. if any. Some features. Migraine without aura may indeed mimic headache associated with structural pathology (13). There is much clinical wisdom behind the required five episodes necessary to confirm a diagnosis of migraine without aura. THE ICHD-2 CRITERIA FOR MIGRAINE WITHOUT AURA The ICHD-2 criteria for migraine without aura are presented in Box 1. At least five attacks fulfilling B–D Headache attacks lasting 4–72 hrs (untreated or unsuccessfully treated) Headache has at least two of the following characteristics 1. and each of these is potentially responsive to ‘‘migraine-specific treatment. C. Aggravation by routine physical activity (i. septic meningitis (15). Moderate or severe pain intensity 4. B. E. There are a variety of alternative methods that may have greater relevance in clinical practice by which the diagnosis of migraine can be made. The next two criteria (C3 and C4) define headache associated with migraine as being of moderate or severe intensity and aggravated by routine physical activity. and/or vomiting (D1) for the formal criteria to be met. especially in the primary-care environment. migraine and responds to migrainespecific medications (19). indeed. given the time constraints and the fact that primary-care providers are responsible for patients with a gamut of diseases. Although clinically it has been understood that migraine is characterized by a unilateral throbbing headache (criteria C1 and C2). where it typically can come on and resolve rapidly. 40% of attacks are not associated with either unilaterality or throbbing (18). Headaches associated with at least two of these four criteria are required for an ICHD-2 diagnosis of migraine. the attack must also be accompanied by phonophobia and photophobia (D2). While the ICHD-2 criteria remain the gold standard for regulatory studies of migraine. However. If the attack is characterized by all but one of the required criteria. not just headaches. previously called ‘‘migrainous’’ headache. Understanding the nuances of criteria C and D is also critical to assuring accurate diagnosis. a nonthrobbing. . Thus. but one hour or less in children. doubts have remained as to the utility of these criteria in the clinical setting. The duration of the typical untreated attack is generally between 4 and 72 hours in adults. The ICHD-2 criteria are based on a consensus of experts and represent the traditional symptombased approach to diagnosis (20). bilateral headache with sensitivity to light and sound satisfies the criteria for the diagnosis of migraine without aura. nausea.Migraine Without Aura 175 Figure 1 Worrisome signs and symptoms associated with migraine. Figure 2 Comfort signs and symptoms of migraine. the ICHD-2 codes it as probable migraine. which in the authors’ opinion is. 176 Sheftell and Cady If one examines the criteria for migraine without aura. medication overuse. weather. A more narrowly focused but well-validated tool is the ID MigraineTM (21). The first of these is the four-question screener proposed in ‘‘Patient-Centered Strategies for Effective Management of Migraine’’ (30): 1. The validation study found that when two out of three crucial headache features are present. stressful circumstances. those questions do not provide any sense of impact. There have been several tools developed over the years targeting temporary impairment related to migraine (see Chapter 12) (24–29). including brief screeners. How frequently do you experience headaches of any type? Frequent headaches indicate the need for preventive medication and raise the possibility of medication overuse. 93% of patients who screen positive receive an ICHD-2–based diagnosis when they . 4. I often can’t show up at family functions. This makes the ICHD-2 criteria less clinically relevant because much of the crucial information required for effective decisions about management of migraine patients is lacking in these criteria. For example.’’ elicits a better understanding of the impact than. Has there been any change in your headache pattern over the last six months? New or unstable headache patterns require complete medical evaluation. This tool is designed to screen for migraine in the primary-care setting. these questions identify patients likely to have migraine. in a patient with intermittent migraine who looks perfectly well during the initial visit. physicians are more likely to treat more aggressively and appropriately versus a simple reporting of symptoms (29). and response to medications. or social functions has a high probability of being migraine. frequency. it is apparent that a minimum of eight questions are necessary to make a diagnosis of migraine without aura. I’m missing two to three days of work every month. 2. A variety of other means of diagnosis are also available (21. Headache-related impact is an essential part of the history and is vital in the diagnosis of migraine and in understanding the effects of headaches on the lives of patients. 3. change in patterns. and I can be sensitive to light and sound!’’ The use of disability instruments such as Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) can be enormously helpful in accurately diagnosing and understanding the therapeutic needs of the patient. Pattern-based recognition of migraine is often more clinically valuable for both specialty-based practitioners and primary-care providers. As framed. Lipton et al. and secondary headaches. disability. are also useful as efficient means of considering migraine as a diagnosis. The use of headache calendars may be extremely helpful (23) in revealing patterns such as menstrually associated migraine and migraine triggered by foods. or medication overuse. How do headaches interfere with your life? A stable pattern of episodic headaches that interfere with work. ‘‘Doctor. have shown that when impact is introduced into the history. throbbing. hearing ‘‘Doctor. How often and how effectively do you use medication to treat headaches? Coping strategies and timing of therapeutic intervention are assessed. family. However. my headaches are one-sided. response to treatment. A variety of other instruments.22). Moreover. a stable pattern. inability to function. recurrent. if without obvious signs of secondary headache. the headache patient is likely to believe that they experience more than one type of headache. Thus. normal examination. For example. They suffer from headaches more frequently. see Chapter 12). patterns of medication use. For most people in the general population. frequency. but if they awaken the next morning without headache and can function fully. They found over a 90% correlation with ICHD-2 criteria for migraine. Thus. Further. To summarize. the Landmark Study (32) established that over 90% of patients who seek medical evaluation with a complaint of headache to their primary-care physician. aided by the mnemonic PIN (for a complete description of ID migraine. MIGRAINE IN CLINICAL PRACTICE Understanding the patient with a primary-headache disorder is more complex than simply applying the academic diagnostic criteria to each primary-headache complaint.Migraine Without Aura 177 see a headache expert. headaches are self-diagnosed and self-managed throughout their lifetime. the individual who seeks medical care for headaches is likely to be experiencing more frequent disabling headaches that do not always resolve with sleep. and. The Brief Headache Screener (BHS) (31) addresses impact. What separates the headache sufferers in the general population from headache patients seen in medical practice is that headache patients have a lower threshold to headaches. and the need for prophylaxis. in an outpatient setting where a patient presents with an established pattern of headache rather than a new onset or evolving headache. which creates greater impact and disability in their lives. they have generally failed for years at self-management and often have developed fixed ideas as to the cause and diagnosis of their headaches. Primary headache is nearly a universal human experience and as such can be considered part of human biology.33). poorly informed health-care providers. will screen positive for migraine. episodic headache associated with disability. at times. Maizels and Burchette were also among the first to develop a tool to aid in migraine recognition in the primary-care environment. However. they must often overcome the inherent biases the patient has acquired from such sources as the media. and headache is generally only one of several physical complaints that they are experiencing (3. satisfaction with current therapy. In addition. Consequently. One study showed that 29% of patients in the waiting room of primary-care practices for any reason screen positive for migraine (20). well-meaning friends and family. migraine should be considered the default diagnosis unless there are compelling reasons to the contrary. clinicians frequently evaluate primary headaches imbedded amidst other medical concerns and must carefully dissect the relevant symptoms from which a proper diagnosis can be formulated. The features include photophobia. a person in the general population experiencing infrequent severe migraine may seek bed rest for that rare attack. it is critical that providers understand the unique biological and sociological aspects of a headache patient and factors that separate them from the general headache population. they are unlikely to consider headache a medical problem. and lack of worrisome features is most likely migraine. . and nausea. By the time patients seek out medical care for a primary headache disorder. The Phases of Migraine Without Aura Many factors undoubtedly determine an individual’s susceptibility to an attack of migraine. Premonitory Phase When the nervous system of a person susceptible to migraine is exposed to a risk environment. 3) (34. trauma (both physical and psychological). efforts have been made to link these clinical phases of migraine to its underlying pathophysiology. These symptoms are defined in ICHD-2 nomenclature as premonitory symptoms but will often coalesce into a recognizable pattern that allows a migraine sufferer to accurately predict the event of migraine. This susceptibility to attacks of migraine often changes throughout an individual’s lifetime and is quite variable from one individual to another. . symptoms that are harbingers of the impending event of headache often emerge. More recently. biological factors such as age and hormonal status. the initiation and susceptibility of the nervous system are determined by the complex interaction of human physiology and environmental factors. This Figure 3 Phases of migraine in clinically observable primary headache diagnoses. These observations have important implications for diagnosis and treatment of the migraine process and the patient living with the disorder. which not necessarily happen in all patients (Fig. and environmental factors (36). (iii) headache.35): (i) premonitory features. The clinical evolution of migraine without aura can be divided into several distinct clinical phases. and (iv) postdromic features. (ii) aura. Included are genetic factors linked to a more ‘‘excitable’’ neurological system.178 Sheftell and Cady Understanding Migraine The episode of migraine is a neurological event that most often begins well before the symptom of headache emerges. Clearly. diffuse in nature. From a therapeutic standpoint. if the premonitory period of migraine persists or occurs frequently without evolving into a migraine headache. Although the premonitory symptoms pale in impact compared to the drama of severe headache. many patients can predict future headache with remarkable accuracy. this phase of migraine is considered by patients to be a tension-type headache particularly if it is associated with muscle pain. the pathophysiological process leading to migraine may resolve through natural history or proactive steps such as rest or even medication. first as awareness that headache is beginning and then intensifying over minutes to hours to eventually become recognizable as migraine. These symptoms can emerge hours to days before the onset of headache. muscle pain. leading to an erroneous diagnosis. Consequently. cognitive dysfunction. Frequently observed premonitory symptoms include fatigue. For example.38). food cravings. this therapeutic approach has been described as ‘‘early intervention. and not necessarily aggravated with activity or associated with significant photophobia or phonophobia. and pressure in the face (6. subjects who reported a 90% chance of having headache developed headache 90% of the time. In many instances. nasal congestion.10).Migraine Without Aura 179 recognizable pattern of premonitory signs and symptoms is commonly referred to as a prodrome. The mild headache phase of migraine has relevance both clinically and therapeutically. Despite the therapeutic value of treatment during this phase of migraine. Interventions during this time with triptans improve painfree rates by 50% to 100% over interventions initiated during moderate-to-severe headache. and sinus headache if it is associated with facial pain and nasal symptoms. The early headache is often mild in intensity. and yawning. During the premonitory phase. there is no current allowance for premonitory symptoms without headache. these symptoms may not be recognized as a phase of migraine. however. pharmacological intervention particularly with oral triptans is most efficacious when initiated during this phase of migraine (40–42). though many other unique symptoms are also reported in the premonitory phase (37. The clinical relevance of this phase of migraine is also important to understand. Mild Headache The headache associated with migraine often (but not always) begins insidiously. and reduce headache recurrence and the occurrence of drug-related adverse events (44). Associated with this headache is often muscle tension or pain in the head and neck or nasal congestion. Although. they can and often do create a significant impact (37–39). nonpulsatile in character.44). At this stage. Although the ICHD-2 classification allows a diagnosis of migraine aura without headache. It is. many patients do not initiate treatment during the mild headache phase of migraine because they are waiting to see if a specific headache will evolve to become a ‘‘real . mood changes. Pharmacoeconomic models also suggest increased value and reduced cost of treatment when this strategy is consistently employed (45–47). the use of an electronic diary ensured that the prediction preceded the reported headache onset (37). the patient’s estimate of the probability of headache corresponded almost exactly to the actual probability of having headache. essential to bear in mind that not every premonitory phase evolves into migraine or even headache.’’ it is more accurate to characterize it as treatment during the mild headache phase of migraine (43. In an electronic diary study. patients frequently experience symptoms described as a postdrome or the ‘‘hangover of migraine. and phonophobia. Postdrome Following the resolution of the headache phase of migraine. These symptoms may continue for 24 or more hours and may add to the impact and disability associated with an attack of migraine. The mild headache phase. However. It is common for patients to describe cognitive difficulties.’’ These symptoms are often a continuation of symptoms similar to those observed during the premonitory phase of migraine. and probable migraine. especially with activity. and mood and affective changes (10. The headache intensifies during this phase to the point of being moderate-to-severe in intensity and throbbing. Like all previous phases of migraine. In clinical practice. muscle pain in the neck and shoulders. migraine without aura. The frequency with which the mild headache resolves without pharmacological intervention is unknown. and is frequently associated with nausea. In delaying intervention many patients may not achieve optimal therapeutic response and extend the time that migraine disrupts their function.180 Sheftell and Cady migraine’’ (48). many of the symptoms observed during the earlier phase of migraine also persist into and through the moderate-to-severe phase of headache. facial pressure or pain. As this phase of headache reaches its zenith. several . migraine becomes a significantly disabling disorder and frequently requires withdrawal from activity and bed rest. most people suffering with episodes of severe migraine believe these less severe headaches to be a tensiontype headache. This underscores the need to educate appropriate migraine patients about the value of accurately recognizing this phase of migraine. nasal congestion. Consequently. it may produce significant disability for up to 72 hours and occasionally longer. When this occurs. like the premonitory phase. these symptoms are more frequent and prominent than the symptoms selected as diagnostic criteria for migraine without aura. many patients will initiate pharmacological agents (especially over-the-counter drugs) during mild headache. Moderate-to-Severe Headache Symptoms occurring during the moderate-to-severe headache phase of migraine constitute many of the features required to diagnose migraine by the ICHD-2 criteria. can resolve without evolving into a more severe headache. photophobia. However. but are not part of the formal diagnostic taxonomy. which undoubtedly distort the underlying symptomatology of the evolving migraine. the moderate-to-severe headache phase also resolves even if treatment is not initiated. without effective intervention. In addition. The Spectrum of Migraine The ICHD-2 diagnostic criteria for migraine include diagnoses of migraine with aura. they may simply consider these episodes to be of a less severe nonmigraine headache. In many instances.49). This underscores some of the diagnostic confusion surrounding migraine recognition. The most common headache self-diagnoses were migraine. A larger placebo-controlled study of over 3000 subjects was reported by Schreiber et al. The diaries records were used to assign an ICHD-2 diagnosis to each treated headache. reported on a population of subjects with self-diagnosed or physician-diagnosed sinus headache (6). In the American Migraine Study II (3). Thus. sinus headache. completed a survey inquiring about the types of headaches they were experiencing. subjects with a history of migraine were allowed to treat up to 10 moderate-to-severe headaches of any type. These different events may impact on the nervous system in unique ways resulting in different premonitory symptoms. Subsequently. Diaries were used to record the severity and quality of headache. These changes are witnessed clinically as premonitory symptoms. When these subjects treated a headache with 50 mg of oral sumatriptan. they also experienced headaches that fulfilled criteria for probable migraine and tension-type headache.Migraine Without Aura 181 or all of these different presentations may be experienced by the same patient. . Thus. (51) and confirmed the results seen in the earlier pilot study. Invariably. This model proposes that an episode of migraine is initiated when a vulnerable nervous system is exposed to an environment (internal or external) that puts it at risk for migraine. Analysis of treatment response to sumatriptan suggested statistically significant efficacy over placebo for all headache presentations as well as similar response rates between these different headache diagnoses. The authors conclude that there were underlying pathophysiological mechanisms shared by these phenotypically different primary headaches at least in the migraine population (19). it would appear that most ‘‘sinus’’ headaches are in reality part of the spectrum of primary headache presentations observed in the migraine population. and treatment response. the migraine patient often considers some of their headaches to be tension-type headaches. Numerous events may individually or in conjunction with other events set the environment for nervous system disruption. the nervous system undergoes changes in its normal homeostatic mechanisms. Cady et al. explored the relationship of different primary headaches in the patient with migraine. The Spectrum Study. and tension-type headache. Detailed interviews revealed that 98% had enough symptoms to establish a diagnosis of migraine with or without aura (70%) or migrainous headache (28%). these subjects reported multiple types of headache regardless of the medical diagnosis(es) they had received. THE CONVERGENCE HYPOTHESIS The Convergence Hypothesis (51) is proposed as a clinical model of migraine that attempts to connect clinical diagnosis of common primary headaches with the pathophysiology of migraine and the observed clinical phases of migraine. associated symptoms. with 50 mg of oral sumatriptan. In addition. as diagnosed by a validated telephone interview and a medical diagnosis of primary headache(s). In this study. there was an observed spectrum of primary headaches in the population with migraine. Placed in this migraine-risk environment. published in 2000 (50). over 1600 subjects with migraine. The results of this study demonstrated that although the subjects experienced some headaches that fulfilled criteria for migraine with or without aura. the efficacy was similar to that observed in treating migraine. During some attacks. As higher orders of the nervous system are sensitized. This is prominent during activities that increase intracranial pressure (and consequently mechanical pressure on the trigeminal afferents innervating meningeal vessels) such as cough or bending forward. This speculation is supported by the observation that 70% of women may experience headache during the week of placebo pills when using oral contraceptive pills (55) and by the frequent exacerbation of migraine observed during the perimenopausal time period. skin sensitivity. Evidence suggests that falling levels of estrogen are involved in the pathophysiology of these migraine attacks (54). the entire spectrum of primary headaches can be understood as arising from the same pathophysiological process. . These symptoms may be erroneously interpreted as evidence for sinus headache or muscle tension headache. and clinical management can shift to understanding the pattern of headache rather than diagnosing each individual headache. The diagnostic implications of the Convergence Hypothesis are that a diagnosis of ICHD-2 migraine defines the extent and capability of the nervous system to experience the entire pathophysiological process of migraine. they also happen unrelated to the cycle. the moderate-to-severe headache phase of migraine primarily would relate to neurovascular activation of trigeminal afferents. The early perception of headache is often related by patients as secondary to muscle tension and pain. the mild headache phase of migraine results from a net loss of central inhibitory modulation of peripherally generated sensory inputs arising from trigeminal afferents and/or sensory input from the C-2-3 dermatomes. the attacks are restricted to the menstrual cycle. As is noted with the other phases of migraine. The clinical symptoms observed during the moderate-to-severe headache phase of migraine evolve as underlying pathophysiology of migraine progresses.182 Sheftell and Cady The first phase would be followed by cortical spreading depression (CSD). suggesting a unique role for estrogen withdrawal in initiating activation of the trigeminal vascular system. or ‘‘sinus’’ pressure or congestion. Both pure menstrual migraine and MRM are not associated with aura. There is much folklore surrounding MRM. MRM is often considered a more virulent variant of migraine than those attacks not associated with menses and is described as being more difficult to treat or longer in duration. Later. In pure menstrual migraine. Menstrually related migraine (MRM) is not formally recognized by the ICHD-2 diagnostic criteria as a separate diagnostic category but has been added to the appendix. According to the Convergence Hypothesis. Once this diagnosis is made. As second-order neurons become sensitized. This physiological phenomenon is used to explain the aura associated with 20% of migraine attacks. the moderate-to-severe headache phase can be arrested or terminated at any point in its evolution. sensory inputs are registered as unpleasant or painful. MENSTRUALLY RELATED MIGRAINE Perhaps the most consistent risk event for migraine in women throughout their reproductive years is menses. The classification notes that there are two subtypes of menstrual migraine. For example. physical activity aggravates the pain. Although MRMs are clustered in the menstrual period. It remains unknown whether CSD occurs in migraine without aura (52). the headache begins to intensify and may localize. Initially. patients may develop cutaneous allodynia (53). the study period of the clinical trials was only 24 hours. though they are not approved by the Food and Drug Administration. However. MRM is in most instances predictable by both the occurrence of premonitory symptoms and its cyclic nature. MRM is an important form of migraine to understand for both its clinical importance and theoretical value. This neurological process can resolve at any point in its evolution. Migraine is a neurological process that is initiated when a susceptible nervous system of a migraineur is exposed to an environment that places that nervous system at risk for migraine. Clinically. Unlike many medical diseases that providers manage. Migraine is a unique medical condition in that it arises from human physiology. migraine often evolves through several recognizable phases before progressing into an attack fulfilling all the ICHD-2 criteria for migraine without aura. In general. which limits conclusions on migraine recurrence. Both strategies appear to have efficacy.Migraine Without Aura 183 However. when migraine is uncontrolled. CONCLUSION Migraine without aura is a common. This results a more accurate diagnosis through integration of the pattern and impact of migraine with the associated clinical symptoms. These include efforts to prevent estrogen levels from decreasing. Based on the predictable nature of MRM. it can literally destroy decades of a person’s quality of life. data from clinical trials suggest that MRM responds to triptan intervention with about the same efficacy as non-MRM (56. migraine has no obvious catastrophic medical end point nor is there any etiological toxic agent or infection to resolve. Many patients assume that headache associated with facial pain is ‘‘sinus’’ in origin and headache associated with muscle pain is ‘‘tension’’ in origin. Patients living with a nervous system that has the potential to express migraine often experience multiple clinical presentations of migraine. data are generally lacking to either support or refute these claims. the potential of the nervous system to express a fully developed migraine appears to occur in approximately 12% of the adult population. Understanding migraine as a neurological process permits a more complete comprehension of these different clinical nuances of migraine. Although headache is nearly a universal human experience. And this provides opportunities to educate patients for a better understanding of the rationale for important therapeutic paradigms such as early intervention. Medical providers can do much to assist patients living with this disorder to improve their quality of life by providing education. close analysis reveals that in most instances these headaches do achieve enough symptoms to satisfy the ICHD-2 criteria for migraine. and appropriate therapeutic interventions. Studies with triptans used in a preemptive manner have interesting implications as to the early use and perhaps limited prophylactic use of these drugs in the future (38. which may in part explain the multiple unique and varied clinical phenotypes of the migraine process. support. .57). though under-recognized medical condition.58–60). However. However. such as with unopposed use of oral contraceptives and the use of oral triptans in a preemptive method. numerous novel efforts have been made to prevent attacks from occurring. These unique presentations of headaches can create diagnostic confusion for the patient and provider. (ICD-10-CM). Neurology 1994. Tenth Revision. Available at http://www. a combination of a simple analgesic and pseudoephedrine. Diamond ML. Stewart WF. 8. Diamond S.cdc. which affects her ability to function. International Classification of Diseases. Physical/ neurologic examination is within normal limits. . Accessed 12/15/2004. 11. Headache 2001. Cady RK. The pain is at least of moderate intensity. 37(2):267–288. Type I: The ones that occur monthly with her menses are the most severe and characterized by severe bilateral squeezing pain. Why migraine is misdiagnosed as sinus headache: the patient’s perspective. 44:479. Gladstone JP. Stewart WF. Amatniek JC. 5. and may cause her to lie down if she can. Diamond S. These episodes formerly called migrainous headache are now called probable migraine according to ICHD-2. REFERENCES 1. Diamond ML. Her mother had sinus headaches. She experiences several ‘‘different types’’ of headache. Cephalalgia 1999. Going back to the ICHD-2 criteria and the screeners you can see how all of these are migraine! Type I headache incorporates only sensitivity to light and no other Group B symptoms. Simon D. 24(suppl 1):9–160. 10. Type III: These start in her neck and involve the occipital region as well. Headache Classification Subcommittee of the International Headache Society. Cady RK. Eross EJ. but she will avoid bright light. Schreiber CP.gov/nchs/ search/search. which she blames on the medication. Headache 2004. Headache 2004. National Center for Health Statistics. Sinus headache: a clinical conundrum. which takes the edge off the headache. identifying and removing barriers to care. Reed M. 2.184 Sheftell and Cady ILLUSTRATIVE CASE HISTORY MR is a 35-year-old female with a history of headache going back to adolescence starting around the time of menarche. and sensitivity to sound. Migraine headache misdiagnosed as sinus headache: You can only find what you are looking for. Sinus headache or migraine? Considerations in making a differential diagnosis. 7. Clinical Modification. 58(9 suppl 6):S10–S14. Reed M. She denies vomiting. 6. nausea. 9. Lipton RB.htm. 19(suppl 25):20–23. Epidemiology and socio-economic impact of headache. 44:479. Dodick DW. 3. 4. Ferrari MD. Headache 2001. Migraine. 41(7):638–645. 38(2):87–96. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 1998. sometimes triggered by stress. Gross M. The international classification of headache disorders: 2nd ed. Neurology 2002. Gladstone JP. Otolaryngol Clin North Am 2004. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. with the lights off and sound at a minimum. 41(7):646–657. The pain can throb when severe and she may get mildly nauseated. Lipton RB. Climbing stairs making it worse. Cephalalgia 2004. Lipton RB. Eross EJ. Her grandmother had ‘‘sick’’ headaches. Rasmussen BK. Type II: These are associated with weather changes with moderate pain located above the bridge of her nose between her eyes and involving both infraorbital areas. 44(6 suppl 4):S63–S68. Schreiber CP. Dodick DW. which dissipated after her menopause. Stewart WF. Lipton RB. Medical consultation for migraine: results from the American Migraine Study. Rapid and sensitive paradigm for screening patients with headache in primary care settings. 11:63–73. 13. Neurology 1993. 29. 31. Newman CW. 46(9):626–627. Headache 2001. Headache 2002. Headache 2004. Headache 1995. Kinski M. Schreiber CP. 44(4): 323–327. Rev Contemp Pharmacother 2000. Blakeborough P. Edmeads JG. Stewart WF. Headache 2004. 28. Cady RK. Diagnostic lessons from the spectrum study. Neurology 1994. Dodick D. Lipton RB. Dev Med Child Neurol 2004. Neurology 2003. Ganesan V. Neurology 2002. Bille MB. Sheftell FD. Sawyer J. New paradigms in the recognition and acute treatment of migraine. Dahlof CG. Dodick DW. Newman CW. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the landmark study. Borchert LD. 21. 33. Neurology 2002. 44(10 suppl 7): S33–S36. Wilks K. 61(3):375–382. 14. A selfadministered screener for migraine in primary care: The ID Migraine validation study. 44(9):856–864. In press. Cady RK. 22. et al. Ramadan NM. Migraine and tension-type headache: an assessment of challenges in diagnosis. et al.Migraine Without Aura 185 12. 44:837–842. Ramadan NM. 38(suppl):1173–1182. Dowson A. Stewart WF. Forsyth PA. Neurology 1994. Relationship of stroke and migraine. Patient-Centered Strategies for Effective Management of Migraine. Aggarwal SK. 32. 16. 20:320. 58(9 suppl 6):S27–S31. Simple and efficient recognition of migraine with 3-question headache screen. Welch KM. Ware JE. 20. Arteriovenous malformations presenting with papilloedema. 27. Guidelines for the diagnosis and management of migraine in clinical practice. Primary Care Network 2000. Jacobson GP. Migraine: diagnosis and assessment of disability. 23. Ware JE Jr. Lipton RB. 156 (9): 1273–1287. Tepper SJ. Bjorner JB. Sadovsky R. Hall C. J Cereb Blood Flow Metab 2002. ID Migraine validation study. . La Mantia L. Pryse-Phillips WEM. Burchette R. Sheftell FD. 19. Cosensitization of pain and psychiatric comorbidity in chronic daily headache. Norris L. Headache disability inventory (HDI): short-term test-retest reliability and spouse perceptions. Practical implications of item response theory and computerized adaptive testing: a brief summary of ongoing studies of widely used headache impact scales. 25. 58(9 suppl 6):S15–S20. Sawyer JP. Erbetta A. Bjorner JB. 41(9):854–861. 24. Diamond M. Headache 2003. 17. Maizels M. Cephalalgia 2000. et al. Headache and inflammatory disorders of the central nervous system. 18. Lipton RB. 42(1):58–69. Farmer KU. et al. 26. Neurology 2000. et al. Cady RK. Keilwerth N. Posner JB. Lipton RB. 43(5):441–450. Headaches in patients with brain tumors: a study of 111 patients. Med Care 2000. Kosinski M. Hoffmann O. 25(suppl 3):S148–S153. Ware JE. Validation of the headache impact test using patient-reported symptoms and headache pain severity [abstract]. 54(suppl 3):A453. Goadsby PJ. 30. Spalding W. Kaniecki RG. Tepper SJ. The Henry Ford Hospital Headache Disability Inventory (HDI). Measuring the impact of migraine and severe headache with the headache impact test: using item response theory (IRT) models to score widely-used measures of headache impact and assess disability due to migraine or other severe headaches [abstract]. Neurol Sci 2004. Can Med Assoc Mat 1 1997. 22(8):988–996. Bayliss MS. Fung LW. Advisory Board of the Primary Care Network. 43(9):1678–1683. Kosinski M. Stewart WF. Edmeads JG. Dexter JK. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. 15. Triptans reduce the inflammatory response in bacterial meningitis. Hart CC. 35: 534–539. Jacobson GP. Farmer KU. Headache. Primary headaches: a convergence hypothesis. 60:935–940. Carter D. Lipton RB. Bajwa ZH. Farmer K. Sheftell F. Sheftell F. Boas DA. An association between migraine and cutaneous allodynia. Schreiber CP. Batenhorst AS. 45(5):538–545. Cady R. Cady RK. MD: Johns Hopkins University Press. Cady RK. Hoffman L. Eletriptan in the early treatment of migraine. 56. Prevention of migraine during prodrome with naratriptan. Solbach P. Batenhorst AS. Giffin NJ. 40: 103–110. 40(10):792–797. Sikes CR. 22:355. Lipton RB. 44. 40:783–791. Cabarrocas X. 22(9): 1035–1048. Pait D. 164:1769–1772. 82:769–772. Cady RK. Ann Neurol 2000. Bolay H. Sun W. et al. Treatment of menstrually associated headache with subcutaneous sumatriptan. Cephalalgia 2005. Cady RK. 42:204–216. Preece C. et al. Burstein R. 40. 43:518. 53. Kudrow D. Ransil BJ. The effect of prodrome on cognitive efficiency [abstr]. 42(10): 984–999. Lipton RB. 52. 55. Tiseo PJ. Schreiber CP. et al. 43. Dunn AK. Stewart WF. 1987:3–17. Costs and outcomes of early versus delayed migraine treatment with sumatriptan. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study. influence of pain intensity and timing of dosing. Lipton RB. 42. Kwong WJ. Arch Intern Med 2004. 36. Obstet Gynecol 2000. Cady RK. Blau JN. Halprin MT. Headache and Other Head Pain. Webster CJ. Understanding the patient with migraine: the evolution from episodic headache to chronic neurological disease. Lipton RB. Within-patient early versus delayed treatment of migraine attacks with almotriptan: the sooner the better. 48. Yarnitsky D. 38. 25(9):735–742. Watson C. Baltimore. Headache 2002. Waymer R. Low migraine headache recurrence with naratriptan: clinical parameters related to recurrence. . Wolff HG.186 Sheftell and Cady 34. et al. Workplace productivity: a review of the impact of migraine and its treatment. Huang Z. Reeves D. Nat Med 2002. 46. Cephalalgia 2000. Ruggiero L. Neurology 2003. 47. Headache 2002. Treatment of mild headache in disabled headache sufferers: results of the spectrum study. 41. O’Quinn S. 51. 2nd ed. Hormone withdrawal symptoms in oral contraceptive users. 54. Hutchinson S. NY: Oxford University Press. Headache 2000. Cady RK. Pharmacoeconomics 2001. Burden of migraine in the United States. Headache 2000. Markson LE. Goor-Aryeh I. Hu XH. Headache 2002. Stewart WF. 159:813–818. 47:614–624. 1963:227–301. Headache 2000. The role of estrogen withdrawal in the etiology of menstrual migraine. Treating early vs treating mild: timing of migraine prescription medications among patients with diagnosed migraine. Obstet Gynecol 1993. Reuter U. Foley KA. et al. Brandes JL. 35. Arch Intern Med 1999. et al. ed. Headache 2003. 37. Headache 2004. Mario KO. 19:231–244. Cady RK. Early treatment with sumatriptan enhances pain-free responses: retrospective analysis from three clinical trials. 50. Luciani R. Migraine Clinical and Research Aspects. Premonitory symptoms in migraine: an electronic diary study. In: Blau JN. et al. Adult migraine: the patient observed. Sheftell F. Scow RD. A proposed classification of patients with headache. Winter P. New York. 55:1517–1523. et al. 2005. 8(2):136–142. Pascual J. Stang P. Cady RK. Mannix L. Berger ML. 49. Hall C. 45. 44:1–10. Cadt RK. Moskowitz MA. Schreiber C. Martin V. 39. Prevalence of migraine among patients with a history of self-reported or physician diagnosed ‘‘sinus’’ headache. Farmer KU. Somerville BW. Clin Ther 2000. 20(2):122–126. 42(1):28–31. Sulak PJ. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Neurology 1972. Rappaport AM. 63(2): 261–269. et al. Obstet Gynecol 2000. Naratriptan in the prophylaxis of transformed migraine. Solomon S. Silberstein SD. 39(7):506–510. Neurology 2004. 59. 60. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Massiou G.Migraine Without Aura 187 57. Schreiber CP. 58. Elkind AH. Silberstein SD. LeJeunne C. Rizatriptan in the treatment of menstrual migraine. Newman LC. Sheftell FD. Coddon DR. Headache 1999. Keywood C. A pilot study of oral sumatriptan as intermittent prophylaxis of menstrually-related migraine. . Neurology 1998. 52(6): 1301–1302. Lipton RB. 96:237–242. Lay CL. . certain clinical features must be present and organic diseases must be excluded. Denmark INTRODUCTION Migraine with aura is characterized by transient focal neurological symptoms called aura. or across the face).14 Migraine with Aura Malene Kirchmann Eriksen and Jes Olesen Department of Neurology. as well as at least one first. vomiting. over a few minutes. Glostrup Hospital.2. from one hand to the lower arm.2. the aura symptoms usually develop gradually. zigzag lines. The Danish Headache Center.2). either by clinical or by subsidiary investigation (see Chapter 11).3). In brief. and dysphasic aura are the most common symptoms. Visual.or phonophobia as seen in migraine without aura.5) is characterized by motor weakness in addition to typical aura.4) is characterized by motor weakness in addition to the typical aura.or second-degree relative with the same disorder (Table 3). University of Copenhagen. and often spread over the area of initial clinical manifestation (across the visual field.1–3) is characterized by visual. There are four major subtypes of migraine with aura and more than one subtype may occur in one individual (Table 1). to establish a diagnosis of migraine with aura.2. or prickling paresthesias) followed by negative symptoms (blind spot and numbness). or occur without headaches (1.or second-degree relative has hemiplegic 189 . Copenhagen. Familial hemiplegic migraine (FHM) (1. or photo. but other aura variants such as motor aura may occur. typical aura (ICHD-2 codes 1.1) or nonmigraine headaches (1. but aura attacks may also occur in isolation. sensory. Sporadic hemiplegic migraine (1. nausea. The visual and sensory aura are generally characterized by positive symptoms (flickering light. but no first. or dysphasic aura (Table 2) that may be followed by a migraine headache (1. CLASSIFICATION According to the second edition of The International Classification of Headache Disorders (ICHD-2) (1). The aura symptoms may be followed by headache. Furthermore. The diagnosis of migraine with aura requires at least two attacks fulfilling the ICHD-2 criteria. sensory. This chapter describes the classification and clinical features of migraine with aura. The aura duration is usually less than one hour. 2.2.. Not attributed to another disorder .e.2. spots. Fully reversible dysphasic speech disturbance C.2.2 Migraine with aura 1. Fully reversible visual symptoms including positive features (i.190 Eriksen and Olesen Table 1 Classification of Migraine According to the Second Edition of the International Classification of Headache Disorders 1. Each symptom lasts !5 min and 60 min D.2 Typical aura with nonmigraine headache 1..2.3 Typical aura without headache 1.6. At least two of the following: 1.2)..1 Typical aura with migraine headache: Headache fulfilling criteria B–D for 1. and typical aura without headache (1. and lines) and/or negative features (i. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 3.1 Migraine without aura begins during the aura or follows aura within 60 min. but no motor weakness: 1.2.2. The ICHD-2 criteria for migraine with typical aura and familial.e.1). flickering lights. Homonymous visual symptoms and/or unilateral sensory symptoms 2. The ICHD-2 criteria for migraine with aura have been improved compared to the ICHD-1 criteria (1988).1 Migraine without aura 1..1 Migraine without aura begins during the aura or follows aura within 60 min.2. pinprick and needle sensation) and/or negative features (i. but no motor weakness (Table 4). Migraine with typical aura is subtyped according to the characteristics of the headache following the aura: typical aura with migraine headache (1. typical aura with nonmigraine headache (1.6 Basilar-type migraine 1.and sporadic hemiplegic migraine were based on the analysis of empirical Table 2 Diagnostic Criteria for Migraine with Typical Aura According to the Second Edition of the International Classification of Headache Disorders A.5 Sporadic hemiplegic migraine 1. migraine (Table 3).6) is characterized by aura symptoms clearly originating from the brainstem. Fully reversible sensory symptoms including positive features (i.1 Probable migraine without auraa 1.4 Familial hemiplegic migraine 1. or both hemispheres simultaneously affected.2.e.2. numbness) 3. Attacks fulfilling all but one of the criteria for migraine with aura or any of its subtypes.2.2 Typical aura with nonmigraine headache: Headache that does not fulfill criteria B–D for 1.2.e. Aura consisting of at least one of the following. This criterion determines the subdiagnosis of migraine with typical aura: 1. or 1.3) (Table 2).6 Probable migraine 1.3 Typical aura without headache: Headache does not occur during the aura nor follow aura within 60 min E.2 Probable migraine with aurab a b Attacks fulfilling all but one of the criteria for migraine without aura. At least two attacks fulfilling criteria B–D B. scotoma) 2.2. basilar-type migraine (1.6. or 1.1 Typical aura with migraine headache 1. Fully reversible dysphasic speech disturbance C.. Visual symptoms simultaneously in both temporal and nasal fields of both eyes 7. At least one first. flickering lights. data (2–4). and in FHM2..or second-degree relative fulfills criteria A–E.1) begins during the aura or follows aura within 60 min E. Headache fulfilling criteria B–D for migraine without aura (1.e. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 2. Decreased level of consciousness 9. Each symptom lasts !5 min and 24 hr 3. Tinnitus 4. but no motor weakness: 1.e. New genetic data have allowed a more precise definition of FHM since specific genetic subtypes have been identified: in FHM1 there are mutations in the CACNA1A gene on chromosome 19. Not attributed to another disorder Note: The diagnostic criteria for sporadic hemiplegic migraine are identical to the criteria for familial hemiplegic migraine except no first.e. Hypacusia 5. Diplopia 6. Ataxia 8. At least two attacks fulfilling criteria B and C B.Migraine with Aura 191 Table 3 Diagnostic Criteria for Familial Hemiplegic Migraine According to the Second Edition of the International Classification of Headache Disorders A. and lines) and/or negative features (i. At least one of the following: 1. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 2. Not attributed to another disorder . Simultaneously bilateral paresthesias C.. pinprick and needle sensation) and/or negative features (i. mutations occur in the ATP1A2 gene on chromosome 1 (see Chapter 9).e. At least two attacks fulfilling criteria B–D B. spots. Aura consisting of at least two of the following fully reversible symptoms. Vertigo 3. Dysarthria 2. Each symptom lasts !5 min and 60 min D. Aura consisting of fully reversible motor weakness and at least one of the following: 1. Fully reversible sensory symptoms including positive features (i.or second-degree relative has attacks fulfilling criteria A–E E. scotoma) 2. numbness) 3. Table 4 Diagnostic Criteria for Basilar-Type Migraine According to the Second Edition of the International Classification of Headache Disorders A. At least two of the following: 1. Headache fulfilling criteria B–D for migraine without aura (1. It is likely that further genetic subtypes of FHM will be added..1) begins during the aura or follows onset of aura within 60 min D. Fully reversible visual symptoms including positive features (i. In a 16-year follow-up study of 53 patients. affecting 5% to 8% of the population.10). cerebrovascular ischemia) should always be considered in patients with paresthesias and/or aphasia without visual symptoms and in patients with multiple aura symptoms without headache (see Chapter 11). and 6% had exclusively migraine aura without headache (9). 32% had attacks of both migraine aura with and without headache. Males have exclusively aura without headache more often than females (6). respectively (10). Visual aura occurs in almost every attack. In those who continued to have attacks of migraine with aura at follow-up. visual aura occurs in isolation in 76% (5) to 84% of patients (10). sensory. while sensory or aphasic aura occurs in only a fraction of an individual’s total number of attacks (5. and the visual aura is usually followed by the sensory or aphasic aura (10.13). 31% (10). while typical aura without headache may develop later in life (mean age at onset 36 Æ 15 years) (5). In a population-based sample of 163 patients (ICHD-1 criteria). When more than one aura symptom is observed. Attacks had stopped in 41% of patients with visual aura without other aura symptoms and in 25% of those with sensory or aphasic aura besides their visual aura. . General Symptom Characteristics Migraine with typical aura is characterized by attacks of visual. and the frequency was improved in 41% of patients (6). but later in life aura attacks often appeared without a following headache.10). and 4%.15). 40% (11). Another study of 80 patients with migraine with aura showed that 35% of patients had been attack free for one year at 10 to 20 years follow-up (7). the attack frequency shows wide periodicity. Dysphasic aura has been reported in 32% (5). occurring in 99% of patients at least in some attacks (5. In typical aura with headache. visual aura occurs without other aura symptoms in 39% (5) to 68% (10) of patients. or dysphasic aura often followed by a headache (Table 2). whereas sensory and aphasic auras usually occur in combination with another aura type (usually visual) (5. and 30% (12) of patients. 18% (10). 38%. many patients experience attacks of typical aura with headache. organic diseases (e.10. The attack frequency varies from few in a lifetime to several per week. At the time of follow–up.g.192 Eriksen and Olesen MIGRAINE WITH TYPICAL AURA Prevalence and Prognosis Migraine with typical aura is the most prevalent subtype of migraine with aura. Patients with a strong familial predisposition to migraine with aura have an earlier age at onset and a later age of cessation of attacks than patients from the general population (5.12). and 17% (12) of patients. Visual aura is the overwhelmingly most common aura symptom. In a study of 320 patients with a positive family history of migraine with typical aura (ICHD-2 criteria). At onset.. with a male to female ratio of 1:2. the long-term prognosis for migraine with nonhemiplegic aura was good (6). In typical aura without headache. they occur in succession in more than 96% of patients (5. The following subsections describe the features of the aura symptoms and the associated headache.5 (see Chapter 2). Most patients develop typical aura with headache in the first three decades of life (mean age at onset 21 Æ 12 years). the corresponding figures were 58%. and furthermore. especially in men.14. 20% (11).11. attacks had ceased for two years in 36% of patients. Sensory aura has been reported in 54% (5). Therefore.8). 63% of patients had migraine aura with headache in every attack. the headache intensity was improved in 44%. 10). or jamais vu (21). usually behind the advancing scintillation (14. Eriksen). (2) A zigzag-shaped line of scintillating lights develops leaving a scotoma in its wake. but the spectrum may also appear without a scotoma (18–20). The prevalence of the visual aura characteristics has been described in detail by Eriksen et al. and then it dissolves.K.19). No headache. . (5) and Russell and Olesen (Table 5) (10). The visual aura develops gradually over more than five minutes in 81% (5) to 97% of patients (10) (Table 5).17).19). that is. Other patients observe a nonscintillating scotoma (Fig. mosaic vision. deja vu. 1) (16. but colored lights are experienced in some patients. (5) The fortification spectrum reaches the midline of the visual field and dissolves in shimmering.12). may be observed in the entire visual field (5.. and subsequently a star-shaped figure of scintillating lights develops.10. or may only come to the attention of the patient when it reaches a certain size (15). but tiredness follows the aura. The zigzag line comprises parallel lines of white light. in the inner circle of the spectrum. The fortification line or scotoma is most often unilateral. Less characteristic visual aura symptoms include shimmering. while less characteristic visual disturbances. or rare metamorphopsia such as micropsia. The fortification spectrum often starts as a hazy spot near the center or in the periphery of the visual field. 2).Migraine with Aura 193 Visual Aura The most common visual aura phenomenon is the fortification spectrum (or teicopsia. The duration of the visual aura is less than one hour in 90% of patients (5. ‘‘heat waves’’ (20).14). telescopic ´ ` vision. The fortification line may change its shape during the gradual development.g. e.15. In the wake of the fortification line.17. flickering light. macropsia. which gradually expands into a semicircular zigzag line (fortification) (18–20). The visual aura develops gradually over 20 minutes: (1) Shimmering in the right lateral part of the visual field. a scotoma (partial loss of sight) often follows. The scotoma may develop into a complete hemianopsia (15). Repetitive fortification spectra or scotoma in the same attack have been observed (15. (3.4) The fortification spectrum migrates across the visual field and expands reaching a maximum diameter of 20 cm. photopsias (flashes of light). the Greek translation of ‘‘seeing fortifications’’) almost diagnostic for migraine with aura (Fig. This negative scotoma might completely escape observation. The fortification line keeps expanding or moving across the visual field until it reaches the midline (or crosses the midline) or the periphery of the visual field. The side of the visual aura may differ between attacks (20). Figure 1 Fortification spectrum in visual aura experienced by the author (M. it affects only one side of the visual field in two-thirds of patients (5. The visual aura is unilateral. that is. Sensory Aura Sensory aura is characterized by paresthesias (pinprick. This may not be misinterpreted as motor weakness. The aura duration is 45 minutes and a migraine headache begins during the aura. The scale quantifies the importance of the cardinal characteristics of the visual aura. Eriksen). scotoma (two points).20). The sensory aura is unilateral in 85% of patients (5. (A) The word ‘‘European’’ in the heading of a poster as observed before the onset of aura. The VARS serves as a supplement to the ICHD-2 criteria. .194 Eriksen and Olesen Figure 2 Negative scotoma in visual aura experienced by the author (M. a difficulty reading text located to the left of the center of fixation is noted. Eriksen and Olesen developed and validated a simple diagnostic scale for migraine aura known as the visual aura rating scale (VARS) (22).12. The involvement of the tongue is very typical for migraine aura and is rarely seen in cerebrovascular ischemia (13). Less often. If the hand and arm is affected. develops gradually (two points). then subsequently affects the face. Involvement of the tongue may result in dysarthria. needle sensation. The VARS score is the weighted sum of the presence of five visual symptom characteristics: duration 5 to 60 minutes (three points). zigzag lines (two points). The choice of the visual aura for quantification is based on the fact that most patients having migraine with aura experience visual symptoms. Blind spots cover part of the word and the letters still visible seem fractioned. the aura involves the lower extremity or torso (Table 5). The aura often starts in the fingertips and spreads slowly up the extremity. and unilateral (one point). (B) The same word as perceived during an attack of visual aura. and tingling) or numbness most often experienced in the upper extremity (89–96% of patients) or periorally (68% of patients) (5. lips. The initial sensation of sensory aura observed by the patient is usually paresthesia followed by numbness (14). If the visual aura is followed by a headache. A VARS score of 5 or more predicted the diagnosis of migraine with aura with a sensitivity of 96% and a specificity of 98% (22). Initially hazy spots in the entire visual field develop.14. the patient may have problems holding on to things due to numbness or loss of position sense in the affected extremity. the duration of the visual aura is longer (median of 30 minutes and interquartile range 15–45) than if the visual aura occurs in isolation (median of 18 minutes and interquartile range 13–22) (5).10).K.10). Because the symptomatology of the visual aura can be complex. Then. or tongue (cheiro–oral/hand–mouth distribution) (10. and is a useful tool in the differential diagnosis of migraine with visual aura. b In the study by Russell et al. this figure does not include patients with impaired language due to paraphasia. . A total of 76% of patients had paraphasia.05. The data were recorded as numerical data.Migraine with Aura 195 Table 5 Characteristics of Migraine with Typical Aura According to the Second Edition of the International Classification of Headache Disorders Visual aura (%) Eriksen 2004 (5) (n ¼ 358) à Sensory aura (%) Eriksen 2004 (5) (n ¼ 196) à Aphasic aura (%) Eriksen 2004 (5) (n ¼ 116) — Russell 1996 (10) (n ¼ 29) — Symptoms Acute onset of aura Gradually developing auraa 5–30 min 31–60 min >60 min Patient cannot say Durationa <5 min 5–30 min 31–60 min >60 min Location Unilateral Visual aura starting in: The center of visual field The periphery of visual field Patient cannot say Scotoma Preserved central vision Zigzag lines (fortification) Flickering light Sensation of sensory aura: Face Tongue Hand Arm Foot Leg Body Impaired production language Impaired comprehension of language (not due to headache) à a Russell 1996 (10) (n ¼ 161) à Russell 1996 (10) (n ¼ 51) à 19 3 25 2 à 68 4 0 9 à 82 11 4 — — 69 20 8 69 à 58 4 — 12 — 64 22 14 86 — — — — — — — à 82 2 14 — 2 67 12 20 84 — — — — — — — — — — — — 44 23 22 — — — — — — — — — — — — — — — — 96 26 — — — — — 59 24 17 — — — — — — — — — — — — — — — — 72b 38 <1 72 18 10 64 à à 28 49 à à 62 28 23 70 à 12 à à 10 50 à 22 à à 57 91 81 87 — — — — — — — — — — — — — — — — — — 68 41 89 à 52 14 à 14 9 — à 67 62 96 à 78 24 à 24 18 — à — — p < 0. and before the aura in 3% (10) to 8% (5) of patients.and phonophobia was identical. if the visual aura is exclusively negative (e. the patient may report the subsequent headache as an attack of migraine without aura. including olfactory hallucinations. Furthermore. basilartype migraine (see below). The headache following the aura differs from migraine without aura (see Chapter 13) in many patients. vomiting. A syndrome of various atypical aura symptoms has been defined as a subtype of migraine with aura. Approximately half of patients with aphasia also experience problems articulating words (dysarthria) (5. In a clinic population. but less frequent aura symptoms may cooccur.12). the evolution of aura and headache was observed during the attack (24). with a median duration of 30 minutes (5). the headache that followed aura was less intense and shorter lasting than that following migraine without aura (25). automatic behavior. Attacks of migraine without aura and migraine with aura may cooccur in the same individual (5. it is more likely to be a tension-type headache (9). sensory. and transient global amnesia (23). In two large retrospective studies of migraine with aura. In 58 out of 59 cases. the aura came before the headache. Other symptoms have not been documented by systematic observations.25). The duration of the sensory aura is less than one hour in more than 80% of patients (5.8. neglect.10.10).12. In a study with regional cerebral blood flow. Many patients experience speech disturbances when their paresthesias reach the face or tongue. The sensory aura spreads gradually over more than five minutes in 75% (5) to 98% of patients (10) (Table 5). simultaneously with the aura in 5% (10) to 11% (5). Dysphasic Aura Dysphasic aura is characterized by aphasia. In a population-based study of 38 patients with migraine with aura and 58 patients with migraine without aura randomly selected among 1000 Danes. Atypical Aura Symptoms Visual. (5). but additionally dysarthria may occur (5.14). and photo. The tendency for nausea. Headache and Associated Symptoms in Migraine with Aura The relationship between the aura and the headache is still not fully clarified (see Chapter 6).10. the headache occurred after the onset of aura in 82% (5) to 93% (10). Dysarthria is reported in 15% of patients with sensory aura without aphasia (5).. if the aura occurs during sleep. a scotoma). Aphasic aura is defined as impaired production of language (not due to dysarthria) or impaired comprehension of language. and a mean duration of 43 Æ 43 (SD) minutes according to Russell and Olesen (10). The duration of the aphasic aura is less than one hour in more than 75% of patients (Table 5) with a median duration of 30 minutes (interquartile range 8–53) according to Eriksen et al.g.196 Eriksen and Olesen but the affected side may change from attack to attack (14). or aphasic aura symptoms are essential to diagnose migraine with typical aura. also observed a less intense and shorter-lasting headache than in migraine without . Manzoni et al. When the headache occurs before the aura. Most patients with impaired production of language have problems finding the right words (paraphasia) (Table 5). anxiety. or even a headache related to febrile illness or some other systemic condition. or if the aura phenomenon occurs in areas of noneloquent cortex (see Chapter 6). depersonalization. and torso in 15% to 30% (3. FAMILIAL AND SPORADIC HEMIPLEGIC MIGRAINE The prevalence of hemiplegic migraine in a population study conducted was 0. 55% to 70% of the patients have throbbing headache.10.30). The headache following the aura fulfils the ICHD-2 criteria for migraine without aura in 57% of patients.10). problems controlling the movement of the affected extremity (80%). and the sensory aura is more widespread and always has a unilateral localization (4. Attacks of hemiplegic migraine may be precipitated by minor head injuries (3. and 0% (12) of patients with migraine with aura. Other organic diseases should always be considered in patients with hemiparesis (see Chapter 11). Most clinical features of familial and sporadic hemiplegic migraine are similar (3.4). 28% had three aura symptoms and 68% had four aura symptoms (3. In two studies where symptoms were recorded during attacks (24) or prospectively (20). or aphasic) is present during attacks (4. Accordingly.01% (26). Other associated or premonitory phenomena as seen in migraine without aura may also occur (see Chapter 13). motor weakness has been reported in 21% (14). and aphasic aura are identical to the features described in migraine with typical aura. The motor aura is always unilateral (3. the headache almost always occurred over the hemisphere affected by the aura (therefore contralateral to the clinical manifestation of aura). while the remaining are nonfamilial cases (sporadic hemiplegic migraine) (Table 3) (see Chapter 9). The motor aura develops focally and then gradually spreads to involve more and more muscles (4.26). sensory.10). The vastly differing results may be caused by difficulties distinguishing true weakness and dysfunction due to sensory loss.29). hand or arm in 95%.4. Approximately 90% of the attacks reach moderate or severe headache intensity. In 252 patients with familial or sporadic hemiplegic migraine (ICHD-1 criteria) studied by Thomsen et al.28. at least one typical aura symptom (visual. or problems holding their arm above their head (68%). The motor aura affects the face or tongue in approximately 50% of the cases. The features of the visual. except that in hemiplegic migraine the aura has a significantly longer duration. motor aura is observed in an extremely small fraction of migraine patients. Although the aura is prolonged.4. In clinic-based studies. Half of the cases of hemiplegic migraine show an autosomal dominant mode of inheritance with variable penetration (FHM). more often in females than males (5). sensory. and 60% have a unilateral headache (5.26).30). the patients had problems holding on to things (91%). photophobia in 85%.26).. vomiting in 50%. 18% (11). The duration of the visual. The headache is associated with nausea in 75%.26.26. Besides the motor aura. The duration of the motor aura exceeds one hour in 59% of sporadic cases and 48% of familial cases (4. 6% (27).26).10. some patients had problems walking (45%) or they experienced dragging of their leg when they walked (36%) (26). and phonophobia in 60% of patients (5. 85% have aggravation of headache by routine physical activity or simple head movements..14. or aphasic aura exceeds one . sensory.28).4.Migraine with Aura 197 aura (12). If the leg was affected. If the arm was affected. and it has a hemiparetic distribution in half of the patients (4.10). foot or leg in 60%. the motor aura was characterized by reduced strength (99%) or flaccid paralysis (49%) (26). problems carrying the same load as usual (96%). In a study by Thomsen et al. the duration of the motor aura lasts less than 24 hours in more than 90% of patients (4. of 147 patients with FHM.10). and the headache fulfils the diagnostic criteria for migraine without aura (see Chapter 13) in 75% of these patients (4.26).29.28. Basilar-type symptoms are seen in 70% of patients with hemiplegic migraine (4. shortlasting attacks. bilateral visual symptoms or paresthesias. but because involvement of the basilar artery territory is uncertain (i. The chronic ataxia may progress independently of the frequency or severity of hemiplegic attacks. During the headache phase. without motor weakness. Changes in consciousness from confusion to coma have been reported as well (3. vertigo.34). tinnitus.26. sensory. bilateral visual symptoms or paresthesias. A headache follows every aura in more than 90% of patients with hemiplegic migraine. tinnitus. most patients have typical visual. Basilar-type symptoms such as dysarthria. Attacks of basilar-type migraine co-occur in 8% of patients with migraine with typical aura (9). the term ‘‘basilar-type migraine’’ is preferred (see Chapter 6). it may be diagnostic for . and motion sensitivity) or vertigo (illusion of movement) are often reported minutes to hours before a migraine attack.4).e. If vertigo lasts minutes and occurs just before the onset of a migraine attack in the context of other aura symptoms. In the study by Thomsen et al. pain.29).32). There is considerable diagnostic uncertainty regarding this syndrome. basilar-type aura.31). or aphasic aura during attacks. vertigo.29). to severe attacks including vertigo or impaired consciousness.198 Eriksen and Olesen hour in more than one-third of patients with hemiplegic migraine (4. found only 49 patients with basilar-type migraine in one department over a 10-year period. most frequently including dysarthria. and the basilar-type aura is always followed by a headache (9. Struznegger et al. decreased level of consciousness. the disturbance may be bihemispheric). hypacusia. In a study by Eriksen et al. and disturbed finger–nose and knee–heel test (3. Diagnostic caution is recommended if these symptoms are absent.4. was present in 70% of patients (3. but attacks of basilar-type migraine are rarer than attacks of typical aura (34).31).26). The severity of basilar-type migraine varies between patients. only 0. The basilar-type aura symptoms comprise dysarthria.28. from mild.26). and the diagnosis should be made only after the exclusion of other possible causes. but a basilar-type migraine diagnosis requires that motor symptoms be absent (ICHD-2). diplopia. and ataxia (Table 4). The occurrence exclusively of attacks of basilar-type migraine is rare. more often in migraine with aura than in migraine without aura (25). vomiting. of 252 patients with familial or sporadic hemiplegic migraine. but the duration is 24 hours or less in 90% of patients (4.29. diplopia. which fulfilled the ICHD-1 criteria. wide-based ataxic gait. tinnitus. where FHM is caused by mutations in the CACNA1A gene on chromosome 19 (28. tremor. BASILAR-TYPE MIGRAINE Basilar-type migraine is characterized by aura symptoms clearly originating from the brainstem or both hemispheres simultaneously. of whom 20 had exclusively basilar-type attacks (34).6% (two patients) had exclusively basilar-type migraine (9). Originally. These patients may present ataxic speech. and malaise may incorrectly be reported as dizziness. of 322 patients with migraine with nonhemiplegic aura. and decreased level of consciousness are frequently reported in hemiplegic migraine during the end of the aura (3. In general. hypacusia. the terms ‘‘basilar artery migraine’’ or ‘‘basilar migraine’’ were used (33). dizziness (severe imbalance. In addition. diplopia. nystagmus. or bilateral visual symptoms or paresthesias. Cerebellar ataxia during attacks or chronically progressive ataxia is seen in FHM1. hypacusia.. nausea. J Neurol Neurosurg Psychiatry 2005. confusion. patients almost always have a visual aura besides other aura symptoms. Rømer SF. DIFFERENTIAL DIAGNOSES In clinical practice. In migraineurs. Sensitivity and specificity of new diagnostic criteria for migraine with aura.g. In cases with diagnostic uncertainty. with attacks lasting minutes to 2 hours or 6 to 24 hours (35). a sleepy patient with dysphasia may seem confused to relatives. Thus. patients have at least one additional aura symptom besides their motor aura. it is important to know the clinical features of aura-like symptoms. and patients with hemiplegic migraine seldom have attacks after the age of 50 (3. Brain 2002. More clinical studies are needed to fully elucidate if basilar-type migraine is a rational entity different from other migraine subtypes. Nevertheless. Eriksen MK. in many cases. In all subtypes of migraine with aura. In hemiplegic migraine. the aura is almost always followed by a migraine headache. The most frequently reported symptoms are confusion lasting from 15 minutes to 24 hours and syncope from one to five minutes (34). 76:212–217. Cephalalgia 2004. dizziness/vertigo frequently occurs during headache-free periods (35–37). or motor symptoms occur without visual symptoms. which prompt further investigation. agitation. epilepsy (postictal weakness following seizures or Todd phenomenon). psychogenic attacks. However. these symptoms may have a secondary nature. In migraine with nonhemiplegic aura. Impaired consciousness during migraine attacks is difficult to diagnose by history. 3. and in acute onset of aura-like symptoms. Russell MB. but in hemiplegic migraine. stroke. Cutrer and Baloh found that the duration of migraine dizziness/vertigo had a bimodal distribution. aphasic. REFERENCES 1. Thomsen LL. attacks of aura without headache may occur.Migraine with Aura 199 basilar-type migraine (35). Olesen J.34. syncope. Coma has been reported mainly in patients with FHM with cerebral edema after trivial head trauma or with cerebrospinal fluid sterile pleocytosis and fever during attacks (28. A population based study of familial hemiplegic migraine suggests revised diagnostic criteria. Andersen I. hemiplegic migraine is seen mostly in the younger segment of patients.4). the aura symptoms develop gradually or occur in succession. somnolence.39. Thomsen LL. In a study of 91 patients. The interrelation between migraine and dizziness/vertigo is not well understood. 24(1):1–160. Diagnostic caution is required if sensory. Olesen J. appropriate investigations should rule out intracranial pathology. Further. If more than one aura symptom is present in a subject with migraine with aura.40). and visual disturbances in migraine without aura. 2. when aura-like symptoms are not followed by a headache. especially in adolescents (33. Eriksen MK. and coma have been reported during migraine. e. . The main differential diagnoses of migraine with aura are transient ischemic attacks.38). 2nd ed. The International Classification of Headache Disorders. and syncope may be caused by vasovagal attacks or changes in cardiac rhythm due to vomiting. the age at onset of hemiplegic migraine is usually below the age of 35. stupor. 125:1379–1391.. 50:1105–1110. Cephalalgia 2004. Haan J. Airy H. Ophoff RA. On a distinct form of transient hemiopsia. Cephalalgia 2004. Timing and topography of cerebral blood flow. Lykke Thomsen L. Tfelt-Hansen P. The migrainous scotoma as studied in 618 persons. et al. Faerch Romer S. Classic migraine: clinical findings in 164 patients. 7. Bana DS. Olesen J. 60:595–601. . Manzoni GC. Sacks O. Migraine. 24:163–169. 25:801–810. Farina S. aura and headache during migraine attacks. migraine accompagnd). Graham JR. Cologno D. 17. Olesen J. The migraine tradition. Friberg L. 25:801–810. Thomsen LL. et al. Cephalalgia 2002. An epidemiological study. Arch Psychiatr Nervenkr 1974. 11. Arch Neurol Psychiatr 1941. 12:221–228. Solari A. An epidemiological survey of hemiplegic migraine. Olsen TS. 16. Thomsen LL. 49:1–19. Jolly F. Cephalalgia 1996. New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients. Eriksen MK. 6. Fisher CM. 23. The clinical spectrum of familial hemiplegic migraine associated with mutations in neuronal calcium channel. Kirchmann Eriksen M. Tfelt-Hansen P. Klinik und Pathophysiologie der initialen neurologischen ¨ Symptome bei fokalen Migraenen (Migraine ophthalmique. Russell MB. Lashley KS. Eur J Neurol 2004. Terwindt GM. 26. 17:1033–1042. Jensen K. Philos Trans R Soc Lond B Biol Sci 1870. Olesen J. 11:583–591. Migraine with aura and migraine without aura. Joutel A. Cephalalgia 1998. 46:259–264. Fenger K. Olesen J. Baumgartner G. Olesen J. Stroke 1986. Eriksen MK. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Berlin Klin Wschr 1902. 5. The Headaches. Russell MB. Improved description of the migraine aura by a diagnostic aura diary. 15. ¨ 18. Eur Neurol 1985. 13. Thomsen LL. Duscros A. 14. 345:17–24. Olesen J. Cephalalgia 1994. Late-life migraine accompaniments: further experience. 73:359–362. Thomsen LL. Neurology 1998. A nosographic analysis of the migraine aura in a general population. Lanfranchi M. Cephalalgia 2005. Olesen J. 28:791–798. Patterns of cerebral integration indicated by the scotomas of migraine. Variable clinical expression of mutations in P/Q-type calcium channel gene in familial hemiplegic migraine. Migraine with aura: a review of 81 patients at 10–20 years’ follow-up. 16:239–245. Thomsen LL.200 Eriksen and Olesen 4. 8. Olesen J. Olesen J. 25. 10. Headache 1986. Acta Neurol Scand 1986. Neurology 2003. 219:37–52. 26:216–219. 20. eds. Lauritzen M. N Engl J Med 2001. Prognosis of migraine with aura. Schiller F. Manzoni CG. 12. 119:335–361. Cephalalgia 1992. 24:18–22. A prospective recording of symptoms. Cephalalgia 2005. et al. Eriksen MK. 22. Iversen HK. Ostergaard E. Bull Hist Med 1975. Russell MB. Alvarez WC. Olesen J. Evidence for a separate type of migraine with aura—sporadic hemiplegic migraine. The Visual Aura Rating Scale (VARS) for migraine aura diagnosis. 9. Ann Neurol 1990. Observations on prodromes of classic migraine in a headache population. In: Olesen J. 22:361–375. Denier C. Rasmussen BK. Philadelphia: Lippincott Williams & Wilkins. 2000:345–358. Rasmussen BK. 160:247–264. 24. 18:690–696. Welch KMA. Clinical characteristics of 362 patients with familial migraine with aura. Classic migraine. Russell MB. Olesen J. et al. 42:973–976. 28. 29. 21. Uber Flimmerskotom und Migraene. 19. Olesen J. 24:564–575. Migraine with aura and its subforms. Cutrer MF. 14:107–117. 27. Torelli P. Eriksen MK. Brain 1996. Faber & FaberLondon1991. Bucking H. Brain 1984. 55:1040–1042. et al. Is familial hemiplegic migraine a hereditary form of basilar migraine? Cephalalgia 1995. Leopold M. 15:477–481. 1:15–17. Headache 1985. Birm MD. 38. Bos PLJM. 32:300–304. coma. Ducros A. 31. 25:408–415. et al. vertigo and migrainous vertigo. Ferrari MD. Vol. Vahedi K. Kayan A. Arch Neurol 1978. 37. The natural history of acute confusional migraine. Ann Neurol 2001. 40. Denier C. Olesen J. 87:543–522. Bickerstaff ER. 33. Migraine-associated dizziness. 107:1123–1142. 13. et al. 36. ed. Cutrer FM. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Fenichel GM. 32. Kors EE. Terwindt GM. Baloh RW. 34. Ophoff RA. Vermeulen FL. Frants RR. Basilar artery migraine. Frontiers in Headache Research. Struznegger MH. Migraine with aura and its borderlands. Hood JD. Basilar artery migraine: a follow-up study of 82 cases. The interrelations of migraine. Ophoff RA. Oxford: Oxford University Press 2005: 62–70. Neurology 2001. Cell 1996. Terwindt GM. Arnold G. Vergouwe MN.Migraine with Aura 201 30. 49:753–760. CACNA1A gene de novo mutation causing hemiplegic migraine. Lempert T. Ehyai A. Lancet 1961. and cerebellar atrophy. In: Olesen J. Neuro-otological manifestations of migraine. Neurology 2000. Haan J. . Neuhauser H. 56:436–441. Headache 1992. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Thomsen LL. von Brevern M. Terwindt GM. 39. 35:368–369. Meienberg O. 35. Eriksen MK. . and Federico Dazzi Department of Child and Adolescent Neurology and Psychiatry. recurrent headaches. Behcet’s syndrome. 203 . Moreover. a benign course. and other PS. Periods of similar duration. and recurrent limb pain]. As for PS. or negative life events. CV. onset in infancy with persistence for years are the most common characteristics. who noted the prevalence of migraine in adult relatives of children with PS. Federica Galli. Italy INTRODUCTION Medically unexplained physical symptoms are common disorders in pediatric practice. The definition of PS is descriptive and covers a large number of pediatric disorders characterized by repeated attacks with complete remission between episodes (7). The periodic syndromes (PS) are one of the most recurrent complaints in so-called ‘‘pain-prone’’ children (1). The PS were further described by Cullen and MacDonald (4). There is no detectable organic cause for these disorders. and abdominal pain in childhood and suggested that these disorders might persist into adult life. depression. periodic fever. cyclic neutropenia. According to Arav-Boger and Spirer (2). and familial periodic paralysis) and PS without fever [cyclical vomiting (CV). headache. the PS are a group of disorders characterized by limited periods of illness that recur regularly for years in otherwise healthy individuals.15 Childhood Periodic Syndromes Vincenzo Guidetti. hereditary angioedema. the associated symptoms are more significant than head pain per se and often occur in the absence of headache. Barlow (5) noted that the PS were frequently associated with migraine. Wyllie and Schlesinger (3) coined the expression ‘‘periodic disorders of childhood’’ to describe the occurrence of episodic pyrexia. the outstanding feature of migraine is the paroxysmal or periodic occurrence (6). In 1933. during a long follow-up period. hyperimmunoglobulinemia. Azzurra Alesini. In many cases. Migraine is frequently associated with a range of other symptoms such as periodic abdominal pain. vomiting. poor psychosocial adjustment. University of Rome La Sapienza. benign paroxysmal vertigo (BPV). Rome. recurrent abdominal pain (RAP). patients may pass from one syndrome to another. and most are expressions of reaction to stress. These disorders may be divided into two major categories: periodic fever syndromes (familial Mediterranean fever. The positive familial history of migraine in subjects with PS [65% in abdominal migraine or CV. vertigo.19). benign paroxysmal torticollis (BPT). It was based on the similarities in clinical features.12). Their results support the view of PS as predictive of the subsequent development of migraine or of a psychosomatic pathology. of vomiting and intense nausea. BPT.204 Guidetti et al. 2004) (10) as ‘‘recurrent episodic attacks. and eating disorders) in a group of migrainous children and adolescents. The disorder.e. CYCLICAL VOMITING CV is a rare and easily misdiagnosed syndrome. the relationship between PS and migraine remains unclear.9% (19). The syndrome was first described by Heberden in France (16) and by Gee in England (17). not included in the first edition of the ICHD [International Headache Society (IHS). childhood PS that were considered as equivalents of migraine were BPV. i. because the evidence is not sufficient to insert them in the main body of the classification. In the first International Classification of Headache Disorders (ICHD) (13). evidenced that only a percentage of PS subjects develop migraine. There is a peak frequency of attacks (usually every 10–15 minutes). Many reports consider PS as equivalents or precursors of migraine (7).’’ Attacks are associated with autonomic symptoms such as pallor and lethargy (87% and 91%. There is no accordance about which disorders may be collected as PS. according to Al-Twaijri and Shevell (9)]. and vertigo should be among them (6–10). The initial presentation of CV is controversial: it usually occurs between 3 and 5. usually stereotypical. abdominal pain. Lanzi et al. 1988] (13). and also migrating limb pain. however. abdominal pain. paroxysmal torticollis. is defined in the second edition (ICHD-2.8). Another study (8). sleep disturbances. . (7) assessed the prevalence of PS (recurrent vomiting. CV is a self-limiting episodic condition of childhood. recurrent hyperthermia with no visible cause. abdominal migraine. and BPV. The frequency of attacks ranges from 1 to 70 per year. Al-Twaijri and Shevell (9) consider PS [BPV. and disappears before puberty or during adolescence in two-thirds of the cases (8). as well as their response to antimigraine treatment. more often during the night or early morning. the co-occurrence of both disorders in the same child. and the positive family history of migraine (18). and treatment are yet unclear (15). car sickness. The episodes have a rapid onset. and alternating hemiplegia of childhood (14).1 to 5. develop into typical migraine. but according to Li (18). pathogenesis. acephalgic migraine. strengthen the hypothesis of a common pathogenesis (7.11. respectively) (Box 1) (18). with an estimated prevalence of 1. The second edition of the ICHD (10) considers the following as precursors of migraine: CV. Whitney. abdominal migraine or CV.. recognized a potential connection between CV and migraine. with a mean of 12 attacks per year (6). whose etiology. in 1898. and emphasize the fact that children with PS often also suffer from migraine or develop it later in life (11. with periods of complete recovery between attacks.3 years of age (6. and acute confusional migraine] as migraine equivalents. CV is a recurrent disorder in children. However. but there is consensual agreement that CV. and that some of these PS have a common outcome. with a steady decrease over time. BPT and alternating hemiplegia of childhood are considered in the appendix of the second edition (2004). To distinguish the migraine equivalent from abdominal epilepsy. hypothesizing that CV transforms into typical migraine. and a chronic. CV associated with behavioral disturbances. Dignan et al. Not attributed to another disorder Li (18) made a distinction between a severe but intermittent pattern of CV. (19) supported the association between CV and migraine. in the absence of a recognized pathophysiology. Wilson (22) outlined that the distinction between epilepsy and migraine is not always plain in children—vomiting and alteration of awareness may suggest both a diagnosis of complex partial seizures and the so-called abdominal migraine. The treatment of CV remains controversial and unsatisfactory (6). Vomiting during attacks occurs at least 4 times/hr for at least 1 hr D. Support for the relationship between CV and migraine comes from several sources. even if most cases of CV seem to be related to migraine (6). an ictal EEG recording is needed. migraine patients may continue to have episodic vomiting. intense nausea. and aggression. including electrophysiological studies. The five strategies to manage a child with CV are outlined in Box 2. or the syndrome of periodic adrenocorticotropin and vasopressin discharge.3–0. daily pattern. abortive drugs may be ondansetron (0.3 years). Quantitative electroencephalographic (EEG) changes are similar in CV and migraine. Moreover. At least 5 attacks fulfilling criteria B and C B. (21) reported that recurrent vomiting without gastrointestinal disease can be a manifestation of epilepsy. Moreover. but different etiologies. when identified Family support . according to these authors. Migraine symptoms refer more frequently to the first category. the onset of CV precedes migraine (about 8. but not severe. According to Li (18). and in 27% of cases. Visual-evoked responses identified similarities between CV and migraine with or without aura (19). However. Episodic attacks. a relationship between CV and migraine has been suggested frequently: up to 40% of patients with CV have headache during attacks. and occasionally analgesics to reduce abdominal pain) Abortive pharmacologic agents [the drug used most commonly to relieve nausea and vomiting is intravenous ondansetron (6)] Prophylactic pharmacologic therapy Avoidance of triggers. has been called acute confusional migraine. Symptom free between attacks E. Also. However.Childhood Periodic Syndromes 205 Box 1 Diagnostic criteria of CV according to the ICHD-2 A. and vomiting lasting from 1 hr to 5 days C. CV progresses to migraine in adulthood (20). Oki et al. the relationship is only empirical. The diagnosis should be reviewed if the patient is not symptom-free between attacks. including withdrawal. By a clinical point of view.4 mg/kg IV or Box 2 Principles of treatment for CV Supportive care during the episode (quiet and dark room. avoid overstimulation. abdominal migraine. there are patients with similar symptoms. irritability. According to Li (18). stereotypical in the individual patient. Attacks of abdominal pain lasting 1–72 hr (untreated or unsuccessfully treated) C. and moderate or severe intensity D. urinary tract disorder) or a surgical correction involves just a small percentage of children. Prophylactic drugs (18) are propanolol (10–20 mg. At least 5 attacks fulfilling criteria B–D B. According to Cavazzuti and Ferrari (8). Abdominal pain has all the following characteristics: midline location (periumbilical or poorly localized). Li (18) reported that this term was coined in 1956 to identify a group of children with recurrent episodes of abdominal pain. orally 4–8 every 4–6 hours). although it appears to be gaining greater acceptance. amitriptyline (20–25 mg/ day every hour). Most children with abdominal migraine will develop migraine later. half of the cases of RAP disappear before puberty or during adolescence. During abdominal pain. The ICHD-2 (10) describes RAP as ‘‘an idiopathic recurrent disorder. The pain is usually severe enough to interfere with normal daily activities. ketorolac (0. phenobarbital (2–3 mg/kg/day every hour). carbamazepine (5–10 mg/kg/day. sumatriptan [25–59 mg orally or 20 mg nasal (more than 40 kg)]. beginning between 4 and 10 years of age and resolving within two years.9 mg/kg every 6–8 hours). dull or ‘‘just sore’’ quality. Not attributed to another disorder . The pallor is often accompanied by dark shadows under the eyes. Children may find it difficult to distinguish anorexia from nausea. The origin of the term is controversial: according to Symon the term ‘‘abdominal migraine’’ was introduced by Brams in 1923 (24) (probably referring only to adults). RAP AND ABDOMINAL MIGRAINE Abdominal symptoms are common in children and adults with migraine. vomiting.. and pallor E. characterized by episodic midline abdominal pain. at least 2 of the following are seen: anorexia. and midrin (2–6 years old: max 75 mg/die in three doses.5–1.206 Guidetti et al. Abdominal pain probably relates to migraine (23). and its occurrence without headache in adults was first described by Buchanan in 1921 (6). manifesting in attacks lasting 1 to 72 hours with normality between episodes’’ (Box 3). 7–12 years old: max 100 mg/die in three doses). divided twice a day). seen mainly in children.25): 10% to 25% of schoolchildren and 10% to 14% of adolescents. Al-Twaijri and Shevell (9) considered RAP as a migraine equivalent. It is important to recognize that RAP is a relatively uncommon cause of recurrent abdominal pain in children and that most children will have other conditions that may or may not be found on investigation. Sometimes. Authors agree about the high prevalence of RAP (1. RAP is a common problem in childhood and an organic cause (e. divided 2–3 times per day). Box 3 Diagnostic criteria of RAP according to the ICHD-2 A. 2 or 3 times per day). cyproheptadine (0.g. The diagnosis of abdominal migraine is not yet universally accepted by neurologists. According to Symon (6). and erythromycin (20 mg/kg/day. granisetron (10 mg/kg every 4–6 hours).3 mg/kg/day divided 3 times a day). flushing is the main vasomotor phenomenon. nausea. children with RAP or headache exhibited primarily anxiety or mood disorders (25). travel. these episodes resolve within Box 4 Diagnostic criteria of BPV according to the ICHD-2 A. Robinson et al. If symptoms are frequent and severe despite treatment. no associated neurological or auditory abnormalities. In most children.g. Vertigo has long been recognized by clinicians as a frequent accompanying symptom of the adult migraine. Vomiting frequently gives relief. pallor. BPV OF CHILDHOOD Vertigo is a common symptom in childhood.. and vomiting. At least 5 attacks fulfilling criteria B B. children may undergo unnecessary evaluations (28). unilateral throbbing headache may occur in some attacks. ‘‘this probably heterogeneous disorder is characterized by recurrent brief episodic attacks of vertigo occurring without warning and resolving spontaneously in otherwise healthy children’’ (Box 4).Childhood Periodic Syndromes 207 Apart from the location of the pain. too. fearful and timid. (26) found that RAP children suffered from a greater number of stressful experiences in the few months before the onset of pain. as a consequence. children and adolescents with RAP have been described as anxious. Usually. the attack will subside if they lie down in a quiet and darkened room.. Trigger factors are similar to those for migraine headache (stress. with 20% of schoolchildren presenting one episode over a 1-year period (27).g. Even if there is no definitive evidence from controlled studies to support the hypothesis of a psychological ‘‘cause’’ of RAP (6). which prevents drug absorption. There is little evidence-based treatment for RAP. the pain is of moderate-to-severe intensity and associated with vasomotor symptoms. abdominal migraine resembles migraine. This may be due to gastric stasis. According to the ICHD-2 (10). and sometimes fear. occurring without warning and resolving spontaneously after minutes to hours C. Normal EEG . and. These episodes may occur in association with trauma or infections or be ‘‘nonassociated. flunarizine). and with complete recovery between attacks (6). prophylaxis may be suggested (e. The episodes of BPV are characterized by unsteadiness. BPV is often associated with nystagmus or vomiting. paracetamol and ibuprophen). The attack may be preceded by a prodromal period of listlessness or drowsiness. Multiple episodes of severe vertigo. In their study. exposure to bright or flickering lights. and some foods) and should be avoided when possible. This association has not been so easily identified in the pediatric population. A prevalence as high as 85% to 100% of anxiety or mood disorders has been found in children with RAP. Normal neurological examination and audiometric and vestibular functions between attacks D. even if as equivalent of migraine. and suffering from other somatic symptoms. nausea. BPV was recognized in the first ICHD (13). but they are not always successful in relieving pain (e. anorexia.’’ Recurrent transient episodes may present as unreal sensation of rotation of the patient or patient’s surroundings with no loss of consciousness. Analgesic drugs may be given. self-limiting. structured interviews.208 Guidetti et al. Attacks first happen during infancy. with all of the following characteristics and fulfilling criteria B: tilt of the head to one side (not always the same side). Parker (31) highlighted that migraine in children can be associated with neurologic disturbances such as vertigo. irritability. He coined the term ‘‘Benign Paroxysmal Vertigo of Childhood. with onset in the first year of age (Box 5). which may last from hours to days. because further scientific evidence must be presented before it can be moved into the main body of classification. and attempts by antimigraine drugs have been done (e.. causes.g. and longitudinal data collection. and clinical features of BPV—the overlap in the clinical features of BPV and migraine (mode of presentation. and ataxia C.’’ More recently. relief factors are lying. BPT may evolve into BPV or migraine. between two and eight months of age (14). with episodes occurring from every two weeks to every two months (33). The most common trigger factor for BPV is fatigue. seizures. The differential diagnosis needs to consider gastro-esophageal reflux. triggering and relieving factors. vomiting. During attacks. The child’s head can be turned to the normal position during the attacks: some resistance may be encountered but can be overcome. but there are no controlled trials on therapy (6). in a young child. It is a rare paroxysmal dyskinesia characterized by attacks of only head tilt or accompanied by vomiting and ataxia. and tending to recur monthly B. It is defined as recurrent episodes of head tilt to one side. This observation needs further validation by patients’ diaries. Episodic attacks. BENIGN PAROXYSMAL TORTICOLLIS BPT of infancy is an under-recognized. Cavazzuti and Ferrari (8) referred that most cases of early-onset vertigo disappear before puberty or during adolescence. lasting minutes to days.’’ A few years later. including CV and RAP (6). The condition occurs in infants. Basser described attacks of headache ‘‘associated with clockwise rotational vertigo. Abu-Arafeh and Russell (27) studied the prevalence. and associated gastrointestinal symptoms) supported the strong relationship between the two disorders. diphenylhydramin). remitting spontaneously. According to Weisleder and Fife (28). two years after their onset (9). The ICHD-2 considers BPT in its appendix. Fenichel (30) suggested that BPV in younger children was an early manifestation of migraine. Normal neurological examination between attacks D. malaise. with slight rotation and spontaneous remission. Basser (29) was the first author to note the association between balance disorders and headache. Moreover. or stops without further symptoms. and movement disorders the so-called migraine variants. vasomotor symptoms during attack. benign disorder (32). or sleeping. No treatment is usually given. and resolve by five years. BPV children may have other features of the PS. with or without slight rotation. Not attributed to another disorder . symptoms and/or signs of one or more of the following occur: pallor. sitting down. idiopathic torsional Box 5 Diagnostic criteria of BPT according to the ICHD-2 A. The link is so strong that many authors consider BPV as a precursor or early manifestation of migraine (28). Childhood Periodic Syndromes 209 Box 6 Diagnostic criteria of alternating hemiplegia of childhood according to the ICHD-2 A. Recurrent attacks of hemiplegia alternating between the two sides of the body B. Onset before the age of 18 mo C. At least one other paroxysmal phenomenon is associated with the bouts of hemiplegia or it occurs independently, such as tonic spells, dystonic posturing, choreoathetoid movements, nystagmus, or other ocular motor abnormalities and autonomic disturbances D. Evidence of mental and/or neurological deficit(s) E. Not attributed to another disorder dystonia, and complex partial seizure, but particular attention must be paid to the posterior fossa and craniocervical junction, because congenital or acquired lesions may produce torticollis. Moreover, a family history for BPT is common (34,35), as is family history for migraine (36). In conclusion, torticollis may not be so evident if other manifestations (vomiting, pallor, ataxia, etc.) of the attack are more impressive. However, the recognition of the symptom at the beginning of the attack may increase the likelihood of identifying the childhood migraine equivalent to plan the right antimigraine therapy (33). ALTERNATING HEMIPLEGIA OF CHILDHOOD The ICHD-2 (10) considers this disorder in its appendix. It is defined as ‘‘infantile attacks of hemiplegia involving each side alternately, associated with a progressive encephalopathy, other paroxysmal phenomena and mental impairment’’ (Box 6). This is a heterogeneous condition that includes neurodegenerative disorders. A relationship with migraine is suggested on clinical grounds. The possibility that it is an unusual form of epilepsy cannot be ruled out. Finally, there are other PS that are sometimes recognized as being somehow related to migraine. We briefly describe them as follows:  Episodic spontaneous hypothermia: Episodic hypothermia lower than 35 C, marked facial pallor, and absence of shivering. The episodes could last for a few hours or days, and recur once a week or every two to three months (37).  Car (motion) sickness: General discomfort, characterized by nausea, vomiting, pallor, and perspiration (7).  Migrating limb pain: Pain presenting gradually and with low intensity, localized in the lower limbs, and not aggravated by an erected position or walking. Duration varies between a few minutes and several hours (7). CONCLUSION Some authors (11,18) stressed the chronological pattern and long-term aspects of PS symptoms. They concluded that the first symptom to appear is CV, followed by abdominal pain and paroxysmal vertigo. Headache is the final symptom in this group. The sequentiality of such disturbances in each subject leads to the assumption that the PS is the expression of a single disorder, which manifests itself 210 Guidetti et al. polymorphously, rather than a precisely timed process (11). In particular, Li (18) supported the hypothesis that PS is an age-related presentation of migraine. Giffin et al. (33) gave further evidence that it may be considered as a childhood migraine equivalent and may be associated with a calcium channelopathy. In light of these observations, we believe that the identification of PS in childhood is extremely important—a series of useless investigations can be avoided, helping the diagnosis of migraine. In conclusion, the relationship between PS and migraine is still not clear, but the probable predictive value of PS may be useful to classify and manage migraine. REFERENCES 1. Campo JV, Fritsch SL. Somatization in children and adolescents. J Am Acad Child Adolesc Psychiatr 1994; 33(9):1223–1235. 2. Arav-Boger R, Spirer Z. Periodic syndromes of childhood. Adv Pediatr 1997; 44: 389–417. 3. Wyllie WG, Schlesinger B. The periodic group of disorders in childhood. Br J Child Dis 1933; 30:1–21. 4. Cullen KJ, MacDonald WB. The periodic syndrome: its nature and prevalence. Med J Aust 1963; 2:167–173. 5. Barlow CF. Headaches and Migraine in Childhood. Oxford: Spast Intern Med Pub, 1984. 6. Symon DNK. Equivalents, variants and precursors of migraine. In: Guidetti V, Russell G, Sillanpaa M, Winner P, eds. Headache and Migraine in Childhood and Adolescence. ¨¨ London: Martin Dunitz, 2002:215–227. 7. Lanzi G, Zambrino CA, Balottin U, Tagliasacchi M, Vercelli P, Termine C. Periodic syndrome and migraine in children and adolescents. Ital J Neurol Sci 1997; 18(5): 283–288. 8. Cavazzuti GB, Ferrari P. Childhood periodic syndromes and their long-term development. Semin Pediatr Neurol 1995; 2(2):127–143. 9. Al-Twaijri WA, Shevell MI. Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 2002; 26:365–368. 10. Headache Classification Subcommittee of International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(suppl 1): 1–151. 11. Lanzi G, Balottin U, Fazzi E, Rosano FB. The periodic syndrome in pediatric migraine sufferers. Cephalalgia 1983; 3(suppl 1):91–93. 12. Hammamond JE. The periodic syndrome and migraine. Practitioner 1976; 217:384–389. 13. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):1–96. 14. Winner P, Lewis D. Clinical features of migraine. In: Guidetti V, Russell G, Sillanpaa M, ¨¨ Winner P, eds. Headache and Migraine in Childhood and Adolescence. London: Martin Dunitz, 2002:169–177. 15. Cupini LM, Santorelli F, Iani C, Fardello G, Calabresi P. Cyclic vomiting syndrome, migraine, and epilepsy: a common underlying disorder? Headache 2003; 43:407–409. 16. Heberden W. Chapter 29. In: Payne T, ed. Commentaries on History and Care of Disease. London: Mews-Gate, 1802:99. [Reprinted in Birmingham, AL: Classics of Medicine Library; 1982:99]. 17. Gee S. On fitful or recurrent vomiting. St Bartolomew’s Hosp Rep 1882; 18:1–6. 18. Li BUK. Cyclic vomiting syndrome: age-old syndrome and new insights. Semin Pediatr Neurol 2001; 8(1):13–21. Childhood Periodic Syndromes 211 19. Dignan F, Symon DNK, Abu Arfeh I, Russel G. The prognosis of cyclical vomiting syndrome. Arch Dis Childh 2001; 84:55–57. 20. Haan J, Kors EE, Ferrari MD. Familial cyclic vomiting syndrome. Cephalalgia 2002; 22:552–554. 21. Oki J, Miyamoto A, Takahashi S, Itoh J, Sakata Y, Okuno A. Cyclic vomiting and elevation of creatine kinase associated with bitemporal hypoperfusion and EEG abnormalities: a migraine equivalent? Br Dev 1998; 20:186–189. 22. Wilson J. Migraine and epilepsy. Dev Med Child Neurol 1992; 34:645–647. 23. Anttila P, Metsahonkala L, Mikkelsson M, Helenius H, Sillanpaa M. Comorbidity of ¨ ¨¨ other pains in schoolchildren with migraine or nonmigrainous headache. J Pediatr 2001; 138(2):176–180. 24. Brams WA. Abdominal migraine. JAMA 1922; 78:26–27. 25. Liakopoulou-Kairis M, Alifieraki T, Protagora D. Recurrent abdominal pain and headache: psychopathology, life events and family functioning. Eur Child Adolesc Psychiatr 2002; 11:115–122. 26. Robinson JO, Alverez JH, Dodge JA. Life events and family history in children with recurrent abdominal pain. J Psychos Res 1990; 34:171–178. 27. Abu-Arafeh I, Russell G. Paroxysmal vertigo as a migraine equivalent in children: a population-based study. Neurol Res 2002; 24(7):663–665. 28. Weisleder P, Fife TD. Dizziness and headache: a common association in children and adolescent. J Child Neurol 2001; 16:727–730. 29. Basser L. Benign paroxysmal vertigo of childhood. Pediatr Ann 1964; 87:141–152. 30. Fenichel GM. Migraine as a cause of benign paroxysmal vertigo of childhood. J Pediatr 1967; 71:114–115. 31. Parker C. Complicated migraine syndromes and migraine variants. Pediatr Ann 1997; 26:417–421. 32. Snyder CH. Paroxysmal torticollis in infancy. A possible form of labyrinthitis. Am J Dis Childh 1969; 117:458–460. 33. Giffin NJ, Benton S, Goadsby PJ. Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol 2002; 44:490–493. 34. Sanner G, Bergstrom B. Benign paroxysmal torticollis in infancy. Acta Paediatr Scand 1979; 68:219–223. 35. Roulet E, Deonna T. Benign paroxysmal torticollis in infancy. Dev Med Child Neurol 1988; 30:409–410 (Letter). 36. Deonna T, Martin D. Benign paroxysmal torticollis in infancy. Arch Dis Childh 1981; 56:956–958. 37. Ruiz C, Gener B, Garaizar C, Prats JM. Episodic spontaneous hypothermia: a periodic childhood syndrome. Pediatr Neurol 2003; 28:304–306. 16 Retinal, or ‘‘Monocular,’’ Migraine Brian M. Grosberg and Seymour Solomon Department of Neurology, The Montefiore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A. INTRODUCTION Retinal, or ‘‘monocular,’’ migraine is a rare and poorly understood disorder characterized by attacks of monocular visual impairment associated with migraine headache. Galezowski first described this entity as ‘‘ophthalmic megrim’’ in 1882 in a series of four patients with permanent retinal defects attributed to migraine (1). In two of these patients, prior attacks of migraine headache were associated with bouts of transient monocular visual loss (TMVL). Since then, a number of patients with monocular visual defects beginning before, during, or after attacks of otherwise typical migraine have been reported with various designations (2–46). The term ‘‘retinal migraine’’ was introduced by Carroll in 1970 to describe patients with episodes of TMVL and permanent monocular visual loss (PMVL), specifically in the absence of migraine headache (47). Most subsequent observers have used the term ‘‘retinal migraine’’ for those cases of monocular visual impairment temporally associated with attacks of migraine. Some have noted that unilateral visual loss was not restricted exclusively to the retina and advocated the term ‘‘anterior visual pathway migraine’’ or ‘‘ocular migraine’’ (6,48). The authors prefer the term ‘‘monocular migraine,’’ because it distinguishes between the loss of vision in one hemifield and that of one eye and includes sites other than the retina, such as the choroid or the optic nerve. DIAGNOSTIC CRITERIA Over the last two decades, there have been several proposed definitions for retinal migraine. In 1986, Troost defined retinal migraine as a transient or permanent monocular visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migrainous episodes (49). Two years later, the first edition of the International Classification of Headache Disorders (ICHD-1) developed by the International Headache Society (IHS) established more rigid criteria, requiring at least two attacks of fully reversible monocular scotoma or blindness lasting less than 60 minutes, associated with headache (type unspecified) (50). 213 214 Grosberg and Solomon Table 1 2004 IHS Criteria for the Diagnosis of Retinal Migraine A. At least two attacks fulfilling criteria B and C B. Fully reversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) confirmed by examination during an attack or (after proper instruction) by the patient’s drawing of a monocular field defect during an attack C. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins during the visual symptoms or follows them within 60 min D. Normal ophthalmologic examinations between attacks E. Not attributed to another disorder Abbreviation: IHS, International Headache Society. Criteria for the diagnosis of retinal migraine were revised in the 2004 edition of the ICHD-2 to include positive and/or negative monocular visual phenomena. Visual features still had to be transient in nature, but were no longer limited to 60 minutes. In addition, the headache had to fulfill criteria for migraine without aura (Table 1) (51). Based on our patients and a review of the literature [Grosberg BM, Solomon S, Friedman DI, Lipton RB. Retinal migraine reappraised (submitted for publication).] (52–54), we believe that either migraine without aura or migraine with aura occurs with retinal migraine, that the visual defects may occur before, during, or after the headache, and that PMVL may be part of the syndrome, comparable with the syndrome of migrainous infarction. Our suggestions for revision of the criteria of retinal/monocular migraine are noted in Table 2. In a review of the English language medical literature (53,54), we identified 73 cases and added four new cases from the Montefiore Headache Unit that fulfilled our criteria of retinal migraine with TMVL or PMVL. Because most cases were Table 2 Proposed Modification of Criteria for Retinal (or Preferably Monocular) Migraine Monocular migraine with TMVL or defect A. At least two attacks fulfilling criteria B and C B. Fully reversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) confirmed by examination during an attack or (after proper instruction) by the patient’s drawing of a monocular field defect during an attack C. Headache fulfilling criteria B–D for 1.1 Migraine without aura or 1.2 Migraine with aura begins during the visual symptoms or precedes or follows them within 60 min D. Normal ophthalmologic examination between attacks E. Not attributed to another disorder Monocular migraine with PMVL or defect A. At least one attack fulfilling criteria B and C B. Irreversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) confirmed by examination during or following the attack C. Headache fulfilling criteria B–D for 1.1 Migraine without aura or 1.2 Migraine with aura begins during the visual symptoms or precedes or follows them within 60 min D. Abnormal ophthalmologic examination E. Not attributed to another disorder Note: The vast majority of patients experienced only one attack of PMVL. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss. Retinal, or ‘‘Monocular,’’ Migraine 215 described before the publication of IHS criteria, some of the details of the headache and visual loss were sometimes incomplete. CLINICAL FEATURES In most cases of TMVL and PMVL, the migraine headache was ipsilateral to visual loss. In contrast to the current IHS criteria for retinal migraine, nearly 75% of patients with monocular visual loss had a history of migraine with aura (Fig. 1). With the exception of two patients who had somatic sensory phenomena (12,33), all others had typical cerebral visual auras. The temporal relationship between the visual loss and the headache was quite variable. In the vast majority of patients, the onset of visual loss preceded or accompanied the headache; less often, the visual loss followed an attack of migraine. The visual symptoms occurred within one hour of the attack. Recurrent visual disturbances were strictly unilateral and without side shift in the majority of patients, although some experienced side-alternating attacks. Patients with the transient form of retinal migraine were more than twice as likely to have visual loss in which strict laterality was not preserved during repeated attacks. The duration of TMVL varied widely between patients and within individual patients. The duration of the transient visual symptoms was as short as a few seconds but usually was many minutes to one hour (Fig. 2). One-third of cases experienced repeated attacks of TMVL, lasting both less than 30 minutes and more than one hour. Prolonged but fully reversible monocular visual loss rarely occurred, sometimes lasting hours, days, or even, weeks (12,14,19,26,28,45). As one may expect, ophthalmologic examination during an attack was infrequent. When such examinations were Figure 1 Relative frequency by migraine type of TMVL, TMVL leading to PMVL, and PMVL. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss; MA, migraine with aura; MO, migraine without aura. 216 Grosberg and Solomon Figure 2 Frequency distribution of duration of monocular visual loss in patients with the transient form of retinal migraine. performed, they usually were normal. Severe narrowing or occlusion of retinal arteries or veins was rarely observed (1–4,8,11,12,17,18,23,28,31,32,39,43). The diagnoses of anterior or posterior ischemic optic neuropathy was reported in a dozen or so cases (6,7,10,22,25,29,30,35,37,38,46). Other findings included retinal pigmentary change (4), central retinal venous occlusion (5,13,20), central serous retinopathy (49), optic nerve atrophy (13), optic disk edema (22), and hemorrhages of the optic nerve, retina, or vitreous (1,9,15). Positive and negative visual phenomena were reported in retinal migraine associated with TMVL and PMVL. Typical descriptions of positive visual phenomena included flashing rays of light, zigzag lightning, and other teichopsia, whereas perceptions of bright-colored streaks, halos, or diagonal lines were less commonly experienced. The negative visual losses included blurring, ‘‘grey-outs’’ and ‘‘blackouts,’’ causing partial or complete blindness. Elementary forms of scotoma were perceived as blank areas, black dots, or spots in the field of vision. Visual field defects may be altitudinal, quadrantic, central, or arcuate. Complex patterns of monocular visual impairment, such as the appearance of ‘‘black paint dripping down from the upper corner of my left eye,’’ the coalescence of peripherally located spots and tunnel vision, were noted rarely. Only approximately 50% of the cases met the current IHS criteria for TMVL and, of those, approximately 50% subsequently developed PMVL. The authors believe that irreversible visual loss is part of the spectrum of retinal migraine, probably representing an ocular form of migrainous infarction. Irreversible monocular visual loss resulted from retinal infarction or optic nerve ischemia or was otherwise not specified (Fig. 3). Retinal migraine is primarily a disorder of young women. The gender and age ranges are noted in Table 3 (54). The gender difference was striking in patients with PMVL. The condition occurred 16 times more commonly in women than in men. Those with PMVL also tended to be approximately 10 years older than those with TMVL (37 vs. 26 years, respectively). A family history of migraine was noted in approximately 25% of the patients with TMVL and in almost one-third of patients with PMVL. Because many reports did not include information on family history, these numbers may be underestimated. Only two patients had familial retinal migraine (36). Retinal, or ‘‘Monocular,’’ Migraine 217 16% 36% 48% Vasopasm/Occlusion Ischemic optic neuropathy Not classified Figure 3 Etiologies of PMVL in patients with the permanent form of retinal migraine. Abbreviation: PMVL, permanent monocular visual loss. EPIDEMIOLOGY AND PROGNOSIS Retinal migraine is thought to be a rare disorder, but its true prevalence is unknown. Recent studies with automated perimetry have demonstrated subclinical visual field defects in patients with migraine (55). There was a direct correlation between these findings and duration of disease and advancing age. Although retinal migraine usually has been viewed as a benign condition, it appears that subclinical precortical visual dysfunction and permanent attacks of partial or complete monocular visual loss occur in patients with migraine more often than commonly appreciated (56). In one study, the records of 413 patients with nonarteritic anterior ischemic optic neuropathy (AION) were reviewed. Of these, 2.2% had migraine-related AION (57). Table 3 Demographic and Clinical Features of the Patients with Retinal Migraine Analyzed in Our Review (n ¼ 77) Characteristics Men Women Age at onset (years) (Range of ages) Subtypes of HA MwA M w/o A PM a b TMVL (n ¼ 21) 11 10 27.0 (12–53) 16 (8F,8M) 2 (2M) 1 (1F) Transformed PMVLa (n ¼ 20) 5 15 25.0 (8–54) 13 (9F,4M) 2 (2F) 5 (4F,1M) PMVLb (n ¼ 36) 2 32 37.1 (15–64) 22 (20F,2M) 9 (9F) 2 (2F) Transformed PMVL refers to patients who experienced TMVL and subsequently developed PMVL. In PMVL, the gender and subtype of migraine were not reported in two and three patients, respectively. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss; n, number; MwA, migraine with aura; Mw/oA, migraine without aura; PM, probable migraine; F, female; M, male. 218 Grosberg and Solomon In our survey, approximately half of the patients who experienced TMVL, subsequently experienced PMVL (52). Some patients with TMVL may present with considerable variation in phenotype (either continue to have TMVL or experience new attacks of PMVL), while others may only experience PMVL without a preexisting history of TMVL. No specific factor has been identified to account for this variation in phenotype or for the heterogeneity of this condition. Minor risk factors for vascular disease were identified in only a few patients with TMVL and PMVL. They included hypertension, hyperthyroidism, pregnancy, diabetes, oral contraceptive use, smoking, and increased levels of factor VIII. These conditions were not thought to be the main cause of the visual loss. PATHOPHYSIOLOGY The underlying pathophysiology of retinal migraine remains largely unknown. In some cases, vasospasm of the retinal or ciliary circulation may have caused retinal or optic nerve ischemia; this may explain the amaurosis and rare funduscopic findings during acute attacks of retinal migraine (58). An alternative theory is spreading depression of retinal neurons, a phenomenon that has been demonstrated in the chick retina (59). Similarly, we believe that those rare cases with prolonged monocular defects associated with migraine headache could have a mechanism similar to that seen in the cerebral cortex of migraineurs who have persistent aura without infarction. DIFFERENTIAL DIAGNOSIS When evaluating a headache patient with the complaint of visual impairment, it is important to establish whether one or both eyes are affected. Retrochiasmatic lesions usually cause homonymous hemianopias with varying degrees of congruence, whereas prechiasmatic lesions (i.e., optic nerve, retina, or media) produce monocular visual loss. Patients often have difficulty distinguishing between the loss of vision in one hemifield and the loss of vision in one eye. To accurately make this distinction, the patient must alternately cover each eye and compare their views. Once unilateral visual loss is confirmed in this manner, the clinician needs to identify or exclude secondary causes of transient monocular blindness (TMB), because retinal migraine is a diagnosis of exclusion. Differentiating retinal migraine from other causes of TMB can be challenging. Visual loss associated with retinal migraine is usually of longer duration and the evolution is usually slower in onset than with microembolization. Moreover, the typical shade dropping over one visual field described by many patients who have microembolization has not been described by patients with retinal migraine. If atypical features are present in a patient’s history or general physical, ophthalmologic, or neurologic examinations, imaging studies or other diagnostic testing are warranted. Features that should prompt concern for an underlying secondary cause of headache with TMB include absence of history typical for migraine, onset after age 50, incomplete resolution of monocular visual loss, concomitant medical problems that can precipitate attacks of TMB, and the presence of atypical neurologic signs or symptoms (Fig. 4). All cases with persistent monocular visual loss should be fully investigated. To exclude the possibility of a cardioembolic Retinal, or ‘‘Monocular,’’ Migraine 219 Figure 4 Clinical factors favoring retinal migraine versus other causes of monocular visual loss. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss. source, investigations such as electrocardiography, echocardiography, and holter monitoring need to be performed. Diagnostic testing in patients with suspected ischemic disease of the eye or brain should include duplex scanning, computed tomography (CT), magnetic resonance imaging (MRI) and angiography (MRA), fluorescein angiography, and in uncertain cases, conventional angiography. Neuroimaging can exclude an orbital or intracranial mass. Other diagnostic possibilities such as vasculitis, hypercoagulable states, illicit drug use, and rheumatologic disorders require a complete laboratory evaluation consisting of a complete blood count with differential and platelet count, prothrombin time, partial thromboplastin time, toxic drug screen, lupus anticoagulant and anticardiolipin antibody levels, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody titer, antiphospholipid antibodies, protein C and S, antithrombin III levels, and serum protein electrophoresis. MANAGEMENT There are no clear guidelines on the management of patients with retinal migraine. One approach to treatment has focused on the avoidance of potential migraine triggers (i.e., stress, use of oral contraceptives, or smoking) in patients with infrequent attacks. Hemorrhage in hyaline bodies (drusen) of the optic disc during an attack of migraine. Fisher CM. tricyclic antidepressants (i. Arch Ophthalmol 1952. 11. Fujino T. Neurol Clin 1983. 44:508–509. this course of action may not be prudent. 1:176–179. i. Ischaemic papillopathy: clinical and fluorescein angiographic review of forty cases. Headache 1997. 6. Miller SJH. Lancet 1882. Knox DL. and oral and intravenous preparations of corticosteroids have been advocated. propanolol). 58:990–1008. Takagi S. Eagling EM. etc. Prophylactic medications that have been tried with anecdotal benefit include calcium-channel blockers (i. Lessell S. Am J Ophthalmol 1967. Occlusion of central retinal vein in migraine. Dunning HS.e. Fisher CM. Ann Ophthalmol 1982. 7.. 14. Coppeto JR. because episodes of PMVL can occur in migraineurs with and without prior attacks of TMVL. Arch Ophthalmol 1951. Shields JA. 13. 12. 8. 14:164–166. Retinal arterial obstruction in children and young adults. 15. beta-blockers (i. Ophthalmic megrim: an affection of the vasomotor nerves of the retina and retinal centre which may end in a thrombosis. 63(6):1693–1696. Complicated migraine: a study of permanent neurological and visual defects caused by migraine. 47:167–203. Friedman MW. acetazolamide.. or nimodipine). 1:973–995. Migraine optic neuropathy. triptans. de Silva HJ. Goldberg RE. 16. 2.e. Neuro-ophthalmic complications of migraine and cluster headaches. nortriptyline). 2:1072–1075. 45:678–682. REFERENCES 1. Amaurosis fugax for a long duration. Br J Ophthalmol 1992. 76:189–190. Connor RCR.. Howe JW.. Brown GC. vasodilators (i. isoproterenol). Cerebral ischemia—less familiar types. 18:267–335.e. Sciarra R. Stommel E.e.e. Recurrent branch retinal infarcts in association with migraine. ergotamines. Resolution of symptoms with divalproex sodium in retinal migraine [abstr]. Early medical management with daily aspirin and a migraine-preventative agent may be advisable in an attempt to prevent irreversible ocular damage. and neuromodulators (i. amyl nitrate or nitroglycerin). Bates D. 3:9–12. should not be used. Allen C. Sanders MD. 3.. Gaynes PM. 10. i. However. Glenn AM. Bear L. Vascular retinopathy in migraine. Arch Neurol Psych 1942. There is currently insufficient clinical information to support specific recommendations for acute and preventive medical therapy in the treatment of retinal migraine.. Central retinal artery occlusion associated with migraine. Neurology 1986. During the acute attacks.. beta-agonists (i.e. Stevens R. Clin Neurosurg 1970. 36:267–270. 17. less than one attack per month (60).e. Shaw PJ. 48:396–406. 5. 4. Br J Ophthalmol 1974. Transient monocular blindness associated with hemiplegia. Galezowski X. Ceylon Med J 1992.220 Grosberg and Solomon It has been suggested that prophylactic therapy be deferred in patients with infrequent attacks. 88:18–25. Headache 2004. Gee JR. Lessell S. Ophthalmology 1981. Towle PA. 37:55–56. medications with vasoconstrictive properties. Corbett JJ. Illangasekera UL. Given the potential risk of worsening any underlying vasospasm.. Complicated migraine resulting in blindness due to bilateral retinal infarction. divalproex sodium or topiramate). J Clin Neuroophthalmol 1983. de Silva U.e. . Cowan CL Jr. Walsh PN. Magargal LE. Intracranial and extracranial vascular accidents in migraine. Shiga H. nifedipine.. verapamil. Akiya S. Lancet 1962. 37:396–399. Beversdorf D. 9. McDonald WI. Steele JC. Savidge GF. Trans Pa Acad Ophthalmol Otolaryngol 1974. Pearce J. Cole BL. 20. 40. 23. 50:81–84. 44. 43. 7(1):1–10. Ischemic optic neuropathy and migraine. Joffe SN. J Neurol Neurosurg Psychiatr 1987. Chase NE. Russell RWR. 34:50–52. Flammer J. Neuroophthalmology 1987. Gartry D. Lyden PD. Gutteridge IF. 342:690. Graham E. Migraine complicated by ischaemic papillopathy. 31. Stroke 1979. Lancet 1971. Laties AM. Visual symptoms in the migraine syndrome. Killer HE. 39. Bilateral cilio-retinal artery occlusion in classic migraine. Bamford CR. 29. The non-benign aspects of migraine. Bowman B. 22. Kupersmith MJ. 38. Migrainous stroke. 45.1468-2982. Pediatr Neurol 2004. Occlusive migraine. Rothner AD. 67:282–284. 2:521–523. 61: 517–518. 34. Migrainous optic neuropathy. Carroll JD. Shevell MI. 37. O’Hara M.01056x. 19. Swenson MR. Morales-Asin F. Migrainous ischemic optic neuropathy. Mauri JA. Hass WK. 23(2):253–254. Hachinski VC. Ring C. 23:570–579. Harrison P. A contribution to the paralytic and other persistent sequelae of migraine.’’ Migraine 221 18. Complicated retinal migraine. Cephalalgia. 52:338–342. Migraine-related visual field loss with prolonged recovery. Iniguez C. J Clin Neuroophthalmol 1984. Solomon S. 41. 33. 27(1):34–38. Lancet 1993. Sanders MD. Ergun U. DOI: 10. The ophthalmological complications of migraine. Retina 2003. Migrainous central retinal artery occlusion.1111/j. Walicke P. 45:63–67. Posterior ischemic optic neuropathy associated with migraine. Grosberg BM. 6(2): 69–71. Miller NR. 270:359–360. 150:313–331. 26. New Engl J Med 1964. Retinal blood vessel diameter during migraine. Retinal vasospasm during an attack of migraine. Forrer A. 24. J Clin Neuroophthalmol 1986. Katz B. J Am Optom Assoc 1997. Permanent visual changes following migraine. 99:489. 23:59–63. Logan WR. Krapin D. Postgrad Med J 1991. Am J Ophthalmol 1985. Transatl Ophthalmol Soc NZ 1971. Karagoz H. Ascaso J. Neurology 1973. Rothrock J. Occlusion of the central retinal artery in migraine. Kupersmith MJ. Buckley SA. Yurdakul M. Isoproterenol treatment of visual symptoms in migraine. 42(4):326–327. Brazis PW. J Neurol Sci 1968. Headache 1994. 20:431. Familial retinal migraines. Elston JS. 32. Gray JA. Retinal artery occlusion in migraine. Larrode P. Warren FA. Porchawka J. 36. Retinal migraine: two cases of prolonged but reversible monocular visual defects. Poole CJM. Inan LE. Hunt JR. James CB. Brazier DJ. The Eye Ear Nose Throat Mon 1972. 30. 42. Hass WK. 6:73–81. Perspectives on migraine: prevalence and visual symptoms.Retinal. Headache 1996. 10(3):299–305. Sullivan-Mee M. 21. 84(2):56–70. Neurology 1985. 30:356–357. Am J Med Sci 1915. Uysal H. 28. O’Connor PS. Katz B. Cock S. 35: 112–114. Arch Neurol 1988. Postgrad Med J 1985. Silberberg DH. 68:377–388. Flurries of migraine (with) aura and migraine aura status. . or ‘‘Monocular. Hykin PG. 4:85–90.2006. Lee AG. 35. Spierings EL. Bilateral sequential migrainous ischemic optic neuropathy. Cephalalgia 2000. 36:506–509. Lewinshtein D. 27. Amaurosis fugax under the age of 40 years. 25. Retinal migraine. Headache 2002. Katz B. Clin Exp Optom 2001. Visual field losses in subjects with migraine headaches. Corbett JJ. Two mechanisms for spreading depression in the chick retina. 9:419–431. Invest Ophthalmol Vis Sci 2000. Lipton RB. Neurology 2005. Clinical Ophthalmology. Neurology 2005. Zagami AS. Troost BT. Keltner J. Arch Ophthalmol 1982.222 Grosberg and Solomon 46. Troost BT. eds. 56. 48. J Neurobiol 1978. 54. Walsh FB. 33:221–236. Kline LB. Feman SS. 24(suppl 1):1–160. Solomon S. Ophthalmology 1989. The Headaches. Curr Pain Headache Rep 2005. cranial neuralgias and facial pain. 60. Retinal migraine. Watson C. Retinal migraine. Grosberg BM. Vol. Horizonte B. 50. Lewis RA. 100:1097–1100. Headache Classification Committee of the International Headache Society. 58. Visual disturbances of migraine. 61(suppl 1):221. 10:9–13. Johnson CA. 61(suppl 1):221. 3rd ed. Philadelphia: Lippincott Williams & Wilkins. 2. Classification and diagnostic criteria for headache disorders. Is irreversible visual loss part of the retinal migraine spectrum. Classification and diagnostic criteria for headache disorders. 96:321–326. Cephalalgia 1988. Grosberg BM. Clinical Neuro-ophthalmology. . Hagerstown: Harper and Row. Surv Ophthalmol 1989. 53. Neurology 1998. Ophthalmoplegic migraine and retinal migraine. 8(suppl 7):35. Retinal migraine: two new cases and a review of the literature. Solomon S. Migraine. In: Duane TB. Badcock DR. 57. Cephalalgia 2004. cranial neuralgias and facial pain. 55. Grosberg BM. Lipton RB. 52. Ischemic optic neuropathy in migraine. Lana-Peixoto MA. Welch KM. In: Olesen J. 2nd ed. Mattos RM Jr. Baltimore: Williams and Wilkins. McKendrick AM. 1969. Lipton RB. 47. Headache Classification Subcommittee of the International Headache Society. Vingrys AJ. Solomon S. Weinstein JM. Heywood JT. Hoyt WF. Bigal ME. Headache 1970. 59. Tfelt-Hansen P. Bigal ME. Hupp SL. Visual field loss in migraine. Migraine-related anterior ischemic optic neuropathy [abstr]. 49. ed. 50(suppl 4):A4. 1986:11–12. 2000:511–517. 51. Carroll D. 41:1239–1247. 9:268–271. Van Harrevald A. Vijayan N. many migraine sufferers experience hours or days of disability. persistent migrainous aura. and John F. STATUS MIGRAINOSUS The current International Headache Society (IHS) classification system defines status migrainosus as an attack of migraine with severe. The prevalence and incidence of status migrainosus are unknown.17 Status Migrainosus. U. Rothrock Department of Neurology. which is characteristic of the individual’s usual migraine attacks.S. and regardless. status migrainosus.A. and Migrainous Infarction Jessica Crowder. Some experience prolonged auras and complications of their attacks. including stroke and seizures. In a substantial minority. Mobile. but the headache may build to become atypically severe. Curtis Delplanche. In one clinicbased investigation of 100 consecutive patients with IHS migraine. Episodes typically begin with headaches and associated symptomatology. which exert a disproportionately large adverse impact upon public health. Migraine-Associated Seizures (‘‘Migralepsy’’). Although serious acute complications generally are thought to be rare and chronic sequelae yet more uncommon for many sufferers. and migrainous infarction will be addressed specifically in this chapter. 22% reported at 223 . migraine-associated seizures. University of South Alabama College of Medicine. INTRODUCTION Although migraine is often considered a benign condition. migraine is surely not benign. the symptom complex fails to resolve spontaneously or in response to attempted treatment. Persistent Aura. Of those complications. there exist both well documented and theoretical complications of the disorder. migraine can affect health and quality of life adversely for an extended period and even permanently. Alabama. Beyond the huge economic and social burden migraine imposes is a particular misery endured by that 2% of the general population suffering from chronic migraine. debilitating headache persisting more than 72 hours (1). The following case provides a particularly vivid example. At its most severe. Conditions that clearly appear to predispose to status migrainosus are menses and pregnancy. and refractory to treatment. and aura is less likely to be present. Although her headache attacks had been previously limited to no more than two days in duration. a course of high-dose oral prednisone. it does appear that some of the attacks that happen in association with menses may be different than those suffered at other times of the month. As regards family history. Prior self-administered treatment of this attack with various oral triptans. MRM is often more severe. She had been unable to attend school for three weeks preceding her evaluation. and she had experienced no obvious social dysfunction. and sonophobia. Specifically. Her past medical history was otherwise unremarkable. amitriptyline. While results from investigations on the subject have varied. her mother and maternal grandmother had migraine. Status migrainosus is by no means confined to menstruating females.224 Crowder et al. What causes status migrainosus? Why do some headache attacks fail to resolve with sleep. prolonged. She was discharged the following day. and initiation of prophylactic therapy with propranolol. She was admitted and treated with intravenous hydration and a single dose of droperidol 2. Unpublished data). least occasional attacks persisting for more than 72 hours. hormonal factors must play a major role in generating status migrainosus. or the simple passage of time? Why do some migraineurs appear to be especially prone to prolonged attacks? No easy answers are forthcoming. From 40% to 70% percent of females with migraine experience worsening of the headache disorder just prior to or during menses (menstrually related migraine: MRM). and previous treatment had resulted in only brief and partial alleviation of her symptoms. active treatment intervention. She had been hospitalized twice. and 7% to 12% suffer attacks ‘‘exclusively’’ in association with menses (‘‘pure’’ menstrual migraine) (2–4). contrasted with nonmenstrual attacks (1–4). her headache and associated symptoms ceased and did not recur. and treatment with intravenous dihydroergotamine (DHE)/prochlorperazine.5 mg administered intravenously. and aside from its persistence in all other ways. Unpublished data). (Rothrock J. Her academic record at school was excellent. in some female patients. Within 30 minutes of receiving droperidol. a compound containing butalbital. pulsatile. acetaminophen. and her mother understandably was frantic. the attack precipitating the referral had begun six weeks prior. photophobia. Case 1 A 12-year-old female with a three-year history of episodic migraine was referred for evaluation and management of unremitting headache with associated nausea. vomiting. and divalproex sodium had proved unsuccessful. In another unpublished survey of clinic-based migraine patients. and caffeine. Brain magnetic resonance imaging (MRI) was normal. head pain was nonlateralized. almost half of 50 consecutive females with MRM reported at least occasional menstrual attacks persisting more than 72 hours (Rothrock J. Her general and neurologic examinations were unremarkable. intravenous divalproex sodium. but even then the complication occurs in males as well and also in females when no obvious hormonal influence is evident. identical to her previous migraine attacks. and intravenous magnesium failed to terminate the attack. As evidenced by the comments made previously. . intravenous steroids. intranasal and injectable sumatriptan. In 2003. In such cases. pre.and posttreatment electrocardiograms currently are suggested. In addition. results from scientifically sound studies that have established this drug’s safety and utility for the treatment of acute migraine or status migrainosus.16). Intravenous administration of valproate appears safe and may be effective for treating patients with status migrainosus that has failed to respond to other medications (13. and can be mixed with DHE within the same syringe (9). acute dystonic reactions. we currently lack data to indicate the necessity for such precautions or. The treatment of status migrainosus is based largely on tradition. or divalproex sodium. . frequent attacks of prolonged migraine could alter receptor sensitivity to the point that status migrainosus would become one’s characteristic attack pattern rather than an exception. The utility of such treatment may be limited by the requirement for continuous patient monitoring and immediate access to airway management equipment in the event of acute respiratory failure.5 mg administered twice daily for one week appeared to be effective in treating intractable migraine (8).Status Migrainosus. and akathisia represent potential side effects. or a short course of an oral triptan. for that matter. severe migraine. but precious little scientific data to support such treatment currently exist (7). Migralepsy. has been reported to be effective in treating cases of persistent. severe migraine (10. naratriptan 2. Of the dopamine antagonists. Theoretically. reported a success rate of 88% when they administered intravenous droperidol to a small group of patients with status migrainosus (12). the mainstay of selfadministered therapy has been a short course of high-dose oral steroids. prochlorperazine alone or in combination with DHE is effective in treating acute. dopamine antagonists. Doses of 500 to 1500 mg do not require performance of an electrocardiogram or telemetry monitoring. a drug commonly used for induction of anesthesia. and Wang et al. clinicians and investigators advocated repetitive self-administration of intranasal. recent research has suggested that in such cases the patient’s response to a given therapeutic agent may vary according to the specific stage of central sensitization that he or she has reached (5). and case series rather than class I or II evidence. In one small study. it appears that the peripheral and central pathways that signal head pain may have become acutely sensitized to the point that the migraine will resist most conventional pharmacologic treatment and require days rather than hours to resolve spontaneously. and with droperidol use. For years. Clinician-administered therapies for status migrainosus typically have included vigorous intravenous hydration and parenterally administered DHE. and Migrainous Infarction 225 Attacks involving severe headache that persist despite treatment are more likely to develop into status migrainosus. While treatment usually is performed in an intensive care unit or an recovery room setting. and recent observations that high-attack frequency represents a risk factor for ‘‘transformation’’ of episodic migraine into chronic daily headache would seem to support this notion (6). Persistent Aura. sedation. With all of these dopamine antagonists. Propofol. Parenterally administered metoclopramide or chlorpromazine also can be effective for acute. treatment-refractory migraine (15.14). and the last occurs so commonly with droperidol that coadministration of diphenhydramine or a benzodiazepine is recommended. anecdote. prolongation of the corrected QT (QTC) interval may occur following parenteral administration of a dopamine antagonist. This is a common occurrence in patients who awaken with a fully developed migraine that then fails to respond to his/her typically reliable treatment intervention. subcutaneous. or intramuscular DHE. magnesium. ketorolac.11). Some other pharmacologic interventions listed in Table 1 may be used together or in sequence. if ineffective. and a dopamine antagonist. b a . rizatriptan 10 mg. coadministration of two dopamine antagonists makes little sense and may precipitate side effects. nausea. even relatively modest elevations of blood pressure should be treated with alacrity so as to prevent superimposed hypertensive encephalopathy. if nausea and vomiting have occurred. and at least six hours should elapse before DHE is administered subsequent to treatment with injectable sumatriptan.i. IV steroids. Virtually all patients with status migrainosus who have failed self-administered therapy will require vigorous intravenous hydration.i.5–100 mg IV metoclopramide 20 mg IV prochlorperazine 5–10 mg IV sodium valproate 500–1500 mg in 125–500 mL NS at 20 mg/min dexamethasone 4–10 mg IV magnesium IV propofol IV If no clinical contraindications. promethazine 25–50 mg.d. eletriptan 40 mg. results from the test performed to analyze that level will not be available until the dust has settled and the crisis is long past. then intravenous labetalol 10 to 20 mg often will be effective. one should not administer injectable sumatriptan within 24 hours of the patient receiving DHE. for 3–7 daysa Physician administered vigorous IV hydration with isotonic saline containing glucose meticulous management of acute hypertension sumatriptan 6 mg SCa. if at all.5 mg b. or ‘‘slow-acting’’ triptanc b. Along the same line.5 mg b. IV valproate.d. zolmitriptan 2. Some of these options should be used routinely and some rarely.5 mg. salt/sugar-containing beverages) prednisone 60 mg q. if several doses of labetalol fail to bring down a markedly elevated blood pressure to an acceptable level. and vomiting. unfortunately.5–5 mg. for 2–3 daysa a ‘‘fast-acting’’ triptanb t. and in other cases coadministration is contraindicated.d. electrocardiogram.i. Sumatriptan 25–100 mg. In typically normotensive patients. For example. or frovatriptan 2. A final word: success in treating migrainosus status with intravenous magnesium appears to be restricted largely to patients with low levels of serum-ionized magnesium.d. d Metoclopramide 10–20 mg.75 mg IM plus diphenhydramine 50 IM (with pre. Abbreviation: ECG. c Naratriptan 2.and post-Rx ECG) chlorpromazine 12. ketorolac 30 mg IV DHE 1 mg IVa plus an antiemeticd droperidol 2. An algorithm for a suggested treatment that blends common sense with what clinical data are available is presented in Table 1. If pain relief is insufficient to this task. then it is time to call for help and more aggressive measures. while it is acceptable to treat a patient simultaneously with vigorous IV hydration. almotriptan 12. Table 1 Options and Recommendations for Treating Status Migrainosus Patient administered encourage vigorous oral hydration with appropriate fluids (free water or. All doses recommended in Table 1 are based on the assumption that the patient is an adult with normal weight. and this is particularly so if they have had associated anorexia.226 Crowder et al.d.i. prochlorperazine 5–10 mg. At her follow-up visit three weeks later she reported that she had been entirely headache free for nine days and was experiencing no aura symptoms. along with facial symptoms characteristic of migrainous sensory aura.2. verapamil. migraine with prominent aura. or metoprolol. Persistent Aura. certain of the newer antiepileptic drugs (AEDs) may be effective in treating these patients. was prescribed for migraine prophylaxis.g. and Migrainous Infarction 227 PROLONGED AURA Migraine attacks involving aura with little or no associated headache and aura symptoms atypically prolonged once were lumped together by many as ‘‘complicated migraine. and migraine with prolonged aura frequently are considered to lie on a continuum with migraineassociated stroke (MAS). ‘‘Complicated migraine’’ thankfully was consigned to the scrap heap when the First Edition of the International Classification of Headache Disorders (ICHD-1) was published in 1988. or even months. Brain MRI and electroencephalogram (EEG) were normal. specifically avoiding the use of ‘‘vasoactive’’ medications (e. Her headaches and aura symptoms had failed to respond to prophylactic treatment with propranolol..d. or some other nonmigrainous entity.3). partial seizure activity. however. Migralepsy. and injectable sumatriptan had made no acute impact on her symptoms. and many clinicians persist in regarding these variants with particular suspicion. Case 2 A 53-year-old woman reported a history of episodic migraine beginning at age 33.5. . persistent aura may be triggered by sudden termination of prophylactic therapy (17).5. and migrainous infarction (1.i.’’ a nonspecific term that possesses little or no clinical utility. While the origin(s) of this phenomenon are obscure. In the past. blind spots. zigzags.3). As the following case demonstrates. and sparkles’’) in association with her migraine headaches. Four years prior to her initial evaluation. and for at least two years preceding initial evaluation. and published case series involving treatment with furosemide or acetazolamide similarly have indicated positive treatment results (19–21). Migraine aura without temporally associated headache (sometimes referred to as ‘‘acephalgic migraine’’). Her aura symptoms became increasingly pervasive. the triptans and ergotamines) when confronted with them. along with headache intensifications characteristic of migraine on an average of once or twice per month. patients with prolonged or otherwise atypical migrainous aura often are misdiagnosed as having transient ischemic attacks. Not surprisingly. The ICHD-2 (2004) again provides a clear distinction between these various clinical presentations: typical aura without headache (1. she noted persistent ‘‘pulsating. persistent aura without infarction (1.Status Migrainosus. days. amitriptyline. The scientific evidence for harm is lacking but so is the evidence for safety. Divalproex sodium 250 mg b.4) (1). prolonged aura was reported to be notoriously difficult to terminate with abortive therapy or to suppress with prophylactic agents (18). During that period she also experienced constant. naproxen sodium. At infrequent intervals clinicians who regularly treat migraine will encounter a patient who reports episodes of aura that persist for hours. she began to experience visual aura (‘‘bright flashing dots of light. with or without associated head pain. bright flashes of light’’ in all visual fields. She remained on divalproex sodium for another two months and had only one attack of migraine (without aura) during that time. lowintensity headache. There were no abnormal findings on physical examination. One also occasionally encounters the phenomenon of ‘‘migraine aura status. (iii) the distinction between migrainous aura and epilepsy can be surprisingly difficult to make. the episodes of aura ceased following initiation of treatment with acetazolamide. Both sensory and visual aura status have been described. but it occurred as an isolated event and in the setting of an acute migraine attack with associated head pain. .228 Crowder et al. Taken further. and then ceased again when treatment was resumed (24).i. the nature of the symptoms typically described and their responsiveness to AEDs that suppress cortical hypersensitivity and cortical spreading depression (CSD) speak less in favor of vasoconstriction as the generator of aura and more toward a primary neuronal origin (22. and (iv) despite the association between the two conditions. MIGRALEPSY The cases that follow highlight four different issues that commonly arise when one confronts the association between migraine and seizure activity: (i) not infrequently. recurred when treatment was stopped. In another case series. not every episode of altered consciousness that occurs during a migraine attack reflects true epilepsy. Her mother had migraine with and without aura.d. Case 3 suggests that an association may exist between migraine and ‘‘idiopathic’’ epilepsy. As in this case. and her last seizure occurred over two years ago. She had had a total of six GTC seizures and no overt evidence of partial seizure activity.23). individuals may have both conditions. for that matter—remains uncertain. This patient definitely had a GTC seizure. Her examination was normal. Case 3 A 28-year-old female who presents with a long-standing history of episodic migraine with and without aura also reported a 14-year history of generalized tonic/ clonic (GTC) seizures.’’ wherein aura episodes of more typical duration atypically follow one another in rapid succession. Does she have epilepsy per se? Does she require chronic treatment with an AED to prevent seizure recurrence? Her case typifies what most would term ‘‘migralepsy. which was severe. as were brain MRI and EEG. She was taking topiramate 50 mg b. Her seizures had occurred both during attacks of severe migraine headache (with or without aura) and independent of migraine attacks. Although the biogenesis of prolonged aura—and aura generally. and a maternal aunt had both migraine and primary generalized epilepsy. divalproex sodium has been reported to help (25). and attacks of one may occur temporally independent of the other. it should be noted that patients with prolonged aura have been reported to experience no adverse consequences from triptan therapy (24). an individual may experience both.’’ and we will devote the majority of this section to addressing the intricacies of this challenging clinical presentation. for prophylaxis of both migraine and seizures. (ii) some migraineurs appear to have seizures only when subjected to the stress of a severe migraine attack. In five patients who ‘‘transformed’’ into daily migraine with aura. Her maternal grandmother had migraine. and in one small case series. phenytoin appeared to provide some benefit (26). Her migraine was well controlled. but there was no known family history of epilepsy.and third-degree relatives had apparent migraine.g. In the midst of one recent attack. of no prognostic significance.’’ i. Her mother. and that the one isolated episode of possible seizure activity that her husband did observe most likely represented a ‘‘syncopal fit. Case 5 represents a situation faced all too often by specialists and nonspecialists alike. At age 28. It is far more plausible that the patient is experiencing migraine-associated syncope rather than seizures. or both may result. and (c) whatever its origin—migrainous or epileptic— hyperexcitability of occipital neurons may be provoked by a triggering stimulus to a threshold beyond which aura. Since that event. Her baseline EEG was normal. with attacks of migraine with and without aura since the age of 12. she developed a highly disorganized pattern of waveforms posteriorly and occasional spike discharges over the posterior leads. a brief.Status Migrainosus. Case 5 A 36-year-old female reported a lifelong history of migraine. Her examination. as was brain MRI. Her father had migraine.’’ On one such occasion while jogging she lost consciousness for about five minutes following the onset of aura. diagnostic evaluation (e. After regaining consciousness she noted a severe headache and found that she had bitten the lateral aspect of her tongue.. and EEG were normal.. tilt-table testing) of patients such as the one presented here often fails to yield results that assist . A neurologic examination performed at that time was normal. father. a brother. brain imaging. seizure activity. There was no known family history of epilepsy.’’ and a previous misdiagnosis needs to be corrected. involved functionally disabling headache and lasted for days. which for years had been most prominent during menses. those intensifications often were heralded by visual and sensory aura. Persistent Aura. the aura’s symptomatology likely reflects a genetically hypersensitive occipital cortex. she recently suffered a GTC seizure (her first ever) with associated tongue biting and postictal confusion/ agitation but no incontinence. but in response to photic stimulation. Although many published reports have suggested that migraine may convey some degree of autonomic dysfunction. and she noted that such episodes tended to occur particularly during menses and especially if at those times she jogged just to the east of a long line of trees behind which the setting sun emitted intermittent ‘‘flashes of bright light. generalized seizure that was provoked by syncope and was.e. she continued to have occasional episodes of similar visual aura with or without temporally associated headache. this patient’s diagnosis and management need to be ‘‘cleaned up. and Migrainous Infarction 229 Case 4 A 34-year-old female. Migraine-associated syncope is common. reported a two-year history of daily headaches that fluctuated widely in severity and at times intensified to resemble her previous migraine. (b) the distinction between migrainous visual aura and partial seizure activity arising from occipital neurons can be difficult to make. Case 4 illustrates a number of interesting issues: (a) in many—if not most— individuals who report migraine with visual aura. Migralepsy. and multiple second. Her neurologic examination and brain MRI were normal. in itself. a ‘‘kaleidoscope’’ that developed over about 15 to 20 minutes and then resolved entirely and without any temporally associated headache. and observers report that while unconscious she exhibited ‘‘stiffening and shaking’’ of all four extremities. she experienced her first visual aura. sometimes a seizure occurs during or following a migraine attack. Derived from combining ‘‘migraine’’ and ‘‘epilepsy.g. Electroencephalography. Lipton et al.9%. While migraine-like headaches are quite frequently seen in the postictal period.2) and (b) a seizure occurring during or within one hour following the migraine aura..5. The classification document also notes that migraine and epilepsy are prototypical examples of paroxysmal brain disorders.5) as a ‘‘seizure triggered by a migraine aura’’ (1). Several researchers have reported that patients with migralepsy may have visual seizures consisting of brief visual hallucinations involving colored dots or discs. the seizures thus described lasted for 1 to 2 minutes and were followed by a scotoma that slowly evolved into unilateral or bilateral hemianopia (30–32). ‘‘intercalated seizure’’ is a more recent term. While the symptoms themselves may be identical in the two conditions. The diagnostic criteria include (a) a history of migraine fulfilling criteria for migraine with aura (1. in clinical management. The reported prevalence of epilepsy in individuals with migraine has ranged from 1% to 17%. sometimes referred to as ‘‘migralepsy. This is a situation wherein common sense should prevail. implying the occurrence of an epileptic seizure during the aura phase of a migraine attack (29). and finally diminish. with a median of 5.28). unless the patient or a reliable observer reports unequivocal. Both conditions are believed to reflect genetically derived neuronal hypersensitivity. but they can share common symptomatology.’’ has been described in patients with migraine with aura (1). In both conditions. then build. wherein they initially appear. seizures frequently are followed by a headache indistinguishable from that of migraine.’’ ‘‘migralepsy’’ is an older term that recently has been reintroduced to indicate a composite of symptoms encountered in both disorders. the EEG of migraineurs may exhibit epileptiform features even in individuals without any history of seizure symptoms (27. a migraine aura is typically longer lasting than an occipital seizure. while the visual symptoms of an occipital seizure most often persist for only 1 to 2 minutes. the symptoms have a dynamic temporal pattern. and the reported migraine prevalence in individuals with epilepsy has ranged from 8% to 15% (33). e. or single or multicolored spots that often rotate. performed when these ‘‘positive’’ symptoms were present. the aura of migraine usually lasts 15 to 20 minutes.4 times more common in individuals with epilepsy than in individuals without epilepsy . and they appear to be comorbid. confirmed they were epileptic in origin. it was proposed that migraine might represent a fragmentary variant of epilepsy.230 Crowder et al. In describing cases of ‘‘migralepsy’’ that involved patients who suffered temporally associated acute migraine and seizure activity. In one study examining the association between migraine and epilepsy. Moreover. The ICHD-2 defines migraine-triggered seizure (1. found migraine to be 2. Both migraine and epilepsy—especially when epilepsy involves seizures arising from the occipital cortex—may produce prominent visual symptomatology. unprovoked seizure activity or EEG (routine or extended/video) is highly suggestive. Migraine and epilepsy typically are distinct from one another. assigning a diagnosis of epilepsy and committing the patient to AED therapy indefinitely would seem to be in no one’s best interest. highly stylized contours of geometric figures. This phenomenon. The Association of Migraine and Epilepsy It requires no great leap of faith to accept that epileptic seizures could result from the same cortical changes that induce migraine attacks. in which case one would expect migraine to predate the onset of epilepsy. can be seen in children without a history of migraine and is thus not specific to that condition (39). leading one to anticipate an increased prevalence of migraine after the onset of epilepsy but not before (35). Electroencephalography has not been shown to distinguish reliably among headache subtypes. While the EEG is a useful tool in evaluating epilepsy. Focal slowing sometimes occurs during migraine aura but is not a consistent finding. however. or both could contribute to these alterations. originally thought to be characteristic of migraine. Shared environmental risk factors could contribute to comorbidity. the comorbidity of the conditions theoretically could result from the effect of head injury in generating both. Although one might presume the two conditions share a similar genetic basis that could account for their comorbidity. including selection bias. and the Quality Standards Subcommittee of the American Academy of Neurology in fact has determined that EEG is of no utility in headache diagnosis (38). those recorded during an attack of migraine with aura are usually normal. the risk of migraine is higher in subjects with epilepsy caused by head trauma. epilepsy theoretically could produce migraine by activating the trigeminovascular system. In what would represent a unidirectional and causal relationship. Epileptiform discharges and focal slowing may occur in the EEG tracings of nonepileptic patients with or without migraine. there appears to be strong evidence for an association between the two conditions. and in contrast to EEGs recorded during a clinical seizure. a lack of appropriate case controls and variable or nonspecific definitions of migraine and epilepsy. and as head trauma may produce ‘‘acquired’’ migraine. Enhanced neuronal excitability and an inherently reduced threshold to triggering stimuli are integrated in this model. some studies have noted correlative EEG characteristics in migraine and epilepsy. In short. Even so. leading one to reject both of these unidirectional causal models. migraine conceivably could produce epilepsy by inflicting ischemic brain injury. the . On the other hand. The biologic basis of the association may be multifactorial. and at the cellular level. Schachter et al. Silberstein and Lipton have proposed that it is simply the similar state of increased excitability within the brain that accounts for the comorbidity of migraine and epilepsy (37). the genetic permutations involved appear to differ. The data actually show an excess of migraine both before and after the onset of epilepsy. Persistent Aura. The EEG in Migralepsy Differentiating between migraine and epilepsy can be difficult. genetic predisposition. a large study by Ottman and Lipton failed to confirm that hypothesis (36). it is far less valuable in the diagnosis of migraine. this specific environmental factor cannot account for all the comorbidity present. Migralepsy. an environmental cause and the ‘‘shared gene’’ hypothesis. In theory. Because their association persists even in individuals with idiopathic or cryptogenic epilepsy. a reduction in neuronal magnesium or disturbances of neurotransmitter systems may provide the pathophysiologic basis for producing the hyperexcitability. while both disorders may possess a genetic basis. With the rejection of a unidirectional model. nor is it an effective screening test for excluding structural causes of headache. environmental factors. Although many of the relevant studies have had methodologic limitations. and Migrainous Infarction 231 (34). For example. reported that among nonepileptic subjects.Status Migrainosus. Even the photic ‘‘harmonic response’’ appearing at greater than 20 Hz. Marks and Ehrenberg studied 395 adult seizure patients. What we observe: there are patients with migraine and isolated or recurrent seizure activity. Summary What we know: migraine and epilepsy are bidirectionally comorbid. EEGs recorded during the transition from aura to partial seizure demonstrated ‘‘distinctive changes’’ on the EEG during the aura. or viral encephalitis). overnight EEGs of 12. The origin of the abnormalities observed remains unclear. continuous video-EEG telemetry demonstrated changes during migraine aura. which were atypical for electrographic epilepsy. None of these patients had any of the usual diseases associated with PLEDs (established stroke. Some of the patients had clinical seizures when PLEDs were present on their EEGs (28). In one study involving two patients with migralepsy. . What we don’t know: how to identify clearly those patients with migralepsy who will require long-term treatment with AEDs. In most reported cases involving migralepsy. MRI and Migralepsy Evanescent brain MRI abnormalities following an attack of migraine complicated by seizure activity have been reported.3% of those with a family history of epilepsy showed spikes. and in two subjects. and their PLEDs usually resolved within 24 hours. glioblastoma. along with the bursts of spike activity more characteristic of EEG findings during an epileptic seizure (41). Mateo et al. Finally. and periodic lateralized epileptiform discharges (PLED) were recorded in five other subjects in close temporal association to their migraine episodes. repetitive epileptiform activity typically observed during pure epileptic seizures. Extended electroencephalography combined with closed-circuit video recording can help differentiate between migrainous and epileptic symptoms and help facilitate the diagnosis of migralepsy. however. despite the persistence of clinical symptoms. Sixteen percent of their migraine subjects experienced seizures during or immediately following an aura. the EEG does not show the progressive increases and declines in the frequency and amplitude of rhythmic. whose MRI demonstrated recurrent and reversible abnormalities (42). have described a patient with repeated episodes of migraine with aura-associated seizures.232 Crowder et al. 20% of whom also had migraine.5% of those with migraine and 13. the following two cases characterize the complexity of that association and the broad clinical spectrum encompassed by MAS. an incidence significantly higher than that observed in the general population (40). the EEG during migraine aura may show a waxing and waning pattern. What we suspect: this comorbidity is derived from the cortical hypersensitivity (presumably genetic in origin) inherent in both conditions. brain abscess. with abnormal sequences separated by completely normal EEG activity. MIGRAINE AND STROKE While migraine and stroke are associated. and subjects with catamenial epilepsy or migraine with aura were at increased risk for an association between the two disorders. whose seizures occur only in the setting of an acute migraine attack (‘‘migralepsy’’). which preceded development of an electrographic complex partial seizure. Emergent catheter-directed arteriography demonstrated tapering stenosis and occlusion of the right internal carotid artery several centimeters distal to the extracranial bifurcation (Fig. and what is it about migraine that leads an individual to be at increased risk for stroke even when he or she is acutely migraine free? No easy answers are forthcoming. Two obvious questions follow: how is stroke generated during an acute migraine attack.’’ serving merely as a marker for another coexisting condition that by itself is independently responsible for . Noncontrasted brain CT demonstrated old infarcts in both cerebral hemispheres at the vertex. and new right eye visual loss slowly improved. visual impairment. Serial brain computed tomography (CT) demonstrated the evolution of a small area of infarction within the left corona radiate. but follow-up angiography performed two days later was normal.44). Her new dysarthria. Her initial neurologic examination was notable for a partial left afferent papillary defect. Persistent Aura. recently reported stroke risk to be similarly increased two to threefold in a large cohort of individuals !55 years of age who reported a history of migraine with aura (43. or migraine may be an ‘‘innocent bystander. and on one other occasion her headache was accompanied by expressive aphasia. and acute/persistent left eye visual loss. pulsatile. she had experienced left hemiparesis during a typical headache. 1). acute worsening of her chronic left hemiparesis.Status Migrainosus. and left hand dysgraphesthesia and tactile extinction. The findings were quite suggestive of internal carotid dissection. most strokes suffered by migraineurs occur temporally remote from an acute migraine attack.and gender-matched general population samples. only about 1000 take place during a migraine episode and meet the ICHD-2 criteria for migrainous infarction (1. and several possible explanations exist. nonlateralized headache with associated dysarthria. 20/400 acuity in the left eye. of the approximately 3000 cases of stroke estimated to occur annually in young-to-middle-aged migraineurs in the United States. Follow-up brain CT demonstrated only the old areas of infarction noted on the baseline study. and Migrainous Infarction 233 Case 7 A 37-year-old woman with a long-standing history of migraine without aura presented with acute and persistent right arm and leg weakness. increased left hemiparesis. Migralepsy.4) (1). Her neurologic examination was notable for pronator drift of the right arm and mild weakness to direct testing of the right hand intrinsics and hip flexors. Migraine may act as a cofactor in producing stroke or interacting with another risk factor.5. she developed a severe. right hemiparesis. and within a month she was back to her neurologic baseline. Elective arteriography was notable only for nonvisualization of the left ophthalmic artery. and new visual loss affecting the right eye. A recent meta-analysis of 14 relevant epidemiologic studies indicated that stroke risk is increased about twofold in young-to-middle-aged migraineurs relative to case controls or age. mild left hemiparesis. extensor plantar responses bilaterally. as Case 7 exemplifies. Four days following elective arteriography. Case 8 A 31-year-old female reported an 11-year history of episodic headaches characteristic of migraine. On four occasions. Interestingly. and Stang et al. without associated headache. or speech disturbance. and in the 1980s. during attacks).234 Crowder et al. Smoking could interact with migraine in a similar fashion. If. or both—then the additional prothrombotic potential provided by an oral contraceptive (OCP) conceivably could be sufficient to produce symptomatic cerebral thrombosis (45–47). migraine may produce a prothrombotic state—acutely (i. and with at least a few of these it is simple to conjecture how they might interact with migraine to produce stroke. felt to be a consequence of migraine–associated vasospasm.. each reinforcing the other’s propensity for promoting arterial thrombosis (48).e. Alternatively. Figure 1 Selective right common carotid arteriogram demonstrates tapering stenosis and occlusion of the extracranial internal carotid. some investigators touted MVP as a potentially common cause of the ubiquitous ‘‘stroke of unknown cause. Is migraine merely an ‘‘innocent bystander’’ in the stroke process? Mitral valve prolapse (MVP) is found more commonly in migraineurs than in the general population. something about the migraine process itself might generate stroke. A number of additive risk factors for stroke in migraineurs have been reported by various investigators. causing stroke. chronically.50). the prevalence of MVP was low (49. as some have suggested. others have identified migraine-associated patent foramen . In a similar vein. In two studies describing relatively large groups of patients with acute stroke complicating a migraine attack.’’ Does the increased stroke risk in migraineurs simply reflect the higher prevalence of MVP in that population? Apparently not. and this is particularly relevant when a patient with no previous aura history develops aura after beginning an OCP. ‘‘migrainous arteriopathy. routinely to deny OCPs to female migraineurs seems to make little sense and invite unwanted conception. Persistent Aura. without ‘‘positive’’ features (22. which may be disproportionately high in those patients whose visual auras consist primarily of amaurosis. and use of an OCP with a relatively high estrogen content by women aged 35 or greater represent a combination of factors that may elevate the risk of stroke or other thrombotic complications to an unacceptable level. Females whose migraine pattern changes drastically for the worse following initiation of OCP use represent another subpopulation in whom alternatives for contraception should be considered. especially if that event was thrombotic or thromboembolic stroke. aura. will result in stroke? CSD is believed to represent the biologic underpinning of migrainous aura. but questions regarding PFO and causation persist (51). Migralepsy. significant aphasia. taken to excess. Bougaslavssky and colleagues found no arteriographic evidence of vasospasm in their patients who suffered ischemic stroke during an acute migraine attack (49). and Migrainous Infarction 235 ovale (PFO) as the potential generator of at least a proportion of cases of migrainous infarction. Certainly migraine. as mentioned previously. in some cases. weakness. Estrogen-containing OCPs or hormone replacement therapy probably are best avoided in all female migraineurs who have suffered a previous thrombotic event. and such patients should be counseled to cease smoking and to consider an alternate means of contraception (or at least an OCP containing less or no estrogen). In one exception to this. migraine-associated arterial dissection. or. and both in those cases and in the others where the spasm selectively involved the symptomatic artery. and. 4 of 6 (67%) patients with migrainous infarction. then particularly severe or prolonged CSD-related cerebral oligemia might produce irreversible neuronal damage.000 unplanned pregnancies annually in the United States (45–47.. however. active cigarette smoking. when the patient with known migraine with aura begins to experience aura that is atypically prolonged or otherwise unusual (e. abnormalities were found in the anterior circulation as frequently as the posterior (52).’’ and genetically associated calcium channelopathies).53. In another study. a study involving a relatively large series of patients with migrainous infarction. dogmatic advocation of any particular treatment strategy for preventing or treating such strokes is difficult to justify. the arterial spasm was widespread. and in terms of primary stroke prevention in the migraine population.g.g.Status Migrainosus. An obvious limitation to the investigation of mechanisms potentially generating migrainous infarction is the fact that very few centers encounter such patients in numbers sufficient to generate compelling case series. even more alarming. If migrainous aura results from CSD that includes an oligemic component. and amongst this group migraine-associated vasospasm deserves particular mention. Given the uncertainties as to the mechanism(s) that may generate migrainous infarction or MAS. it is estimated that implementation of such wrongheaded management on a widespread basis would result in 700. remains controversial. let alone scientifically sound case–control studies. did exhibit clear evidence of cerebral vasospasm.43–47). some studies have reported an increased risk of stroke in populations of migraine patients with aura. Does migraine act directly and independently to cause stroke? Is there something intrinsic to the migraine process itself that. A variety of other mechanisms for the direct production of migrainous infarction have been proposed (e. or both). who underwent arteriography within 72 hours of stroke onset. . extending beyond the symptomatic territory.. Whether a history of migraine further increases the stroke risk associated with OCP use.54). again. intra-arterial angioplasty/thrombolysis/ vasodilators. Manzoni GC.. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centers. Ann Neurol 2004. et al. verapamil) instead (55–58). antiplatelet agents. Allais G. Factors associated with the onset and remission of chronic daily headache in a population-based study. Certainly rapid control of the patient’s pain. but the utility of intravenous tissue plasminogen activator (tPA). the treatment of migrainous infarction and MAS—whether intended for primary prevention. The international classification of headache disorders (2nd ed). the stroke recurrence rate was quite high (10% per patient year of followup). 2. but. 55(1):19–26. 24:707–716. Collins B. Burstein R. 43:991–993. given the absence of evidence-based guidelines. this occurred even in patients treated with anticoagulant therapy. Yet more obscure is what comprises optimal management of the patient with apparent acute migrainous infarction. the evidence to support such treatment is at best sparse. Headache 2003. 33:385–389.g. Cephalalgia 2004. Vohrah RC. in one case–control study involving a relatively large number of patients with migrainous infarction who were followed prospectively. MacGregor EA. Cephalalgia 2004. Gallagher D. Headache 1993. or acute intervention—calls for an especially strong dose of common sense. . 6. 8. Stewart WE. Managing intractable migraine with naratriptan. What constitutes optimal therapy for secondary stroke prevention in patients with prior migrainous infarction remains unknown. 106:81–89. cerebral arteriography is probably best avoided in patients with acute migraine unless the clinical situation clearly demands such diagnostic intervention. Long-term treatment with an antiplatelet agent also is recommended. Martignoni E. 30(suppl 2):550–553. Migraine and menstruation: a pilot study. Cephalalgia 1990. Grannella F. Wilkinson M. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Grannella F. Lipton RB. Sances G. and judicious blood pressure management are interventions that would be difficult for any to dispute. Interestingly (and of concern). but it would seem self-evident that minimizing attack frequency—and particularly the frequency of prolonged. or both (50). Chia H. 3. Treatment of status migrainosus: the American experience. based on tradition more than any scientific basis. severe migraine attacks—would lessen stroke risk. Sances G. Headache 1990. Ricci JA. or other ‘‘heroic’’ measures lacks a basis to justify either vigorous support or vehement opposition. A scattering of case reports have suggested that betablockers may be a poor choice in patients at risk for migrainous infarction. Jakubowski M. Scher AI. Zanferrari C. Costa A.236 Crowder et al. vigorous intravenous rehydration. 4. REFERENCES 1. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. 5. 24(suppl 1): 1–160. Mueller O. and an even thinner scientific basis exists to support the use of calcium antagonists (e. In short. Such management often will require prescription of an effective prophylactic agent and a combination of agents for acute migraine treatment that are effective but do not promote vasoconstriction. 10:305–310. 7. Headache Classification Committee of the International Headache Society. secondary prevention. Finally. Pain 2003. Raskin N. Kosmorsky GS. 15. Wang S. Powers S. Norton J. Headache 2000. Neuroscience 1987. Kabbouche M. Mancia D. Andermann FA. Headache 2000. 23:739. 41:981–984. Persistent positive visual phenomena in migraine. Case report. Amemori T. 32. et al. Migraine-epilepsy relationships: epidemiological and genetic aspects. 12. Migraine and epilepsy with infantile onset and electroencephalographic findings of occipital spike-wave complexes. 28. Intravenous propofol: unique effectiveness in treating intractable migraine. 40:755–757. Marks DA. Silberstein S. Benign Childhood Partial Seizures and Related Epileptic Syndromes. Corbo J. Nett R. Sluis P. Daily migraine with aura: a new migraine variant. . Tolerability and effectiveness of prochlorperazine for intractable migraine in children. In: Panayiotopoulos CP. DeRomanis F. 11. 14. 37:377. Migraine and Epilepsy. Haan J. 1960. ed. Esperanca P. Belanger J. 33. 45:664–668. Manzoni GC. Feliciani M. Funct Neurol 1988. 40:389–392. et al. 2:597–602. 29. 40:224–230. Migraine with prolonged aura. Treatment of a prolonged aura with intravenous furosemide. Krusz J. Eur Neurol 1979. Merima D. Lane P. Popeney C. Young W. Lugaresi E. and Migrainous Infarction 237 9. Headache 2001. Cameron J. Terzano MG. Brain 1994. Headache 2000. 22:29–36. Scher C. 55:1588–1589. and basilar migraine. Pain Med 2002. 18: 124–129. Cerbo R. 17. Lampl C. 21. 3: 187–203. Speechley M. Neurology 1997.Status Migrainosus. 43:2476–2483. Buzzi MG. Vockell A. eds. Neumann K. Neurology 2005. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraine. Lennox WG. Lamotrigine in the prophylactic treatment of migraine aura–a pilot study. Cerbo R. Sluis LH. 20. Hershey A. 64:463–468. IV Depacon and po Depakote ER for treatment of status migrainosus and prevention of episodic migraine. Bento M. 3:366–369. 1999:281–302. Headache 2000. 27. 25. Headache 1991. Persistent Aura. LeCates S. Cephalalgia 2003. et al. Lennox MA. Rothrock J. 30. Buzath A. Lipton R. Neurology 2000. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Kuritzky A. 16. Triptans in the treatment of basilar migraine and migraine with prolonged aura. Lauritzen M. 19. Acetazolamide treatment for migraine aura status. Propofol: a new treatment strategy for refractory migraine headache. Drummond-Lewis J. Liu GT. Panayiotopoulos CP. Cephalalgia 1999. Successful treatment of persistent migraine aura with divalproex sodium. Migraine related seizures in adults with epilepsy. acephalgic migraine. Friedman B. London: John Libbey & Company Ltd. Headache 1997. Migralepsy. Use of intravenous valproate sodium in status migraine. 22. Klapper J. 19:58–63. 23. Pediatrics 2001:107. 48:261–262. 13. Spreading depression in the olfactory bulb of rata: reliable initiation and boundaries of propagation. In: Andermann FA. 10. Neurology 1993. 40:52–53. 55:732–733. Burnes J. Pathophysiology of the migraine aura: the spreading depression theory. Possible interference between migrainous and epileptic mechanisms in intercalated attacks. Schatz NJ. Scott V. Rozen T. Acad Emerg Med 1995. 1987:281–291. Ehrenberg BL. Boston: Butterworths. Klinger D. Epilepsy and Related Disorders. 18. Gorelova NA. Neurology 2000. Galetta SL. DeRomanis F. Mathew N. 31:378–383. Andermann E. Droperidol treatment of status migrainosus and refractory migraine. Skobieranda F. 24. Migraine and other clinical syndromes in children affected by EEG occipital spike-wave complexes. Brown. 26. Boston: Little. 117:199–210. Volpe NJ. Neurology 1995. Differentiating occipital epilepsies from migraine with aura. 31. with EEG correlation. Logan W. eds. Poulter N. BMJ 1995. 52. Comorbidity of migraine: the connection between migraine and epilepsy. Greenberg MK. Bogousslavsky J. et al. Wannamaker BB. 53. Visy J. A meta-analysis. 318:13–18. Ito M. Neurology 1995. 41. Semin Neurol 1991. Iglesias S. Stolar MJ. Swenson M. Takkouche B. Rose KM. Ottman R. Hubert J. In: Olesen J. 54. In: Ettinger AB. Johnston S. 37. 15:251–255. Migraine and stroke in young women: case control study. 35. Tzourio C. 11:118–127. Merikangas KR. Van Melle G. Ehrenberg BL. Milhaud D. 47:918–924. Migraine stroke. 20:93–95. Arch Neurol 1988. Regli F. et al. 2002:239–254. Migrainous stroke. Headache. 45:63–67. van Melle G. eds. 45:1411– 1413. Iglesias S. Managing Epilepsy and Co-existing Disorders. The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Risch N. 51. Vincente I. Tfelt-Hansen P. J Clin Neurophysiol 1998. Neurology 1995. et al. Boston: Butterworth-Heinemann. The Italian National Research Council Study Group on Stroke in the Young. Gillum L. Etminan M. 34. Schachter SC. 36. 57:1805–1811. Practice parameter: the electroencephalogram in the evaluation of headache (summary statement). Migraine-associated seizures with recurrent and reversible magnetic resonance imaging abnormalities. 284:72–78. Neurology 2001. Rothrock J. Ischemic stroke and active migraine. Bogousslavsky J. Foncea N. Migraine as a risk factor for ischemic stroke: a case-control study [abstract]. 46. Arch Neurol 1997. Lancet 1996. Neurology 1993. Headache and epilepsy. North J. Neurology 1988. JAMA 2000. Cheng SH. 49. Marini C. 39. Lipton RB. 48. Mamidipudi S. Donaghy M. History of migraine and risk of cerebral ischemia in young adults. Lipton RB. Samii A. 42. Tzourio C. 43. Neurology 1994. and ‘‘the borderland of epilepsy’’ re-explored. 24:171. 45: 1263–1267. Migraine and migrainous stroke: risk factors and prognosis. Hauser WA. Silberstein SD. 44:265–270. Ottman R. 64:1573–1577. Bousser M. Carson AP. Isorna FC. Prendes J. 44:28–32. The utility of the electroencephalogram in the evaluation of patients presenting with headache: a review of the literature. Garcia-Monco J. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology 1996. Considerations on the use of propranolol in complicated migraine. 310:830–833. Fenton BT. Welch KM. Gronseth GS. Headache 1980. Liot P. The trigeminovascular system. Chang C. 38. Beldarrain M. Stang PE. Payot M. The Headaches. Mateo I. 1993:97–104. Risk of ischemic stroke in people with migraine: systematic review and meta-analysis of observational studies. cerebrovascular symptoms and stroke: the Atherosclerosis Risk in Communities Study. 50. 40. Incidence of spikes and paroxysmal rhythmic events in overnight ambulatory computer-assisted EEGs of normal subjects: a multicenter study. Walicke P. Headache 2004. 54:362–368. 55. BMJ 2005. New York: Raven Press.238 Crowder et al. Ehrenberg BL. 45. Neurology 2005. . Lyden P. Devinsky O. Lipton RB. Case-control study of migraine and risk of ischemic stroke in young women. Tehindrazanarivelo A. 38:223–227. 47. BMJ 1999. Madden K et al. Uske A. 330:63. Moskowitz MA. Carolei A. 347:1503–1506. Tehindrazanarivelo A. Unusual clinical manifestations of migraine. 43:2473–2476. DeMatteis G. Report of the Quality Standards Subcommittee. Rothrock J. Ischemic stroke risk with oral contraceptives. Association between migraine and stroke in a large-scale epidemiological study of the United States. 44. Stroke 1993. Stroke in migraine as a consequence of propranolol. Migrainous stroke causing thalamic infarction and amnesia during treatment with propranolol. . 58. Headache 1982. Persistent Aura. Headache 2000. Hamilton W. Migralepsy. Gilbert G. Rothrock J. Mendizabal J. Headache 1987. Bardwell A. 27:381–383. 37:594–596. Case report: migraine-associated seizure: a case of reversible MRI abnormalities and persistent nondominant hemisphere syndrome. Headache 1997. Greiner F. An occurrence of complicated migraine during propranolol therapy. Dodick D. 59. Trott J. 40:487. 57. 22:81–83. and Migrainous Infarction 239 56.Status Migrainosus. Friedenberg S. . and nonpharmacologic treatment (4). covering diagnosis as well as acute. INTRODUCTION William Osler’s principle that it is more helpful to approach the person who has the disease than the disease the person has is well taken in regard to headache (1). careful physical and neurological examination. the U. All diagnosis and treatment takes place in the atmosphere of a relationship between the physician and patient. Rapoport The New England Center for Headache. Husid Department of Neurology.K. The Canadian Headache Society (5) and the U. as well as in the details of the medical complaint’’ (2). New York. As John R. No two physicians approach the evaluation and management of headache patients in exactly the same way. preventive. patients. Georgia. Graham once wrote. It is the quality of that atmosphere which often constitutes the difference between treatment success and failure. Headache Consortium developed evidence-based guidelines for the management of migraine. and Department of Neurology. U. the assurance that the physician and patient derive from all the information available that everything possible has been done to exclude the presence of organic causes of headache (3).A. and in particular. Walton Headache Center. ‘‘Any style will be effective providing it clearly demonstrates to the patient that the physician is interested in him and his life as a person.S. . U. Appropriate treatment begins with the initial interview. Stamford. Medical College of Georgia. Migraine in Primary Care Advisors Migraine Guidelines Development Group 241 . . and their families.A. A nonbiased and nonjudgmental approach should be the template upon which diagnosis and treatment is built’’ (1).S. Connecticut.18 Principles of Headache Management Marc S. Recently. Some headache specialists use established headache guidelines in addition to their own knowledge to develop individualized treatment programs for each patient. Fred Sheftell. nor need they. Alan M. Managing patients with headache disorders can be challenging yet very rewarding to the caregivers. Augusta. New York. ‘‘One can take a logical approach to the diagnosis and treatment of headache and still miss the boat . Columbia University College of Physicians and Surgeons. As noted by Dr.S. using medical assistants. Yet. answer their questions.’’ (10). To enhance the treatment program and maximize physician efficiency. 3. 6. the secret of good history taking is to be a good listener (9). project a positive attitude. This truism dates back to 1904.) ESTABLISHING THE DIAGNOSIS History Taking Accurate history taking is the most important aspect of any medical consultation. Headache patients not only want headache relief. Figure 1 consists of clinical forms we use in gathering patient histories (8). which can make the difference between success and failure of treatment (1). individualized treatment plan Schedule regular follow-up visits to reassess and modify treatment (6) have published similar guidelines. 5. pharmacists. physician assistants. and are willing to listen. on average. amplify. he is telling you the diagnosis. Many doctors feel that their patients are not adept at telling a succinct story and that interruption is necessary to get through the appointment in the allotted time. when Osler said. 7. and summarize all critical factors providing the physician a concise. The use of headache diagnostic questionnaires. The use of intake forms. All of these guidelines recommend similar strategies for management of migraine (Box 1). We have found it helpful to have patients complete the forms prior to their first visit. This is particularly true for the headache patient. physicians who interrupted saved a maximum of 132 seconds. Establish a diagnosis Assess disability and other factors Educate patients about their condition and its treatment Establish realistic expectations Encourage patients to become active in their own care Develop an appropriate. (See Appendix 1. Beckman and Frankel found the average time that a patient was allowed to talk before being interrupted by the physician was 18 seconds. they usually spoke for no longer than 150 seconds. nurse practitioners. 2. and other health care professionals. . the ability to sit back and listen does not come easily to physicians. In more than 90% of cases. and impact assessments further increases efficiency and diagnostic accuracy. However. which may be further clarified by examination and diagnostic testing when necessary (8). and overall satisfaction (10). A nurse or other medical personnel can review. In a study of the effect of physician behavior on the collection of data. his or her compliance with the treatment plan. physician interruptions had a negative affect on the patient’s perception of the physician’s competence. when patients were allowed to tell their stories without interruption. comprehensive overview (Fig. the history will establish the diagnosis or lead to a differential diagnosis. Good history taking enhances mutual respect and trust between the patient and physician. Indeed. and improves care (7). ‘‘Listen to the patient. a team approach may be employed. which the patient can fill out prior to their initial evaluation leverages the busy physician’s time. nurses. and allows him/her to focus on the diagnosis and treatment. diaries. 3). 4. Therefore. and work with them. but also seek physicians who are genuinely concerned about their well being. Furthermore.242 Husid and Rapoport Box 1 General principles for headache management 1. .  Moderate or level 2 headaches interfere with the patient’s ability to function normally. Patients in our headache clinics are asked to differentiate the severity of their headaches on a 1 to 3 scale as follows:  Severe or level 3 headaches are those that render the patient totally or almost totally incapacitated (the patient would strongly prefer to be at bed rest). but are only partially incapacitating (patients would prefer to be medicated).Principles of Headache Management 243 Figure 1 Patient information and medical history form. 244 Husid and Rapoport Figure 1 (Continued) Mild or level 1 attacks are mild or dull, do not interfere with functioning, and may not be noticed when the patient’s attention is distracted. Many patients do not need, but still take medication for these milder headaches. For each headache type present, the following parameters are explored: 1. Age of onset and description of early/first headache 2. Frequency, pattern, and timing of attacks a. Previously (at onset) b. Currently Principles of Headache Management 245 Figure 1 (Continued) 3. 4. 5. 6. c. Mode of increase, gradual or sudden, for those patients who experienced an increase in the frequency over time Location and laterality of typical headache attacks (if unilateral, we ask if it is side-locked or alternating) Quality of pain during a typical headache attack (throbbing, stabbing, pressure, etc.) Duration of pain (with and without treatment) Presence and description of any premonitory features 246 Husid and Rapoport Figure 1 (Continued) 7. 8. 9. 10. Presence and description of aura Associated symptoms Provocative and relieving factors Postural relationships (postural relationships characteristic of high or low pressure headache syndromes may be lost with the passage of time—Saper J, personal communication) (9) 11. Behavior during headache (The new International Classification of Headache Disorders-2 lists aggravation by or causing avoidance of routine physical activity as a diagnostic criteria for migraine, and a sense of restlessness or agitation for cluster headache) 12. Trigger factors Principles of Headache Management 247 Figure 1 (Continued) 13. Presence of and time to recurrence, and how often it occurs 14. Past medications (including nonprescriptional medications). Our forms help collect information on: a. Name and type (brand or generic) b. Dose c. Frequency of administration d. Duration of administration and dates e. Routes of administration f. Effectiveness g. Side effects h. Allergies 248 Husid and Rapoport Figure 1 (Continued) 15. Current medications (for headache and other conditions). Information is collected similar to that described for past medications 16. Past medical history 17. Past surgical history 18. Family history of headache Principles of Headache Management 249 Figure 2 Physician summary sheet. 19. Habit history (including sleep, diet, exercise, smoking, and alcohol/ drugs) 20. Menstrual association and hormonal factors that may influence the headache 21. Psychosocial history As previously discussed, these forms are mailed to a new patient before his/her first visit. At the time of the first visit, a nurse reviews the information with the patient 250 Husid and Rapoport Figure 3 Summary face sheet for the patient information and medical history forms. for completeness and accuracy. For those patients who do not bring the forms, the nurse completes the forms based on the history provided (Fig. 1). Finally, after reviewing the forms, taking the patient’s history by himself/herself, and examining the patient, the doctor arrives at an initial diagnosis/differential diagnosis, determines the need for further testing, and develops the initial treatment plan, which we record on a summary face sheet (Fig. 3). Openness on the part of the physician during the history taking and examination is essential. One approach is to ask the patient to describe a typical day from the time he/she gets up in the morning to the time he/she goes to sleep (Sheftell FD, personal communication). One can get a very good idea about how someone manages his/her time, to what extent he/she is overwhelmed, and how much time he/she leaves for personal ‘‘me time.’’ It is not unusual to see a patient whose life Principles of Headache Management 251 is filled with demands and ‘‘taking care of everyone else,’’ who has no insight as to the extent of these demands and the negative effects that these demands have (1). Alternatively one can say ‘‘This must have really changed your life; how have you dealt with it?’’ as a means of gaining an insight into how headaches have affected the patient’s life and how well he/she has coped (9). A useful final question to ask is if anything has been left out that the patient feels is important or that would help to better understand his/her headaches. By the end of the initial consultation, the physician should not only have an idea in regard to diagnosis and initial treatment plan, but also a good sense of who this person i.e., the patient is (1). Of course, the nature of history taking will vary depending upon the setting (i.e. primary care vs. a headache specialist), the physician’s personal preferences and training, and the amount of time available. To assist in the rapid identification of patients with migraine in the primary care setting, a number of screening questionnaires have been developed. These questionnaires can be completed by the patient before his/her appointment, or in the examination room while waiting to be seen by his/her physician (see Chapter 12). As a follow-up to any of the headache questionnaires, the physician may make additional queries of the patient to confirm the diagnosis, as necessary, keeping in mind that while it is essential to exclude secondary disorders when determining diagnosis (see Chapter 11), a stable pattern of severe, recurrent, disabling primary headache is usually migraine. The Examination The general physical examination performed during the initial consultation for headache, should include at a minimum the following:  Vital signs  Cardiac status  Extracranial structures (sinuses, scalp, arteries, cervical paraspinal muscles, temporomandibular joints)  Thyroid  Range of motion and presence of pain in the cervical spine A screening neurologic examination capable of detecting most of the abnormal signs likely to occur in patients with headaches secondary to intracranial or systemic disease should include the following (7):          Signs of meningeal irritation (e.g., neck flexion) The presence of bruits over the cranium, orbits, or neck Optic fundi, visual fields, and pupillary reactions Sensory function of the trigeminal nerve, including corneal reflexes Motor power of the face and limbs Deep tendon reflexes Plantar responses Gait Mental status A complete examination includes appropriate evaluation of the patient’s mental status. A blunted, restricted, sad, or labile affect may indicate depression and anxiety. Evaluation for the presence of such disorders, including panic attacks, is 252 Husid and Rapoport important because they are comorbid in many patients with chronic daily headache. Cognitive disturbance is suggested by intrusive obsessional thoughts, and the inability to concentrate or provide a good history. Patients with posttraumatic headache may show significant deficits in concentration and memory, and may also have difficulty in performing complex tasks (1). Some simple tests can be useful in assessing cognitive fitness, such as asking the patient to subtract serial 7s, spell five-letter words forward and backward, or recall phone numbers. Screening for psychiatric comorbidity, particularly anxiety and depression, is important. Many centers use the Minnesota Multiphasic Personality Inventory (MMPI), the Hamilton Depression Scale, the Zung Anxiety and Depression scales, the Beck Inventory, or the Prime-MD (8). We routinely use the MMPI-2 for all new patients at our headache clinics, although other centers prefer briefer screenings. ASSESSING DISABILITY Pain is a subjective experience that is often difficult to express. Therefore, the greatest impact on diagnosis and treatment may come not from the patient’s description of pain intensity, location and characteristics, but from specific statements about function such as ‘‘Doctor, these headaches are causing me to miss three or four days of work each month’’ or ‘‘My headaches don’t allow me to care for my family several days a month’’ (10). Assessment of the disability is therefore a crucial part of headache management. The treatment proposal of several guidelines is based on the disability status. The most widely used headache disability tools include the Migraine Disability Assessment questionnaire and the Headache Impact Test (HIT-6). Tools for assessing headache severity and comorbidity are discussed in detail in Chapter 13. EDUCATING PATIENTS ‘‘Migraine is helped a good deal by some old remedies like hope, encouragement, recognition, attention, ventilation, education, and reassurance. These remedies need to be dispensed at each visit, along with others.’’ John Graham (11) Taking the time to educate the headache patient is particularly important because migraine has so many potential aggravating factors that, with the proper knowledge, the patient can control. Patients should be encouraged to lead their lives at a reasonable rate with a comfortable, predictable rhythm. The beneficial role of exercise and relaxation in mitigating headache should be stressed, and patients must be made aware of the correlation between certain activities such as skipping meals and not getting enough sleep and the physiologic responses that lead to triggering a migraine attack. Having patients keep a headache calendar enables them to track and eliminate these ‘‘trigger’’ behaviors. Table 1 lists the common headache triggers. Headache calendars will be reviewed in more detail later in this chapter. In addition, patients must be informed about the dangers of excessive use of pain medications. The most significant causative factor in the production of Principles of Headache Management Table 1 Potential Migraine Triggers Dietary Skipped/delayed meals Foods and Beverages Dairy Drugs Caffeine-containing beverages and medications Ilicit drugs Medications (cimetidine, danazol, diclofenac, digitalis, dipyridamole, disulfiram, H2 receptor blockers, hydralazine, indomethacin, nifedipine, nimodipine, nitrofurantoin, nitroglycerine, estrogen, reserpine, sildenafil, tadalafil, vardenafil, etc.) Endogenous Stress 253 Other exogenous Environmental factors Bright or flickering light Loud noise Changes in behavior Inconsistent sleep times Cured meats Caffeine (and caffeine withdrawal) Alcoholic beverages, especially red wine Sleeping more/less than usual Menstruation Fluctuation in hormonal levels (pregnancy, menopause) Weather changes Strong odors Certain chemicals Aspartame MSG Nitrites Abbreviation: MSG, monosodium glutamate. Source: From Refs. 8, 15–19. Benzene Insecticides Nicotine intractable headaches is the overuse of off-the-shelf medications, bultabital-containing medications, opiates, benzodiazepines, ergotamine tartrate, and occasionally even triptans. This condition was previously referred to as analgesic rebound headaches and, more recently, as medication overuse headache. Patients rarely respond adequately to preventive or acute-care medications or behavioral therapies until these agents have been withdrawn completely for a minimum of two months. As part of the educational process, the physician should also discuss the rationale for a particular treatment, how to use it, what adverse events are likely, what the expected benefits are, and when the patient can expect to see them. All medications may cause adverse effects, and patients must be informed of those that occur most frequently. Patients are usually willing to tolerate some side effects as long as they know in advance what to expect, how long they will last, and when to call for help. Providing medication handout sheets, with details on beneficial effects, adverse 254 Husid and Rapoport effects, and warning signs that should trigger a call for medical attention, helps to reinforce verbal instructions. Starting patients on low doses of acute and preventive medications and increasing the dosage gradually helps to minimize adverse effects and enhances patient compliance. General Care During Pregnancy and Lactation Special instructions are warranted for women with migraine of childbearing potential. They should be warned not to become pregnant while taking headache medication. If they plan to become pregnant, they should be encouraged to schedule an appointment to discuss management of their migraines during pregnancy. They should also be instructed to take 1 mg of folate daily to reduce the incidence of neural tube defects, as should any woman of childbearing potential. If a woman plans to breastfeed her infant, a discussion is held prior to delivery on which drugs are and are not compatible, and how to take triptans when breastfeeding (12). ESTABLISHING REALISTIC EXPECTATIONS Addressing the patients’ expectations is fundamental to reaching a good outcome. Establishing realistic expectations by setting appropriate goals and discussing the expected benefits of therapy and how long it will take to achieve them goes a long way in ensuring patient compliance. Ensure that the patient understands there are no magic remedies that will cure headaches forever (11). Although approximately 90% of patients with migraine can be helped substantially, our present incomplete understanding of the pathogenesis of migraine means there is no complete and permanent fix (3). Therefore, a practical goal of migraine treatment is alleviation and control of pain and substantial reduction of disability, rather than complete elimination of pain (11). One should avoid making assumptions about what brought the patient to the clinic. Each patient is an individual with his or her own concerns, fears, questions, and expectations. Packard notes that while a number of factors may contribute to a poor outcome, frequently it occurs because the patient’s expectations were never properly clarified or discussed, or they were not consistent with the physician’s. In a 1979 survey of 100 headache patients presenting to a general neurology clinic, he found that while two-third of physicians thought patients primarily sought pain relief, the patients themselves reported they were more interested in having the causes of the pain explained to them (13). Dr. Rapoport suggests asking ‘‘Why have you come for help at this time, and how would you like me to help you?’’ You might be surprised when the patient says, ‘‘I need a letter for my boss’’ or ‘‘my mother insisted I visit the doctor’’ or ‘‘I am worried my own physician missed a brain tumor.’’ ENCOURAGING PATIENTS TO BECOME ACTIVE IN THEIR OWN CARE Closely related to educating patients and establishing expectations is the idea of encouraging patients to become active in their own care. The physician must encourage the patient to assume control of his or her own migraine management. If the patient is not willing to do most of the work, and insists on looking for the magic pill (despite the setting of realistic expectations), headache relief may be hard to achieve. Dr. Saper likes to tell such patients, ‘‘Pills can take us a long way, but ’’ And. find headache calendars essential for effective headache management. The completed calendars are discussed with the patient at each revisit and form the basis for treatment decision. If patients repeatedly fail to comply with suggested lifestyle changes. therapeutic failure is likely. Figure 4 shows the blank calendar that we use for clinical purposes. They must also take responsibility for not running out of medication. menstrual cycles. When compliance issues are evident. In addition. medication intake. which automatically involves patients as active participants. Therefore. triggering events. Calendars require self-monitoring of symptoms and medication intake. and degree of relief from acute care medication on a calendar. .Principles of Headache Management 255 can’t fight your behaviors. and for following a mutually agreed-upon treatment plan. Figure 4 Patient headache calendar from The New England Center for Headache. HEADACHE CALENDARS Many physicians. patients should fully understand that without their active participation.’’ (11). the physician should challenge the patients to determine their motivation for behaviors that treat their body with such disregard (10). the information provided is enlightening to both patient and physician. Patients are asked to track the severity of each headache. including us. Just as diabetics must take responsibility for monitoring blood sugar and maintaining an appropriate diet. for calling at appropriate times. it is important for patients and physicians to jointly review obstacles to compliance and discuss the means for getting around them (8). ‘‘Pills can’t address that which you won’t do for yourself. so must headache patients take appropriate beneficial measures. They categorize their headache as mild—1. We use figure 2 to record this information. moderate—2. (ii) important exacerbating factors have been missed. Schedule Regular Follow-Up Visits As with other chronic illnesses that are manageable. symptomatology. intensity. The authors acknowledge that while some patients will remain refractory. the month. For example. . triggers. necessitating a change in the treatment plan. evening. and not the number of hours spent sleeping. When properly completed. it is not uncommon for the pattern of headaches (frequency. but then can often be withdrawn after 6 to 12 months of good control. and their personality. including unrealistic expectations and comorbidity. patients write their names. and grouped them into five broad categories: (i) the diagnosis is incomplete or incorrect. preventive medications may be needed during periods of high attack frequency.’’ and conclude. and impact) to fluctuate or change permanently. During this long period of time. and sleep time. duration. Zero represents no headache on this 4-point scale familiar to headache experts throughout the world. ‘‘Persistence in treating these patients can be very rewarding. The bottom of the calendar is for recording degree of headache relief. 5). response to acute treatment. Lipton and colleagues have summarized common reasons for treatment failure leading to referral to subspecialty headache centers. Migraine usually occurs over many decades of the patient’s life. (iii) pharmacotherapy has been inadequate. their likes and dislikes. INDIVIDUALIZED TREATMENT PLAN Each patient is unique and their treatment plan should be individualized to take into account all facets of their disease process. Potential trigger factors are listed on the back of the calendar. afternoon. (Headaches reported during sleep mean that patients have been awakened from sleep by headache. ‘‘this is a relatively small minority. and (v) other factors. the calendar presents an at-a-glance picture of headache intensity.’’ (14) (see Chapter 32). WHY HEADACHE TREATMENT FAILS Acknowledging that management of patients with headache disorders is often difficult. other medical problems and treatments. and menstrual days. and relationship between headaches and menses. (iv) nonpharmacologic treatment has been inadequate. They freely share their combined decades of personal experience successfully managing these ‘‘refractory’’ patients by providing an orderly approach for us to follow. or severe—3.) Medications are listed in spaces at the left side of the form. Days of the month appear at the top of the form and are divided into morning. regular follow-up visits are essential for successful long-term care (Fig. frequency.256 Husid and Rapoport On the calendar. and the year in the appropriate places. but not yet curable. exist. DEVELOPING AN APPROPRIATE. duration. and interference with family and . experiences for anyone who sees patients with headache disorders is to have a patient describe how their life has been ruined by headaches—through divorce.Principles of Headache Management 257 Figure 5 Revisit sheet. CONCLUSION One of the most poignant. and all too frequent. loss of jobs. Silberstein SD. Watson D on behalf of the MIPCA Migraine Guidelines Development Group. Saunders. 10. 9. Differing expectations of headache patients and their physicians. 13. Mesulam MM. theories. Bigal ME. New Guidelines for the management of migraine in primary care. Hamilton. Edmeads JG. Jackson: University Press of Mississippi. are what led many headache specialists to this field. 2004. New York: Oxford University Press. 57:493–507. 60:1064–1070. Pryse-Phillips WEM. Sender J. Approach to the patient with headache. 1988. eds. Conquering Headache: An Illustrated Guide to Understanding the Treatment and Control of Headache. New York: Churchill Livingstone. 4. Preston DC. Packard RC. 5th ed. et al. 11. Tepper SJ. 5. Dodick DW. Sheftell FD. Psychiatric Aspects of Headache. 1:551–566. eds. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review). Guidelines for the diagnosis and management of migraine in clinical practice. 2nd ed. Dalessio DJ.B. Philadelphia: W. 2. eds. . In: Patten J. Tepper SJ. Neurol Clin 1983. In: Silberstein SD. FURTHER READING (PATIENT EDUCATION RESOURCES) 1. Communicating with the patient. 2002:257–267. Wen P. Patten J. Lipton RB. Rees T. London: Decker DTC. In: Adler CS. Headache. Psychiatric Aspects of Headache. Sheftell F. 1996. 2nd ed. Spierings ELH. Their elation over how much better they feel diminished by the realization of how different their lives could have been if they had only found someone who knew and cared earlier. Adler SM. and answers. 2. Packard RC. Wolff’s Headache: And Other Head Pain. 156:1273–1287. Graham JR. 2003. Why headache treatment fails. Saper JR. Baltimore: Williams & Wilkins. Headache Disorders: A Management Guide for Practitioners. 1987:34–40. South V. In: Samuels MA. 8. Rapoport AM. 14. eds. Experiences like these. Establishing principles for migraine management in primary care. Headache in Clinical Practice. Silberstein SD for the US Headache Consortium. Goadsby PJ. Sender J. Neurological Differential Diagnosis. et al. 7. Sheftell FD. 1987:29–33. Dowson AJ. Packard RC. Lipton RB. Curr Med Res Opin 2002.258 Husid and Rapoport social responsibilities—only to learn that they have never been correctly diagnosed or appropriately managed. Can Med Assoc J 1997. Silberstein SD. 2001:599–606. Lipscombe S. REFERENCES 1. Dowson AJ. Neurology 2003. ed. 12. London: Springer-Verlag. Rapoport AM. 18:414–439. Office Practice of Neurology. Int J Clin Pract 2003. Rolak LA. 1996:1–5. Baltimore: Williams and Wilkins. Sudarsky LR. Adler SM. 3. Pessin MS. 2nd ed. Understanding Migraine and Other Headaches. Many such patients in our practices come in for their first revisit two to three weeks into therapy and tell us they are better than they have been in many years. New York: Churchill Livingston. 2004. Goadsby PJ. Neurology 2000. Feske S. In: Adler CS. Graham JR. which demonstrate the ability to dramatically improve the lives of people with migraine. London: Martin Dunitz. Lipscombe S. Sheftell FD. History-taking and physical examination. Raskin NH. Lipton RB. 6. The headache patient and the doctor. Migraine: questions. 1st ed. 1981. 2003. 1st ed. 2nd ed. Young WB. Breaking the Headache Cycle: A Proven Program for Treating and Preventing Recurring Headaches. Magee KR. Migraine and Other Headaches. Livingstone I.Principles of Headache Management 259 3. Saper JR. 4. 5. 2004. . New York: Henry Holt. New York: Fireside. Silberstein SD. Novak D. Freedom from Headaches. New York: AAN Press. Offer to prescribe preventive medications. 11. Adapt migraine management to changes that occur in the illness and its presentation over the years. who are resistant to acute medications or cannot take them due to contraindications. 2. 9. 8. Provide rescue medication/symptomatic treatment for when the initial therapy fails. 10. 6. Consider the patient’s comorbid illnesses in the choice of appropriate preventive medications. Use questions/a questionnaire to assess the impact of headache on daily living and everyday activities. preferably with migraine calendars or diaries. as well as suggesting lifestyle changes. Understand that almost all headaches are benign/primary and can be managed by all practicing clinicians. . Provide individualized care for migraine and encourage patients to manage their own migraine. 4. for diagnostic screening and to aid management decisions. when pain is mild). Follow-up patients. an international advisory board of headache specialists reviewed published guidelines for the management of migraine in primary care and agreed on the following 12 evidence-based principles (11): 1. 5. 7. 12. even if the pain is controlled by acute care medication. Reevaluate the success of therapy regularly using specific outcome measures and monitor the use of acute and preventive medications. Work with patients to achieve comfort with mutually agreed upon treatment and ensure that it is practical for their lifestyle and headache presentation. or who have very disabling migraines. to patients who have four or more migraine attacks per month. 3. Provide migraine specific acute medication to all migraine patients and recommend they be taken at the appropriate time during the attack (early. Share migraine management between the clinician and the patient.260 Husid and Rapoport APPENDIX 1 In 2003. It is argued that community interventions can play a significant role in a public health approach to the secondary prevention of chronic headache disorders. and reduce headacherelated disability and affective distress. Finally. and via mass media such as the Internet and television are described. a brief overview of the evidence base that supports the effectiveness of behavior therapy for adult and pediatric migraine is provided. as well as to limit reliance on poorly tolerated or unwanted pharmacotherapy. programs for teaching behavioral migraine management skills in community institutions such as schools and the workplace. Athens. Next. although behavioral headache management skills also may be used to abort headaches and to cope with headaches that do occur.A. BEHAVIORAL INTERVENTIONS Behavioral interventions focus on the prevention of headaches. Educational interventions to improve the response of the health-care system to migraine are then described. Relaxation Training Relaxation skills (1) enable headache sufferers to exert control over specific headache-related physiological responses and to lower physiological and mental 261 . The goals of behavioral treatment are to increase personal control over headaches. Holroyd Psychology Department. Behavioral treatments and the clinic and home-study formats for administering these treatments are described first. INTRODUCTION This chapter provides an overview of behavioral and educational interventions for the management of migraine. reduce the frequency and severity of headaches.S. U. Ohio University.19 Behavioral and Educational Approaches to the Management of Migraine: Clinical and Public Health Applications Kenneth A. Ohio. (iv) pain-coping strategies for living with migraine that continues to occur. and in increasing headache-related disability.g. thoughts. progressive muscle relaxation. Biofeedback Training Thermal (hand warming) feedback. and are components or consequences of headache (3–5). Additional treatment components include (i) education about headaches and the principles of behavioral migraine management. and to most effectively use. and. and whenever they notice mental or bodily signs of tension or signs signaling headache onset. as they are able to master increasingly brief relaxation techniques (cue-controlled relaxation and self-control relaxation). and feelings prior to the onset of headaches. are the most commonly used biofeedback modalities. for 30 seconds) throughout the day. feedback of skin temperature from a finger. and to render the patient less vulnerable to stress-related negative effect. they are encouraged to integrate their use of self-regulation skills into their daily routine in the same manner as described above for relaxation skills. then. thereby controlling stress and other negative effects. as they master the physiological self-regulation skills. The goal is to teach patients to ‘‘catch’’ stress-generating thoughts. and sometimes the upper body. Patients monitor the circumstances in which their headaches occur. but as components of an intervention for teaching the self-management of headaches (4). including their bodily sensations. and (v) the .262 Holroyd arousal. feedback of electrical activity from muscles of the scalp. Cognitive targets may be stress-generating thoughts or an underlying belief or assumption that distills the common meaning or theme from many stress-generating thoughts. the patient and counselor collaboratively identify and challenge dysfunctional cognitions. although electroencephalographic (‘‘neurofeedback’’) biofeedback with the goal of teaching self-regulation of cortical excitability has received recent attention (2). neck. Patients are instructed to practice a graduated hierarchy of relaxation techniques (diaphragmatic breathing. to relax briefly (e. and meditation) initially for 20 to 30 min/day.. Cognitive-Behavior (Stress Management) Therapy Cognitive-behavior therapy addresses cognitive and affective variables that may increase vulnerability to headaches and precipitate headaches. (ii) exercises to assist the patient in identifying migraine triggers and early migraine warning signs. migraine medications. Once headache-related stressful situations are identified. the above three treatments are not used in isolation. Patients are instructed to use a home biofeedback-training device or to practice the self-regulation skills they are learning during clinic-based biofeedback training sessions for about 20 to 30 min/day. and electromyographic (EMG) feedback. Cognitive behavioral interventions direct patients’ attention to the role their thoughts and behavior play in generating stress (and stress-related headaches). relaxation imagery. Integration of Treatment Techniques Typically. (iii) instruction on how to evaluate the effectiveness of. but requires more frequent clinic visits. Home-based and clinic-based treatment formats have yielded similar outcomes when compared directly (7–9) or when compared via a metaanalysis of 13 studies (10). in some instances. and. substituting weekly phone calls for the mix of monthly clinic visits and phone calls described above. and 60 to 120 minutes in length. a supportive home environment (11). Clinic visits introduce each new headache management skill and address problems encountered in acquiring or implementing these skills. This treatment format provides more health care–provider time and attention. Telephone supervision of a home-study program has the potential to greatly increase the availability of behavioral treatment because neither clinic visits nor a local behaviorally trained clinician is required. Lipchik et al. and allows the provider greater opportunity to directly observe the patient than a home-based treatment format. Home-Based Treatment Home-based treatment typically involves only three to four (monthly) treatment sessions. (4) and Blanchard and Andrasik (5) provide detailed descriptions of limited-contact treatment. 45 to 60 minutes in length. and can be administered in a clinic-based (clinician-administered) treatment format. TREATMENT DELIVERY Treatment can be administered either individually or in a group. home study requires a motivated patient.12) in the third trial. Clinic-Based Treatment Clinic-based treatment typically involves 6 to 12 weekly sessions. if treatment is administered individually. three successful trials (11–13) have entirely eliminated clinic visits. only phone contact with a clinician. with younger children (7–12 years old). However. See Lipchik et al. (4) for a more detailed treatment description. In two trials with adolescents. Information is needed about appropriate candidates for home study. Descriptions of clinic-based treatment are available in Blanchard and Andrasik (5) for individual treatment.Behavioral and Educational Approaches to the Management of Migraine 263 development of a migraine management plan. Monthly phone calls allow the clinician to address problems that arise in home-based learning and in the application of headache management skills. for children and adolescents. . and about the optimal design of home-study programs. and Scharff and Marcus (6) for group treatment. or in a home-based treatment format that involves more limited ‘‘face-to-face’’ clinician contact. In a logical extension of the above home-based treatment format. including a plan for coping with any reoccurrence of headaches following treatment. home-study programs used workbooks and audiotapes (11. or. The learning of migraine management skills occurs primarily at home and is guided by patient manuals and audiotapes. an interactive computer program–guided home study was followed (13). if treatment is administered in a group. S.’’ Figure 1 Effect size with 95% confidence interval (top axis) and percent reduction in migraine (bottom axis). EMG-BF. cognitive-behavior therapy.264 Holroyd EFFICACY Adults Evidence reviews prepared by Duke University’s Center for Clinical Health Policy Research examined the efficacy of behavioral. thermal biofeedback combined with relaxation training. TBF þ RLX. Abbreviations: CBT. The U. It can be seen that each behavioral intervention produces moderate reductions in migraine activity. Figure 1 presents both the estimated effect size and the percentage reduction in migraine for four widely used psychological treatments. EMG biofeedback. reviewing 70 trials and including 39 trials in a meta-analysis (14). and cognitive-behavioral therapy may be considered as treatment options for the prevention of migraine. thermal biofeedback training plus relaxation training. control. physical. relaxation training. RLX. and pharmacological treatments for migraine in adults. electromyographic biofeedback training. Headache Consortium clinical guidelines for the management of migraine (15. Source: From Ref.16) drew primarily on this evidence report in concluding ‘‘Relaxation training. headache-monitoring control. 14. . an effect size of 1 or greater can be considered clinically significant. meta-analysis provides the best method of comparing the effectiveness of these two treatment modalities. Holroyd et al. on an average. CBT. A comparison of thermal biofeedback training results from four pediatric (N ¼ 49) and six adult (N ¼ 103) trials indicated that children achieved greater control of hand temperature (5. Nearly identical outcomes were reported with propranolol and thermal biofeedback training: each treatment yielded. Because propranolol provides a good proxy for the effectiveness of . INTEGRATING DRUG AND BEHAVIORAL TREATMENTS Adults In the absence of trials that directly compare the effectiveness of drug and behavioral therapies. Pediatric Migraine in children and adolescents appears to be more responsive to behavioral treatment than migraine in adults. (19) compared results reported in 25 preventive drug (propranolol) therapy trials and in 35 thermal biofeedback/relaxation trials that included over 2400 patients.Behavioral and Educational Approaches to the Management of Migraine 265 Figure 2 Within group effect sizes (outliers removed) with 95% confidence interval. whereas (pill) placebo yielded only a 14% reduction in migraine activity. cognitive-behavior therapy. 34% decrease. for one study (12).9% increase) and larger reductions in migraine activity (62% vs. To illustrate. p < 0.5% vs. a 44% reduction in migraine activity when daily diaries were used as the outcome measure. Abbreviations: TBF. Although the mean effect sizes in Figure 2 do not translate directly into equivalent headache improvement values. thermal biofeedback training. relaxation training. Figure 2 presents results from a meta-analysis of 17 trials of behavioral treatments in pediatric migraine (18). RLX. 18. 3.02) than adults (17). and an effect size of about one corresponds to 44% of adolescents showing clinically significant reductions in migraine. an effect size of about two corresponds to 66% of adolescents showing clinically significant (50% or more) reductions in migraine. Source: From Ref. Two trials that examined the benefits of adding propranolol (60 mg to either 120 or 180 mg/day) to relaxation/biofeedback therapy found that propranolol significantly enhanced the effectiveness of relaxation/biofeedback training (24. Fortunately. though the high dropout rate from biofeedback training alone (38% of patients) raises the possibility that outcomes in this trial were compromised because of poor patient compliance (26). three recent cohort studies (N ¼ 54–497) have evaluated the implementation of group headache education programs in staff model health maintenance . asthma. possibly because migraine is not commonly recognized as a chronic disease. in some cases. but only 42% of children who received metoprolol. Little information about the effectiveness of preventive drug therapies for pediatric migraine is available. propranolol and placebo did not differ in effectiveness. disability.266 Holroyd preventive medication in general (19–23). recorded clinically significant reductions (50% or more) in migraine. in one of these trials (25). these results suggest that relaxation/ thermal biofeedback and preventive medication are about equally effective in the management of episodic migraine. and current concerns about long-term preventive drug therapy in children and adolescents. Given the lack of side effects associated with behavior therapy. available evidence suggests that behavior therapy may be at least as effective as drug therapy for pediatric migraine. propranolol was more effective than relaxation/biofeedback training. should be a first-line treatment for pediatric migraine. In contrast. education for self-management has largely been ignored in the headache literature. effective in controlling migraines. One trial with children (mean ¼ 11 years) (29) found a 12-session relaxation/stress-management treatment more effective than metoprolol (50–100 mg/day). and about as effective as the combined treatment. Pediatric Current clinical guidelines for drug therapy in pediatric migraine (27) conclude that there is inadequate data to judge the effectiveness of available preventive medications for pediatric migraine. behavior therapy. EDUCATION FOR SELF-MANAGEMENT Educational interventions designed to help individuals manage chronic diseases such as arthritis. have been effective in reducing symptoms. 80% of children who received relaxation/stress management. but not preventive drug therapy.25). and diabetes. and. medical costs (31–35). However. However. and chronic conditions such as low back pain. A second trial with children (6–12 years old) (30) found relaxation training with self-hypnosis more effective in reducing migraines than propranolol (3 mg/kg/day) or placebo. including relaxation/thermal biofeedback training. a similar evidence-based review of behavioral therapies concluded that there is adequate data to indicate relaxation training is effective and thermal biofeedback training is probably effective for pediatric migraine (28). However. Only two trials have directly compared behavioral and preventive drug therapies for pediatric migraine and both trials found behavior therapy. with the exception of flunarizine (not available in the United States). and even less information is available about the relative effectiveness or combined effects of drug and behavior therapies. Moreover. group education produced significantly greater improvements in headaches and headache-related disability than medical treatment alone.g. . Three 90-minute headache education classes (didactic instruction about migraines and migraine treatment. and in the degree the education program was integrated with other HMO services. stress management). Community interventions have the potential to reach the 50% of individuals with migraine who do not seek conventional medical treatment (45. and improved satisfaction with headache care (38) also were reported. Reduced headache-related visits (36. COMMUNITY APPLICATIONS Programs for teaching behavioral migraine management skills in the community have the potential to play an important role in a public health approach to migraine. including transformed migraine and medication overuse headache. by enabling individuals to acquire behavioral migraine management skills early in the ‘‘course’’ of their migraines. it is recommended that investigators draw on theoretical guidance from social learning theory and on the body of experience that has been obtained implementing selfmanagement programs for other chronic diseases. fewer unscheduled headache clinic visits. and aggravating factors) that also provided opportunity for participant-initiated discussion was integrated with an individual treatmentplanning visit. medical management.g. current self-management interventions seek to foster confidence in the application of both specific disease management skills and general problem-solving skills (31. net cost savings (36).42). and fewer physician phone calls than medical treatment alone. In designing future educational interventions. Group education also was associated with less acute medication use. further. plus opportunity for discussion) were coled by individuals with migraine who had received leadership training. a one-session group headache education program (e. headache recording. Participants experienced primarily chronic (15 day/mo or more) migraine. types of headaches.. controlled effectiveness studies of headache education are needed. Guided by social learning theory (41. transformed migraine. community interventions may also play a role in the secondary prevention of chronic headache disorders. well-designed headache education program can improve the response of the HMO environment to migraine. triggers. At a six-month evaluation.. Consistent findings across three different HMO settings suggests even a brief.43. In each study. implementation of the headache education program was associated with improvements in headache-related disability (severe headaches or standard measures of disability) and reductions in the number of headache-related emergency department visits (34–79%.38). pathophysiology. The three education programs varied in the attention devoted to behavioral change (e.46). These results provide a strong argument for the further development and evaluation of educational interventions to facilitate self-management of chronic headaches. In the single randomized trial to date (39). Fundamental to the notion of education for self-management is the observation that it is the individual who must solve problems that arise in managing and in adapting to their chronic disease in specific daily life situations (40). M ¼ 54%). better medication compliance. 100 consecutive patients at a university-based headache clinic were randomized to medical treatment by a headache specialist.44). In each case. or medical treatment plus group headache education.Behavioral and Educational Approaches to the Management of Migraine 267 organization (HMO) settings (36–38). and/or medication overuse headache. Sweden for 20 years. respectively). breathing/relaxation exercises (19% vs. group relaxation–training program. Unfortunately. This is surprising. and modified diagnosis based on a computer algorithm).g. . Methods of teaching school personnel the clinical skills necessary to effectively administer relaxation training will be needed if behavioral headache management programs are to be offered to the large number of adolescents with recurrent headaches in the school setting. but more impressive reductions in the number of visits to the urgent-care/emergency department for headache (1. in fact. and. The ‘‘Managing Headache in the Workplace Program’’ consists of an informational slide show.5–4 headache days per month).268 Holroyd School Larsson et al. nor a self-help relaxation–training program that included a relaxation manual and audiotapes of relaxation instructions proved similarly effective (only 13% and 17% of students clinically improved. an increased use of behavioral headache management skills. neither school nurse–administered nor self-help relaxation– training programs were more effective than psychological placebo. and written handouts. 34% of participants).P. and communicating with physicians) and access to an onsite neurologist. neither a relaxationtraining program conducted by a school nurse. Schneider et al.. Worksite Worksite interventions have received little empirical attention. and health promotion programs capable of offering programs for headache management are available in many corporations. have taught relaxation skills for the management of headaches in secondary schools in Uppsala. The program provided individualized summaries of headache information (e. who found that relaxation training conducted by school gym instructors was similarly ineffective (48). A summary of the seven relaxation-training trials (N ¼ 228. follow-up data further indicated improvements were maintained for at least 6 to 10 months (47). aggravating factors. also provided generic information on headache management (e. high attrition (51%) between the baseline and follow-up assessments compromised this evaluation. given that lost productivity costs due to headache are estimated at $20 billion in the United States (49). coping with headaches. age 10–18 years) (47) revealed that clinically significant (50% or more) improvements in migraine were obtained in about half (52%) of the students who participated in a 6.42 visits in six months).to 10-session.g. Data from users (N ¼ 177) at a three-month follow-up indicated small but statistically significant reductions in headache days (5. 40% at follow-up). likely triggers. such as keeping a headache diary (11% of participants at baseline vs. Morgan offices in both New York and Delaware. School-based group relaxation training—at least when administered by a behaviorally trained clinician—appears effective in managing migraines for many adolescents. at the New York sites. biofeedback. and regular exercise (20% vs. 39% of participants) were reported. At a one-month follow-up evaluation completed by 75% (of 492) program participants in both office and factory settings. therapist-administered. This was accompanied by significant reductions in headache-related disability on standard disability measures. (50) used multimedia touch screen computer kiosks to deliver a headache management program at J. Unfortunately. This finding is echoed by the second research group.74–0. or simply having students record their headaches. neurologist-led small group discussion session.. Internet Initial efforts to teach behavioral headache management skills via the Internet have been modestly effective. Approximately 15. the 164 participants who completed the program evaluation recorded. the outcome was assessed in only a small sample (N ¼ 271) of participants. Second-generation programs undoubtedly will make more sophisticated use of these capabilities. 10 accompanying radio programs provided an opportunity for participants to hear solutions to representative problems encountered by other program participants. a 50% average reduction in the frequency of headaches. recorded clinically significant (50% or more) reductions in migraine activity. The primary beneficiary of first-generation Internet programs has probably been the highly motivated. Almost 40% of users who completed the migraine management program. The strong public interest in this program. these programs have demonstrated that Internet-based treatment does enable some users to effectively manage their migraines. with uncomplicated headache problems. possibly offered as a part of an ongoing worksite health promotion program. and the preliminary . in addition. chat rooms) (56) or to tailor treatment to the user’s learning style and progress in the program. It is important to identify who learns behavioral migraine management skills via the Internet and to assure that Internet treatment ‘‘failure’’ does not discourage participants from seeking future treatment. could produce significant benefits for both the employee and the employer. However. for example.. However. The online program (downloadable treatment manual and audio files and e-mail communication with a behavioral clinician) was adapted from muscle relaxation and hand-warming materials successfully used in earlier ‘‘offline’’ home-based migraine treatment studies (55).8) years of computer experience. over 40% of participants failed to complete the program. Dropouts reported less severe headaches. than those who completed treatment. but only 6% of controls. Television A series of television programs in the Netherlands on managing headaches best illustrates population-based behavioral headache management (57). Initial Internet-based behavioral migraine management programs have yielded modest results. computer-literate user. the capability to provide support (e.5 days of lost work-time over four months. even when telephone contact has been added to reduce drop outs (51–54). and fewer (2. Unfortunately.Behavioral and Educational Approaches to the Management of Migraine 269 These pilot studies raise the possibility that relatively simple on-site or Web-based behavioral migraine management education programs. particularly when program dropouts are taken into account. initial programs have not made use of the full capabilities of the Internet. but plagued by high (up to 50%) drop out rates. smaller improvements. The best study to date (53) randomized 156 participants from more than 10 countries (who reported a physician diagnosis of either migraine or tension-type headache) to either Internet-based treatment or a delayed treatment control group. on an average.3 vs.000 participants purchased home-study materials (workbook and three audio cassettes) that presented a variety of relaxation and cognitive behavioral skills for managing headaches. However.g. nonetheless. 3. One TV program was devoted to teaching each headache management skill. Controlled trials of worksite headache management interventions are clearly needed. and a reduction of about 4. Dalessio DJ. J Consult Clin Psychol 1983. NY: Pergamon Press. 1985. 51:743–751. and in some individuals. Lipchik GL. 3. progressive in form. New York: Guilford Pubs. Cognitive-behavioral management of recurrent headache disorders: a minimal-therapist contact approach. Jurish SE. 2. Marcus DA. Haddock CK. Wilson PG. ACKNOWLEDGMENTS Support for this review was provided. and will play a central role in any public health approach to the secondary prevention of the chronic and severe forms of migraine that are of growing concern. Behav Ther 1984.270 Holroyd positive-outcome data raise the possibility that behavioral headache management skills can be effectively taught to a large audience via the mass media. 6. 2002:356–389. Biofeedback: A Practitioner’s Guide. 10. 9. 2000. Gatchel RS. CT: Praeger. 7. Hazlett-Stevens H. REFERENCES 1. eds. Jurish SE. Arena JG. Interdisciplinary outpatient group treatment of intractable headache. Rowan AB. Talcott GW. Blanchard EB. . Figure 2 was prepared by Kathleen Romanek. Nash JM. New York. 5. Behavioral management of recurrent headache disorders. Andrasik F. Recent findings indicating that more severe and chronic forms of the disorder may be associated not only with neuroplastic changes in pain transmission/modulation circuits but also with worrisome neurodegenerative change have drawn attention to a long ignored topic—prevention.versus clinic-based treatment of vascular headache. Teders SJ. Borkovec TD. in part. Holroyd KA. McGrath PJ. Relaxation training for tension headache: comparative efficacy and cost-effectiveness of a minimal therapist contact versus a therapist delivered procedure. Schwartz MS. Home-based behavioral treatments for chronic benign headache: a meta-analysis of controlled trials. 15:59–70. Lipton RB. Headache 1994. Andrasik F. Blanchard EB. New Directions in Progressive Relaxation Training: A Guidebook for Helping Professions. CONCLUSION Migraine is a lifetime disorder for many. 29:352–357. Neff DF. Lipchik GL. It has been argued here that behavioral and educational interventions have a significant role to play in a comprehensive approach to the clinical management of migraine. eds. 34:73–78. Scharff L. NY: Oxford University Press. Elmsford. Andrasik F. 17:113–118. Neff DF. Penzien DB. Blanchard EB. In: Turk DC. New York: Guilford Press. 4. Management of Chronic Headaches: A Psychological Approach. Headache 1989. Andrasik F. Cephalalgia 1997. 2001:562–598. 8. Westport. Arena JG. 2003. Teders SJ. Jana Drew provided comments on an earlier draft of this manuscript. Cognitive-behavioral therapy for migraine headaches: a minimal-therapist-contact approach versus a clinic-based approach. Holroyd KA. Home. Wolff’s Headache and Other Headache Pain. Andrasik F. In: Silberstein SD. Psychological Approaches to Pain Management. by a grant from The National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS # NS32374). Stein RJ. Richardson GM. Bernstein DA. Rosenberg J. Newman S. Silberstein S. 22. Von Korff M. Rapoff M. McGrath PJ. et al. Holroyd KA. Drew J. 2001. 251:943–950. 36:1155–1170. Yonker M. Holman H. Pain 1995. Self-management education: history. 19. et al. Thompson N. 31:333–340. Ann Behav Med 2003. Olness K. J Pediat Psychol 1999. 20:325. Practice parameter: pharmacological treatment of migraine headache in children and adolescents. Dahlof C. Gibson J. 24:91–109. Technical Review 2. Duke Center for Health Policy Research (prepared for Agency for Health Care Policy and Research). 12. Collaborative management of chronic illness. 364:1523–1537. 79:593–597. Gray R. Seim J. outcomes. 4:256–262. Ann Intern Med 1997. 17. 127:1097–1102. O’Donnell F. Laurent D. Uden DL. Headstrong: a pilot study of a CDROM Intervention for recurrent pediatric headache. Levy JD. 288:2469–2475. Silberstein S. Arch Neurol 1993. Sobel D. Arch Neurol 1997. Effect of a self-management program on patients with chronic disease. Ziegler D. Mathew NT. Hassanein R. Hirtz D. Empirically supported treatments in pediatric psychology: recurrent pediatric headache. Blanchard EB. Lewis D. Headache 1986. Grumbach K. McCrory D. Vol. Humphreys P. Patient self management of chronic disease in primary care. Tfelt-Hansen P. Headache. Ann Behav Med 2000. 25. Hobbs M. Campbell JK.2. Headache 1981. Muller B. 54:1553–1554. 33. Penzien DB. Holroyd KA. France JL. 50:825–830. Verapamil and propanolol in migraine prophylaxis: a double-blind. 21. Kaniecki R. Holroyd KA. 29. 15. JAMA 2002. Connelly M. Propranolol in the management of recurrent migraine: a meta-analytic review. 16. 34. 63:2215–24. Connely W. 1999. Neurology 2000. 18. 2003. Gruman J. Bodenheimer T. Keene D. Steed L. : US Headache Consortium. Wagner EH. 24. Holden EW. 35. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with pronalolol as an active control. Penzien DD. Behavioral and Physical Treatments for Migraine Headache. Holroyd K. Telephone administered behavioral treatment of adolescent migraine: a feasibility study. Goehring P. Propanolol and amitriptyline in prophylaxis of migraine.Behavioral and Educational Approaches to the Management of Migraine 271 11. Eff Clin Pract 2001. 54:1141–1145. J Neurol 2004. 23. Behavioral and pharmacological intervention studies of pediatric migraine: an exploratory meta-analysis. 20. Curry SJ. Headache 1991. Pain 1992. crossover study. Age comparisons in acquiring biofeedback control and success in reducing headache pain. Enhancing the effectiveness of relaxation/thermal biofeedback training with propranolol HCI. 63:327–330. Pediatrics 1987. et al. Pothmann R. Lancet 2004. 32. Multispecialty consensus on diagnosis and treatment of headache. Lorig K. Sarafino E. 49:321–324. 70:656–677. 60:239–256. J Consult Clin Psychol 2002. Hermann C. 31. A comparison of psychological and pharmacological treatment of pediatric migraine. 13. A comparison of divalproex with pronanolol and placebo for the prophylaxis of migraine without aura. Mulligan K. Holman H. Cottrell C. Self-management interventions for chronic illness. J Pediat Psychol 2005. MacDonald JT. and mechanisms. The efficacy and efficiency of a selfadministered treatment for adolescent migraine. Comparison of self-hypnosis and propranolol in the treatment of juvenile migraine. Metsch J. definition. 2000:Vol. Goslin R. Preskorn S. Ritter P. Neurology 2004. Sartory GM. Kim M. 26:1–7. Evidence-Based Guidelines for Migraine Headache: Behavioral and Physical Treatments. Cordingley G. Hershey A. 26. Deichmann MM. Cordingley GE. Beh Res Ther 1998. Diener H-C. Lorig K. Wall EM. Lorig K. 21:105–109. Prophylaxis of migraine and mixed headache: a randomized controlled study. Ashwal S. In press. 14. 30. . 28. J Consult Clin Psychol 1995. Hurwizt A. Schaefer J. Assessment and psychological treatment of recurrent headache disorders. Solomon G. 27. 22:10–16. Beh Res Ther 2005. 55. Passchier J. Groenman NH. Reynolds R. Tobin D. Verhage F. J Pediat Psychol (in press). A controlled trial of self-help treatment of recurrent headache conducted via the Internet. Andrasik F. Orlebeke JF. 51. Laurent D. Van den Bree MBM. Parada V. Lorig K. Walters N. Headache 2001. 43:353–361. 48. 38. Jurgelski A. Sims C. Fichtel A. Morganstein M. 30:660–664. 53. Key K. Strom L. Blumenfeld A. Reed M. New York: Academic Press. McGrath P. Hicks C. Schneider WJ. 1986. 43:621–627. 42. Health Educ Q 1992. Andersson G. Stewart W. Blanchard EB. Diamond M. Rothrock J.H. Lipton R. 47. Headache 2003. The integration of theory with practice: a 12-year case study. de Bruin-Kofman AT. Minor M. Relaxation training in school classes does not reduce headache complaints. 403:431–440. Chee E. Online psychological treatment for pediatric recurrent pain: a randomized evaluation. von Baeyer C. 40. Creer T. Sorbi MJ. Holroyd K. A controlled trial of self-help treatment of recurrent headache conducted via the Internet. Headache 2005. The impact of Intensive patient education on clinical outcome in a clinic-based migraine population. Lorig K. New York: W. JAMA 2003. Headache 2003. Zweifler R. Maizels M. Impact of a group-based model of disease management for headache. 49. 43:277–292. Devineni T. 45:692–701. CNS Drugs 2002. Furth PA. 37:415–420. Relaxation treatment of adolescent headache sufferers: results from a school based replication series. Wirjo J. Allegrante J. 43. Marnell M. 37. Bernstein A. Samsa G. 1986. 46. 45. 162:792–796. Lorig K. Ann Intern Med 2002. Headache 2003. Ricci JA. Tischio M. 56. In: Holroyd K. 1997. 41. J Occup Environ Med 1999. Headache (in press). Blanchard E. Emmen HH.S. Blalock TH. Carlsson J.272 Holroyd 36. 41:638–645. Lost Productive time and cost due to common pain conditions in the U. 68:722–727. A randomized controlled trial of an internet-based treatment for chronic headache. 57. 52. Bandura A. Marks R. Appelbaum KA. Headache 1990. 290:2443–2454. Strom L. Matchar D. Larsson BM. . Osterhaus SOL. Peterson R. Headache 1985. van de Wiel H. Self-management of Chronic Disease: Handbook of Clinical Interventions and Research. Center of excellence for headache care: group model at Kaiser Permanente. Self-Management of Chronic Disease: Handbook of Clinical Interventions and Research. workforce. Global trends in migraine care: results from the MAZE survey. New York: Academic Press. 44. Freeman. Shipley J. Effects of a mass media behavioral treatment for chronic headache: a pilot study. Headache 2003. 19:355–368. 25:214–220. non-drug treatments of chronic migraine and tension headache. Self-management and social learning theory. 6:37–43. Diamond S. Can a back pain e-mail discussion group improve health status and lower health care costs? A randomized study. Ritter P. Saenz V. Holroyd KA. Health Promote Pract 2005. J Consult Clin Psychol 2000. Creer T. eds. Headache management program improves outcome for chronic headache. The efficacy and cost-effectiveness of minimal-therapist-contact. Lipton R. Headache 1997. 41:868–871. 54. 43:715–724. Andersson G. Migraine diagnosis and treatment: results from the American Migraine Study II. 16:13–18. A review and synthesis of research evidence for self-efficacy-enhancing interventions for reducing chronic disability: implications for health education practice. Sherrill TA. 50. Creer T. Harpole L. Lundstom P. 39. Stewart W. Self-efficacy: The Exercise of Control. A pilot study of a headache program in the workplace. Brandes J. et al. Klip E. Deyo R. Melin L. Examples are aspirin. New Haven. short-acting barbiturates. Instituto de Neurologia. However. speed of onset. especially when administered orally. and sensory phobias. and other pharmacological agents. Headache Center of Rio. In addition. the efficacy of some nonspecific migraine agents.S. vomiting. The nonspecific treatments for migraine attacks are the subject of this chapter. In addition. Acute migraine treatments are often divided into specific and nonspecific categories. such as the triptans and ergots. nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore. to study these compounds is necessary to analyze their efficacy in relation to specific medications. opioids. Rio de Janeiro. such as various NSAIDs. the degree of incapacitation (disability or impact). INTRODUCTION The objective of acute migraine therapy is to restore the patient to normal function by rapidly and consistently alleviating the head pain and the associated symptoms of nausea. consistent. The choice of a medication for migraine depends on individual characteristics such as headache intensity. and Department of Neurology. does not always result in rapid. Yale University School of Medicine. relieve migraine but are generally ineffective on noncephalic pain. triptan monotherapy.20 Nonspecific Migraine Acute Treatment Abouch Krymchantowski Outpatient Headache Unit. neuroleptics. presence of associated symptoms. Nonspecific agents are effective across a broad range of pain disorders not linked to migraine. has been demonstrated in many trials (5). These combinations often include caffeine. Tepper The New England Center for Headache. the use of drugs that target other symptoms besides pain (such as nausea) has been suggested for treating migraine attacks as well. and complete relief of all migraine attacks as desired by patients (4). Several drug options and different formulations are available to treat migraine acutely. U. ideally without side effects and recurrence of the attack within 24 hours (1). It may be argued whether it is still valid to suggest beginning acute treatment of migraine with nonspecific migraine medications in the era of the triptans. the 273 . Migraine-specific medications. Brazil Stewart J. Connecticut. Stamford. acetaminophen (APAP) (and other simple analgesics).3). and Deolindo Couto. and the patient’s response (2. and combination analgesics.A. In the mid-1970s. after most of the studies on ASA were conducted. Tfelt-Hansen and Olesen demonstrated that 1000 mg of ASA was as effective as 1000 mg of APAP in treatment of migraine (7). and the primary end point was pain relief (also called headache response or headache relief) (moderate to severe pain was reduced to mild or no pain within two hours of treatment) at two hours. and then treat three attacks. sumatriptan 100 mg was superior to ASA/MCP. not available in the United States) plus 10 mg MCP versus sumatriptan 100 mg over two attacks. but due to the differences with regard to dosages and formulations. The primary end point was headache relief at two hours after treating moderate to severe pain in the first attack. Recurrence over 48 hours was higher with sumatriptan than ASA/MCP (42% vs. the efficacies were comparable. SIMPLE ANALGESICS The efficacy of acetylsalicylic acid (ASA) and APAP (called paracetamol in some countries) is well established in the acute treatment of migraine. 33%). In the first study. an injectable form of lysine ASA became available in some countries for various pain conditions (not available in the United States). The second study was a comparison of lysine ASA 900 mg (LASA.10). such as APAP plus codeine. ASA was compared to other oral nonspecific antimigraine preparations. No information on four-hour relief or pain-free results was published. Dipyrone (not available in the United States but widely used worldwide) was also proven effective for migraine attacks (6). Several recent studies showed that oral aspirin is more effective than placebo in the treatment of migraine and associated symptoms (9. ASA has been studied in tablet form (doses ranging from 500 to 1000 mg) and also intravenously. this time for either attack. patients were instructed to wait until they had moderate to severe pain. In several controlled trials. Aspirin Although ASA has anti-inflammatory activity and antinociceptive properties. a data not statistically significant. It was studied . or ergot alkaloids. but six-hour complete relief (migraine free) was higher for sumatriptan in all three attacks (11). a few studies with ASA are worthy of evaluation in migraine. the various study results remain comparatively inconclusive (8). In the first attack. and the appropriate strategy for selecting acute migraine medication to maximize the likelihood of getting to the right treatment the first time. Nonetheless. There was no significant difference between the LASA/MCP and the sumatriptan. four-hour headache relief and pain-free data were not published (12). As with the previous study. Two randomized controlled studies compared 100 mg sumatriptan with 900 mg ASA plus 10 mg metoclopramide (MCP). In the second and third attacks. it is generally grouped with the analgesics. Migraine free at two hours and recurrence over 24 hours were statistically the same for LASA/ MCP and sumatriptan. In 1980.274 Krymchantowski and Tepper possibility of increasing the treatment efficacy by combining more than one drug. It is worth remembering that standardized migraine trial designs were first established in the early 1990s. Overall. headache relief occurred in 45% of the patients taking ASA/MCP compared to 56% of those taking sumatriptan. the combined use of APAP 1 g with 20 and 30 mg of domperidone (an antinauseant not available in the United States) proved to shorten the duration of a headache attack from 17 hours (when used with placebo) to 12 hours. Thus. 250 mg aspirin. the studies on AAC for acute migraine treatment are not as strong methodologically as those suggesting effectiveness for triptans. and phonophobia were significantly improved in both groups of female migraineurs.05). when used with both dosages of domperidone (21). With regard to pain severity. photophobia.5 to 6 hours (p 0. The combination of AAC was also evaluated for menstrually related migraine (MRM) in a post hoc analysis of 1220 subjects (16).01) than in the group with menstrually related attacks. a population of migraineurs for whom over-the-counter (OTC) medications were appropriate (15). functional disability. as noted above. and 781 women with treated migraine not associated with menses. photophobia.18). the evidence for effectiveness in the acute treatment of migraine is not equivalent for AAC and the triptans. while in the triptan studies. it was superior to placebo. As a result. as soon as 0. nausea. In comparative trials. when APAP was used alone. less disabling migraine attacks. an NSAID. the proportion of responders was significantly greater (p 0. In the OTC medication studies. as well as for the parameters of functional disability. 89 were randomized to the AAC and 83 to placebo. when both were used with 10 mg MCP (20).01) for AAC than placebo. vomiting. as effective as nonoral ergotamine. but not vomiting during more than 20% of their attacks and not presenting severe attackrelated disability (requiring bed rest for more than 50% of their attacks) were included in this analysis. and 65 mg caffeine. Most studies taken into consideration enrolled patients with less severe.5 hour postdose through six hours (p 0. Acetaminophen APAP was evaluated in combination with MCP and in combination with codeine (17. At all time points from one to six hours (p 0.01).S. it was no better than placebo (19). the migraine characteristics of functional disability. In three large-scale placebo-controlled studies. From one hour and continuing through six hours postdose. . In another study. Both groups also demonstrated significant relief of pain intensity over placebo. 1220 patients either with migraine without aura or migraine with aura were preselected as efficacyevaluable subjects. Among them. and less severe attacks). and phonophobia were rated at baseline and at several time points after medication. low disability. they were preselected using strict and nonstandard inclusion criteria. The end points of pain intensity. each containing 250 mg APAP. p 0. and phonophobia in which the AAC group responded significantly greater than placebo from two to six hours postdose. In both trials. these patients took two tablets of AAC. Once the pain reached moderate or severe intensity.Nonspecific Migraine Acute Treatment 275 for migraine attacks and proved to be superior to placebo. patients were selected to mimic the population that uses OTC medications more often (reduced frequency of vomiting. and less effective but better tolerated than subcutaneous sumatriptan (13). subjects with low frequency of attacks or mild severity of pain are often excluded.05). who had greater nausea relief than the placebo group at six hours postdose (p 0. Headache Consortium guidelines have suggested that aspirin/APAP/ caffeine (AAC) is effective for moderate-level migraine (14). However. The U. Nausea was relieved sooner in women with migraine not related to menses (two hours postdose. photophobia. 172 patients suffering from migraine. Of these patients. The study included 185 women with treated MRM.05). AAC was superior to placebo from 0. However. APAP 500 mg was not significantly different from mefenamic acid. The first among the so-called new NSAIDs studied was tolfenamic acid. another member of this group. The dosages of naproxen ranged from 750 to 1250 mg and that of naproxen sodium ranged from 825 to 1375 mg.23). tolfenamic acid) and propionic acid class (e. The headache severity as well as the consumption of escape medications was lower in the active-drug group compared to placebo (25. and was superior to both placebo and APAP. In a trial comparing the efficacy of rectal ketoprofen (not available in the United States) and ergotamine in maintaining the working capacity.276 Krymchantowski and Tepper Dipyrone The pirazolonic derivative dipyrone (metamizol).g.35). the rapid release form of 200 mg tolfenamic acid was as effective as 100 mg sumatriptan for headache relief at two hours in two attacks treated. It was tested in the treatment of migraine during the late 1970s. Other nonsteroidal propionic acids such as flurbiprofen. which may belong to different chemical groups. For the acute treatment of migraine attacks.g. with similar efficacy to ASA and ergotamine (22.26). photophobia. The adverse events were similar among the patients using placebo and metamizol (6). such as rheumatoid arthritis. This was confirmed by self-assessment cards and reports of patient’s preferences. In addition. was tested in migraine attacks and was shown to be superior to placebo and APAP (34. which were superior to placebo. placebo-controlled design. The tolerability of injectable diclofenac is similar to placebo (36).32). has been studied for both migraine with and without aura in its intravenous (IV) formulation in a randomized. IV dipyrone was also effective in reducing the duration of the aura in the patients receiving it. As it is one of the few NSAIDs also available for intramuscular (IM) injection in most of the world. double-blind. there were no statistically significant differences between rapid-release tolfenamic acid. naproxen) have been proven effective in randomized controlled studies (5). With regard to recurrence. both were effective and superior to placebo (30). In general they are effective in various inflammatory conditions. When compared to APAP for the treatment of migraine attacks in children. and phonophobia.. The pain-free rates at two hours also revealed nonsignificant differences between the active treatment groups. diclofenac sodium was also evaluated for migraine in this parenteral formulation and showed efficacy when compared to placebo. ketoprofen. the NSAID demonstrated superiority (33). Other NSAIDs that may be used parenterally are ketorolac (available in the United States) and lysine clonixinate (not available in the United States). Ibuprofen. It was found to be highly and quickly effective in its analgesic action as well as in working against the associated symptoms of nausea. Nonsteroidal Anti-inflammatory Drugs There are numerous types of NSAIDs currently used in clinical practice. most of the anthranilic class (e. but not the United States. an inexpensive simple analgesic frequently used in some countries (not available in the United States). an NSAID derivative of acetic acid. In addition. Both were also .. and placebo with percentages ranging from 13% to 27% in all groups treating the first and second attacks (24). The propionic acid derivative naproxen and its more quickly absorbed formulation naproxen sodium were both superior to placebo in treating migraine attacks. was more effective than placebo in dosages ranging from 800 to 1200 or 400 mg as an arginine salt (not available in the United States) (27–29). Diclofenac. sumatriptan. and pirprofen (not available in the United States) were also evaluated in acute migraine treatment and proven superior to placebo and APAP (31. In another study.43. The tolerability of this compound is acceptable. a COX-2 inhibitor is effective in the treatment of migraine. injectable formulations of NSAIDs have been shown highly effective even for severe attacks. Rofecoxib. derived from nicotinic acid and resembling flufenamic acid. despite its effectiveness in reducing head pain and consumption of escape medications when it was used for moderate headache (37). the use of lysine clonixinate IV 200 mg (not available in the United States) was significantly superior to placebo in providing pain-free status and reducing escape-medication use after 60. uncoupling properties of oxidative phosphorylation at supratherapeutic concentrations. However. indomethacin is not commonly encountered in reviews of migraine treatment. MEDICATIONS FOR THE TREATMENT OF NAUSEA During migraine attacks.44).38). especially when combined with MCP. and 25 mg chlorpromazine intravenously (41). indomethacin is not commonly used for therapy as an analgesic or antipyretic because of the high incidence of side effects. Lysine clonixinate. is warranted. 90. as well as higher serum levels within the first 30 minutes after administration. The further development of new formulations. Although indomethacin has been recommended for mild to moderate migraine attacks (47). It has prominent antiinflammatory activity and its analgesic–antipyretic properties are more potent than that of aspirin. inhibition of the motility of polymorphonuclear leukocytes. and depression of the biosynthesis of mucopolysaccharides (46). through inhibition of prostaglandin-forming cyclooxygenase (COX). nausea and vomiting may cause additional suffering and discomfort during headache . placebocontrolled. gastric stasis with consequent delayed absorption of orally administered drugs may impair the treatment response of some patients. except for a higher propensity for severe gastrointestinal consequences such as ulcers and bleeds (38. 100 mg meperidine plus 50 mg hydroxyzine (40). but significantly more patients had mild adverse events with active drug than those who used placebo. and 120 minutes in severe migraine attacks (45).Nonspecific Migraine Acute Treatment 277 effective in treating migraine attacks when given orally (37. which may enable even faster absorption for the oral NSAIDs. However. The efficacy of NSAIDs in the treatment of migraine is unquestionable. Different trials with various dosages and formulations have also demonstrated efficacy orally. Despite its widespread clinical use and known efficacy. In addition. The patients also had significantly better performances with regard to nausea and sustained pain free with the combination. ketorolac 30 mg administered intravenously was superior to 20 mg sumatriptan nasal spray (42). although it is considered safe and has an acceptable profile of tolerability (49). outpatient trials (50). lysine clonixinate 250 mg was not superior to placebo in those patients with severe migraine headache. In its oral form. as demonstrated by one published and one unpublished double-blind. in comparison to 25 mg sumatriptan suppository for moderate or severe migraine attacks (48). it has been withdrawn from the market worldwide due to cardiovascular concerns. also proved effective for migraine attacks (not available in the United States). In addition. The profile of adverse events for ketorolac is similar to other nonsteroidal anti-inflammatory agents. and 60 mg IM ketorolac was found as effective as 75 mg meperidine plus 25 mg promethazine (39). it has proved to be superior to sumatriptan only when used in combination with prochlorperazine and caffeine in a small dose of 25 mg in suppository formulation. As of this writing. A recent randomized controlled trial compared high doses of IV MCP (ranging from 10–80 mg. In one study (70).52–56). or 10 mg intramuscularly for prochlorperazine.21. Prokinetic agents (mostly acting peripherally and as agonists of 5-HT4 receptors or antagonists of 5-HT3 receptors such as ondansetron. both in an open (72) . and therefore fall below the expectations of patients and physicians (64. and adrenergic actions as well (63). which can be used in doses ranging from 25 mg orally or 25 mg intramuscularly for chlorpromazine to 10 mg orally. they may also promote the absorption of antimigraine therapies that otherwise would pass slowly through only the gastrointestinal tract during a migraine attack (51). Up to 31% of patients taking sumatriptan discontinue its use due to lack of efficacy. was also studied in combination with the then available COX-2 selective inhibitor rofecoxib. 25 mg rectally. they are still far from providing optimum efficacy and sustained pain-free measures. and MCP was at least as effective as sumatriptan (64). and promethazine (also used as histamine H1-receptor antagonists) have been also used as medications to combat nausea and vomiting in acute migraine treatment. chlorpromazine. 240 moderate or severe attacks were treated with 100 mg sumatriptan and 200 mg of tolfenamic acid resulting in a decreased recurrence rate from 62. although they may have auxiliary antipain effects in migraine as well (59–62).5% to 23. COMBINATIONS OF NSAIDs AND TRIPTANS Although triptans provide a tremendous positive impact on patient care and clinical practice. and alosetron) and dopamine receptor antagonists may therefore be of value in the management of these migraine symptoms. cyclizine. Both drugs were better than placebo. The combination of a triptan plus an NSAID reduces recurrence in clinical practice and may be more efficacious than the single use of both agents. which occurs in migraine. is promoted by conditions that ‘‘prime’’ visceral afferents by decreasing intestinal motility and slowing gastric emptying (51). Dopamine and reduced cholinergic transmission may be involved in these processes of gastrointestinal hypomotility and delayed gastric emptying. In fact. mean around 40 mg) with subcutaneous sumatriptan 6 mg. headache recurrence.5% compared to the use of sumatriptan plus placebo (p < 0. trimebutine (the latter two medications not available in the United States) have been used as migraine acute therapies. and/or side effects (66–69). domperidone. As noted above. another 5-HT1B/1D agonist. the combination of 100 mg sumatriptan and 550 mg naproxen sodium significantly reduced recurrence from 59% to 25. In a second study. and. The severe nausea and vomiting accompanying migraine attacks may represent one of the reasons for the utilization of these neuroleptics.8% (70). granisetron.65). either as starting medications or in conjunction with triptans and/or NSAIDs (10. Rizatriptan. as well as the muscarinic receptor antagonists diphenhydramine.278 Krymchantowski and Tepper attacks (51). although the mechanisms by which they may work in monotherapy remains unclear despite the hypersensitivity of dopamine receptors in migraine patients (57. histaminic. In addition. recently. and thiethylperazine (the latter medication not available in the United States). cost. therefore emesis. the mechanism of action of the neuroleptics in migraine may be more than their antidopamine activity and extend to serotonergic.0003) (71). Neuroleptics such as prochlorperazine. MCP.58) (see section on ‘‘Neuroleptics’’). and drowsiness.87).84). while another study analyzing this combination with proper methodology did not demonstrate effectiveness against placebo (86). Other oral combinations of APAP þ codeine þ buclizine þ dioctyl sodium sulfosuccinate were compared to placebo as well.75). and remain in bed for at least two hours after it has been given. Prochlorperazine is another neuroleptic with proven efficacy in migraine. One study. lidocaine (50 mg). a mu-opioid agonist plus APAP (325 mg) was compared to placebo in a randomized. IV haloperidol has been recently suggested for severe refractory migraine attacks in the emergency department. double-blind. the combination of 10 mg rizatriptan plus 50 mg rofecoxib was more efficient than rizatriptan alone. and improvement of sustained pain-free measures over the treatment with a single option. or as the combination of rizatriptan plus 200 mg tolfenamic acid. In the controlled study. some of these compounds are powerful alpha-adrenergic and dopaminergic antagonists. receive the administration of 400 to 500 mL of saline before the infusion of the drug. Therefore. based on a small open study (82). sedation.80).5 mg in comparison with placebo. The dosage ranges from 0. and may be better tolerated than chlorpromazine (60). NEUROLEPTICS IN THE TREATMENT OF PAIN The phenothiazine derivatives exert different actions in migraine. it is recommended that the patients have an IV catheter. even in emergency departments (74. 400 mg APAP þ 25 mg codeine and 650 mg APAP þ 16 mg codeine were both superior to placebo (17.1 to 0. Chlorpromazine may cause severe postural hypertension. Its use as an IV injection of 10 mg was superior to placebo as well as to MCP (10 mg) (79. Recurrence was also significantly reduced with both combinations in comparison to rizatriptan alone. did not use a double-blind design (85). These studies suggest the advantage of combining a triptan with an NSAID with regard to efficacy. In addition to an analgesic effect. Studies conducted in migraine patients found efficacy of IV chlorpromazine in doses of 0. and its derivatives represent the members of this group used in clinical practice.83. The combination of tramadol HCl (37.7 mg/kg and can be repeated after 30 to 60 minutes if necessary (76–78). This may render additional efficacy in migraine headache and nausea. For headache patients. thebaine (not available in the United States).5 mg). codeine. placebo-controlled multicenter study evaluating 154 patients who took the active drug and 151 patients who took placebo. but also has implications in tolerability. different codeine-containing oral combinations have been studied. Prochlorperazine may be administered in 25 mg suppositories as well (81). The dosage was 75 mg tramadol þ 650 mg APAP.4 mg/kg). OPIOIDS The opium derivatives used in migraine belong to the alkaloid group known as phenanthrenes. and ergotamine (1 mg) (76–78). which showed superiority over placebo. Morphine.1 mg/kg and 12. making these drugs less attractive for routine use. . meperidine (0.Nonspecific Migraine Acute Treatment 279 and in a controlled design (73). reduction of recurrence. and after two hours. In migraine. Other comparisons between codeine-containing combinations and ASA 1000 mg or ergotamine 2 mg þ cyclizine 50 mg þ caffeine 100 mg did not show statistically significant differences (83. Finally. IM meperidine 75 mg was evaluated against IM ketorolac 60 mg and showed significantly better efficacy over ketorolac after one hour (92). Only two studies.102). Meperidine (75 mg) þ promethazine (25 mg) IM were tested against ketorolac (60 mg) IM. In addition. 34%. The drugs were not significantly different. moderate. Headache relief was defined as a reduction of four or more units on a scale of 0 to 10 in specific time points. the following recommendations were made by the U. The pain intensity was assessed after 45 minutes and chlorpromazine was significantly better than meperidine þ dimenhydrinate (p < 0.022) through six hours (p < 0. comparing the efficacy of sumatriptan or eletriptan with ergotamine tartrate þ caffeine showed the triptan to be unequivocally superior to a comparator drug (101.24.S.280 Krymchantowski and Tepper significantly more patients on the combination achieved pain relief (56% vs.96–100).4 mg/kg þ dimenhydrinate IV was compared with chlorpromazine 0. and both reduced the headache intensity at 60 minutes. In a very elegant review. Parenteral opioids may be considered a choice only in a supervised setting and again sedation will not put the patient at risk and/or the risk for abuse has been addressed’’ (14. Oral opioid combinations may be considered when sedation will not put the patient at risk and/or the risk for abuse has been addressed. In another study. Interestingly.93). The nasal spray of butorphanol (1 mg) was tested against placebo and methadone (10 mg IM) in 96 patients. mild. seven studies did not demonstrate differences favoring the triptans in regard to the primary end points (12.1 mg/kg IV in 15-minute interval dosages to a maximum of three doses. and comparisons made between the triptans and other nonspecific treatments do not always support the superiority of triptans (94). despite clinical practice experience supporting the better effectiveness of the triptans. The clinical trials generally do not reflect the favorable experience with triptans in clinical practice. or severe). double-blind studies. Meperidine (100 mg) þ hydroxyzine (50 mg) IM were compared with ketorolac (60 mg) IM. pain relief was superior among tramadol/APAP patients from 30 minutes postdose (p ¼ 0. However. no significant difference between these two treatment options was observed (39). Transnasal opioids have also been suggested for the acute migraine treatment. although both were effective in reducing headache intensity (91).001) (78). . Headache Consortium: ‘‘Nasal butorphanol is a treatment option when other medications can’t be used or as a rescue medication when severe sedation is not a critical issue for the patient. Nine studies were eligible and most used primary end points of pain relief and pain free at two hours using a four-point categorical pain scale (none. Meperidine 0. which compared an oral triptan with a drug belonging to another pharmacological class and used the criteria of the International Headache Society (IHS) to define migraine (95). Opioids were also compared with NSAIDs. At one hour. there was no significant difference between the two treatment options (40). randomized. After considering the above data.001).85. remains controversial. Butorphanol 2 mg IM was compared to meperidine 75 mg þ hydroxyzine 50 mg IM. p < 0. Parenteral opioids are frequently used for migraine in emergency departments. Butorphanol was superior to both placebo and methadone (89). butorphanol (1 mg) yielded headache relief in two hours in 60% of the patients compared to 18% of the placebo group (90). SPECIFIC TREATMENTS The decision on whether to use a nonspecific treatment or a triptan. analyzed all prospective. NONSPECIFIC VS.001) (88). Lipton et al. in JAMA in 2000. with the more disabled patients receiving triptans first. However.Nonspecific Migraine Acute Treatment 281 These results are inconsistent with clinical practice among experienced headache physicians. One approach is to measure disability. described three strategies for treating diagnosed acute migraine. and stepped up across attacks or in the same attack.’’ ‘‘Step care within attacks’’ (also called ‘‘Staged Care’’). although triptans provide vastly superior efficacy in comparison to nonspecific agents (103). and Stratified care. and ‘‘Stratified Care’’ (104). then step up to an opioid. the clinician is still often faced with the decision whether to begin treating a migraine patient with a triptan or a combination of nonspecific treatments first. not ASA/ MCP and presumably comparable nonspecific treatments. The strategy for deciding nonspecific versus triptan therapy should be stratified care based on disability. this decision was based on common sense but not randomized prospective evidence. The third strategy is stratified care. they are not associated with rapid and complete relief of migraine pain in all patients (64). a study published by Lipton et al. It may be recommended that the patient use this medicine on several attacks. An example of this would be starting with naproxen sodium. and patients without medical contraindications and with more than 10 days of at least 50% disability in the last three months should be given triptan therapy at the outset as their first medication for acute treatment.. gives strong evidence that a stratified approach yields optimal clinical outcome (104). and then if it fails. as opposed to the step care strategies. . Prior to 2000. which suggests that. which he called ‘‘Step care across attacks. usually another nonspecific drug. time loss. Stratified care was superior to step care across attacks and step care within attacks for headache response at one and two hours. This may go on until a medication works. 1). or the doctor finally steps up to a specific medication. or the patient lapses from care. Stratified care was significantly superior for headache relief over Step care across attacks at four hours as well. nonspecific treatment first (Fig. for many patients. If this medication fails to abort the headache satisfactorily. Thus. after the migraine has progressed. the physician will then ‘‘step up’’ to the next drug. and so forth. All primary end points were superior with stratified care as the strategy for treatment. the least expensive nonspecific medication is selected by the physician for the patient to use first. Step care across attacks. Lipton et al. after surveying various approaches to acute migraine treatment. and the patient returns to see the same physician after these treatment failures. Step care within attacks involves starting with a nonspecific medication at the beginning of a migraine attack. The most critical decision for the clinician is deciding which approach will result in the best outcome for patients. or impact as a surrogate marker of disease severity and give triptans to the more disabled patients and nonspecific medications to the less disabled. then a mixture of ASA plus MCP or ASA plus APAP and caffeine. and finally to a triptan. and the question is how to select the right treatment the first time for acute treatment. having the patient take a triptan at that point. However. the DISC study has yielded prospective evidence for matching disability to treatment. defined as matching treatment to a patient’s characteristics or the characteristics of the disease. The Disability in Strategies of Care (DISC) study is the only randomized prospective comparison of Step care between attacks. generally a triptan. In Step care across attacks. and the less disabled patients. The triptan is used as a rescue. drives the choice for specific agents that may or may not be used in combination with another pharmacological class. In a patient presenting with attacks rapidly progressing with frequent nausea and vomiting.282 Krymchantowski and Tepper Figure 1 Treatment strategy for migraine attacks based on disability assessment. the way drug options are used probably may represent the difference between success and ineffectiveness in treating these patients across multiple attacks. . CONCLUSIONS Although the existence of accumulating evidence corroborates the efficacy of some nonspecific therapies for the acute treatment of a migraine attack. the combination of these serotonergic agonists with an NSAID (and perhaps with a gastrokinetic drug as well) seems to provide better outcome on efficacy measures. Individual preference as well as population differences must be taken into account clinically. In addition. The strategy of considering the disability for that specific patient. such as NSAIDs. despite the fact that superiority was not always demonstrated in the few controlled trials comparing triptans with some of the nonspecific pharmacological agents. along with the frequency in which it is provoked. along with the synergy of combinations. Rather. to maximize benefit for our patients. clinical practice suggests that specific treatment options are better. The variation of routes in which drugs are employed may also represent a better path to obtain more consistent pain relief. the rectal administration of indomethacin plus the subcutaneous use of sumatriptan can provide pain-free rates much faster than conventional orally taken drug options. Cephalalgia 2004. ed. Analgesics. Tfelt-Hansen P. 19:684–691. Lasserre V. Graham AN. disabling migraine attacks in an over-the-counter population of migraine sufferers: results from three randomized. 17:30–43. 346:923–926. In: Diener HC. Cephalalgia 1999. et al. 7. Bussone G. Clin Cornerstone 2001. Mulder LJ. Limmroth V. 4:36–52. Placebo-controlled comparison of effervescent acetylsalicylic acid. and caffeine: results from three randomized. Neurology 2000. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. Paracetamol (acetaminophen) versus acetylsalicylic acid in migraine. Headache 2002. Goldstein J. 45(4):283–292. Headache 2005. 16: 282–287. Quiring JN. Delecoeullerie G. for the US Headache Consortium. 24(11):947–954. Boureau F. Limmroth V. Tfelt-Hansen P. 1993:359–362. Henry P. 42(suppl 1):3–9. 18. 10. 9. Diener H-C. Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen. New York: Raven Press. Lancet 1995. Intravenous dipyrone in the acute treatment of migraine without aura and migraine with aura: a randomized. 19:545–551. Lipton RB. de Liano H. Prioritizing treatment. Goadsby PJ. Przywara S. et al. Yataco AR. 16. Olesen J. Rose AJ. Dexter SR. Clin Ther 1999. In: Olesen J. Cephalalgia 1994. double-dummy. Acetylsalicylic acid in the treatment of headache. placebo-controlled studies of the combination of acetaminophen. EMSASI Study Group. Wilkinson MIP. Eur Neurol 1992. Br J Clin Pract 1985. double blind. Bordini CA. et al. Lipton RB. Scheldewaert RG. Treatment of migraine with isometheptene. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. 8. Hoffman HD. Diener HC. Tepper SJ. 19:163–165. 2. aspirin. 14. Monogr Clin Neurosci 2000. Silberstein SD. Tfelt-Hansen P. Hamelsky SW. A Study to Compare Oral Sumatriptan with Oral Aspirin plus Metoclopramide in the Acute Treatment of Migraine. 11. Bigal ME. 17. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. placebo controlled study. Lipton RB. Johnson ES. 3. Chazot G. 21(3):475–491. Headache 1976. The efficacy and safety of Acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the cute treatment of migraine. Welch KMA. 42(9):862–871. Treatment of severe. randomized multicenter parallel group study. Cephalalgia 1999. 13. cross-over trial. Aspirin is efficacious for the treatment of acute migraine. eds. Eur Neurol 1980. Acute and prophylactic management of migraine. 39:388–392. What do patients with migraine want from acute migraine treatment? Headache 2002. Double-blind comparison of an acetaminophen 400 mg-codeine 25 mg combination versus aspirin 1000 mg and placebo in acute migraine attack. Katsarava Z. Silberstein SD. N Engl J Med 2002. 5. 6. Lipton RB. 12. 19. Goldstein J. acetaminophen and dichlorphenazone combination: a double-blind. Schoenen J. sumatriptan and ibuprofen in the treatment of migraine attacks. 55:754–763. 4. Ratcliffe EM. 32:177–184. Armellino JJ. Doubleblind controlled study of Paramax in the acute treatment of common and classical migraine. Tfelt-Hansen P. Migraine–current understanding and treatment. 15. Drug Treatment of Migraine and Other Headaches. Dodick DW. Diener HC for the ASASUMAMIG Study Group. . 19(6):581–588. 346:257–270. Dayno JM. Prum B. Sorrentino JV. Joubert JM. Ferrari MD. The Headaches. 14:156–161. Cephalalgia 1999. Baggish JS. Speciali JG. placebo-controlled studies. and caffeine. Hoffman HD. aspirin. A double-blind.Nonspecific Migraine Acute Treatment 283 REFERENCES 1. Armellino JJ. Diamond S. Hoppu K. 48:103–107. Arq Neuropsiquiatr 2001. Gothoni G. 2:173–177. Turner L. 32. Am J Emerg Med 1995. Bjorkman R. 29:507–509. Headache 1989. Hakkaranainen H. Drugs 1997. Brogden RN. Poggioni M. . 22. Franchini S. placebo-controlled study. Oral lysine clonixinate in the acute treatment of migraine: a double-blind. 15:44–48. Havanka-Kanniainen H. 34. Ketorolac. Gothoni G. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. 32:492–497. Cephalalgia 1991. Partinen M. Efficacy of flurbiprofen in the treatment of acute migraine attacks: a doubleblind cross-over study. 37. placebocontrolled. Nestvold K. Guidotti M. Herrala L. Treatment of acute migraine attack: naproxen and placebo compared. Hakkaranainen H. Domperidone plus paracetamol in the treatment of migraine. Duarte C. Naproxen sodium in the treatment of migraine. acetylsalicylic acid and a dextropropoxyphene compound in acute migraine attacks. Lancet 1979. Davis CP. Stockman O. Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: a randomized. 13: 145–150. Headache 1978. 17:48–54. A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks. Bancroft K. Nappi G. Krymchantowski AV. J Int Med Res 1989.284 Krymchantowski and Tepper 20. Torre PR. 53(1):139–88. 59:46–49. Garagiola U. Kangasneimi P. Wilkinson M. Parantainen J. Bousser MG. Vilming ST. J Int Med Res 1987. 21. Double blind comparison of mefenamic acid and acetaminophen (paracetamol) in migraine. randomized.59–63. 18:145–150. 21:1116–1121. Ann Emerg Med 1992. Cephalalgia 1993. 38. cross-over study. 35. Frederick R. 28. 231:551–554. Kloster R. MacGregor EA. 3:129–134. Awidi AS. Sandrini G. Tolfenamic acid is as effective as ergotamine during migraine attacks. Granella F. Effectiveness of oral diclofenac in the acute treatment of common migraine attacks. 25. Treatment of acute migraine attack: ibuprofen and placebo compared. Cephalalgia 1985. 30. 26. 12:169–171. Myllyla VV. randomized. 23. 2:326–328. Alves LA. Sulkava R. Headache 1998. 13:117–123. Wilkinson M. Cephalalgia 1985. Nestvold K. Kloster R. Ketoprofen and ergotamine in acute migraine. Massiou H. Curr Ther Res 1982. Vapaatalo H. 29. Int J Clin Pharmacol Res 1998. et al. Del Bene E. 5:5–10. 39. Cheim C. Lanfranchi S. A comparative trial of ergotamine tartrate. Serrurier D. Rose FC. parallel-group study. J Intern Med 1992. Lassere O. Dahlof C. Gillis JC. Garagiola U. Ibuprofeno or acetaminophen for the acute treatment of migraine in children: a double-blind. Santavuore P. 13:124–127. prospective. controlled. Cephalalgia 1983. Cephalalgia 1982. 40. Valkeila E. Zanasi S. Gustafsson B. a double-blind study versus placebo. Hamalainen ML. Manzoni GC. Williams C. et al. Pirprofen in the treatment of migraine and episodic headache attacks: a placebo-controlled cross-over clinical trial. Johnson ES. Maresca V. 5:115–119. 11. Petty RG. 31. Barbosa JS. Neurology 1997. Diclofenac-K (50 and 100 mg) and placebo in the acute treatment of migraine. 33. Tolfenamic acid rapid release versus sumatriptan in the acute treatment of migraine: comparable effect in a double-blind. Effectiveness of ibuprofen-arginine in the treatment of acute migraine attacks. double-blind trial. Hakkaranainen H. Vapaatalo H. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Parantainen J. Ratcliffe DM. Havanka H. Tolfenamic acid and caffeine: a useful combination in migraine. 27. Cephalalgia 1993. Kaaja R. Dunaway F. Cephalalgia 1992. Peatfield RC. 24. Aldag J. 36. Intramuscular treatment of migraine attacks using diclofenac sodium: a cross-over clinical trial. 18:35–39. 38:201–207. 49. Dahlof CG. randomized. Brewer KL. JAMA 1989. Limbird LE. 6:49–54. Treatment of migraine with intramuscular chlorpromazine. 44. Drugs effective in the treatment of migraine. prochlorperazine. Walker AM. Dose. 61. McEwen J. 16:758–763. double-blind. Intravenous lysine clonixinate for the acute treatment of severe migraine attacks: a double-blind. 60. Waelkens J. Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicenter. New York: McGraw-Hill 1996. Cephalalgia 2001. Ippolito FM. 45. Singh R. Olshaker JS. 51. et al. Limbird LE. 9th ed. Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. 156:1725–1728. Am J Emerg Med 2003. New York: McGraw-Hill 1996. prokinetic. White W. McClellan DS. Rizatriptan vs. 59. Pathophysiology and pharmacology of migraine. Sklar D. Tepper S. Hayes JE. Dopamine and migraine. Maliekal J. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Neurology 1997. Moreira PF. Krymchantowski AV. Brandes J. doubleblind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Tfelt-Hansen P. Joire JE. 64(8):505–513. 42. Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache. Di Monda V. 18:593–604. 9th ed. cross-over. randomized. Franco E. 62:1552–1557. 48. placebo-controlled study. A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine. and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter. Bridge between prophylactic and abortive treatment of migraine? A dose-finding study. placebo-controlled study [abstr]. 56. Jones K. Chabriat H. 4:85–90. Arthur DC. Danchot J. Headache 1983.Nonspecific Migraine Acute Treatment 285 41. placebo-controlled study. 21(3):173–175. efficacy and tolerability of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua. Traversa G. Headache 2003. The Headaches. Tfelt-Hansen P. Allen CL. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Ann Emerg Med 1990. 47. 53. et al. Philadelphia: Lippincott Williams & Wilkins. Wilhoit T. Bigal ME. et al. 49(3):650–656. eds. Moreden J. Arch Intern Med 1996. Antiemetic. Grippon P. 57. 261:1174–1176. 27: 617–657. Bousser MG. Cephalalgia 1984. Waelkens J. randomized. Krymchantowski AV. Gastrointestinal toxicity of different nonsteroidal anti-inflammatory drugs. Tek DS. 21(9):906–910. crossover trial. Amery WK. Aloisio A. Ann Emerg Med 1987. Dinsdale H. neuroleptic. 54. Is there a place for antiemetics in future treatment strategies? Cephalalgia 1998. Headache 2004. Nicolodi M. eds. Insel PA. Efficacy of a fixed combination of indomethacin. et al. 55. Wait S. 49(1):201–206. Cephalalgia 1994. 19:1083–1087. Randomized. Dopamine blockade with domperidone. Lipton RB. 29:698–701. Gastrointestinal complications associated with intramuscular ketorolac tromethamine therapy in the elderly. rizatriptan plus trimebutine for the acute treatment of migraine: a double-blind. Meredith JT. Jones J. 43:835–844. 2000:445–452. In: Olesen J. Caminero AB. In: Hardman JG. Ann Pharmacother 1995. Hargreaves RJ. 43. Pareja JA. 14:297–300. 46. Neurology 1997. A prospective. Silva MT. 21:487–502. Elboim CM. Peroutka SJ. Neurology 2004. and miscellaneous drugs in the acute treatment of migraine. Ketorolac versus chlorpromazine in the treatment of acute migraine without aura. 44:463. Epidemiology 1995. 52. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. A prospective randomized double-blind trial. Peroutka SJ. Dougherty J. placebo-controlled trial of rofecoxib in the acute treatment of migraine. eds. O’Connor H. Peroutka SJ. In: Hardman JG. Curr Therap Res Clin Exp 2003. Shrestha M. . 2nd ed. 23:37–38. Silberstein S. 58. 50. Welch KMA. Prevention of the last chance: an alternative pharmacological treatment of migraine. Chun E. Jones EB. Arq Neuropsiquiatr 2004. 15(suppl 15):21–28. Grillo JA. Boggs JG. Ferrari MD. Monzillo HP. 23(2):141–148. Barbosa JS. Fernandes D. emesis and antiemetics. Headache 1996. 74. Ashford E. 22(4): 309–312. Preliminary results. Basic mechanisms of antimigraine drugs. Jones J. Leibold RA. Arq Neuropsiquiatr 2000. 70. Comparative trial of three agents in the treatment of acute migraine. eds. 26:541–546. Bruntton LL. Am J Emerg Med 1996. Gallagher EJ. Solorzano C. In: Hardman JG. Agents affecting gastrointestinal water flux and motility. Montoya D. Rizatriptan combined with rofecoxib vs. Peroutka SJ. 1996:917–936. 14:262–265. Elswick RK Jr. Costa AR. de Vriend RH. How does sumatriptan perform in clinical practice? Cephalalgia 1995. Sumatriptan–nonresponders: a survey in 366 migraine patients. 62(2-B):513–518. Ann Emerg Med 1990. JAMA 1961. Ann Emerg Med 1994. 47:46–51. Bijur PE. Subcutaneous sumatriptan during the migraine aura. Jaspers NHWM. Sumatriptan in clinical practice: a 2-year review of 453 migraine patients. Nemoto PH. Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache. Bell R. New York: McGraw Hill. 36:471–475. 82. Ruddon LW. 24:237–241. Naproxen sodium decreases migraine recurrence when administered with sumatriptan. Adv Neurol 1982. 65. 19:1079–1082. Safety and efficacy of rectal prochlorperazine for the treatment of migraine in the emergency department. 63. J Emerg Med 2002. Lasagna L. Molinoff PB. 75. Fozard J. Limbird LE. Neurology 1996. Molinoff PB. 71. Acute treatment of migraine in emergency room: open comparative study between dexametasone and haloperidol. Neurology 1994. Limbird LE. 4(1):10. Sanvito WS. 68. 58(2-B):428–430. Intramuscular prochlorperazine versus metoclopramide as a single-agent therapy for the treatment of acute migraine headache. 1996:399–430. 28. Friedman BW. Dawson R. Lane P. 33:295–307. Drugs and the treatment of psychiatric disorders: psychosis and anxiety. 77. 67. placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Bates D. Krymchantowski AV. Tolfenamic acid decreases migraine recurrence when used with sumatriptan. 9th ed. Corbo J. 81. rizatriptan for the acute treatment of migraine: an open label pilot study. 66. Esses D. Bigal ME. Bordini CA. Ann Emerg Med 1989. Jaspers NHWM. eds. Visser WH. 38:18–22. Pack S. Randomized. BMC Neurol 2004. 64(3):463–468. Goodman & Gilman’s The Pharmacological Basis of Therapeutics.286 Krymchantowski and Tepper 62. Gilman AG. New York: McGraw Hill. Speciali JG. Cephalalgia 2002. 9th ed. Dekornfeld J. 18:360–365. Ann Emerg Med 1995. Methotrimeprazine: a new phenothiazine derivative with analgesic properties. bile acids and pancreatic enzymes. 79. Krymchantowski AV. 64. Bigal ME. In: Hardman JG. de Vriend RH. Adriano M. 76. Krymchantowski AV. Yealy DM. Lee M. 19(3):186–187. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Neurology 2005. 73. Baldessarini RJ. Beyond Monotherapy: Rational polytherapy in migraine. Shuaib A. 178:887–890. 44:1587–1592. Gilman AG. 69. Coppola M. Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. Dahlof CG. Visser WH. 80. McLellan B. . 72. et al. Gonzalez ER. Ferrari MD. Ruddon LW. Krymchantowski AV. Headache 1998. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Baggoley C. 78. Lipton RB. Cephalalgia 1999. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. Compagnon A. 44:464. Belgrade MJ. Larkin GL. 90. Freitag FG. Efficacy of oral ketoprofen in acute migraine. American Academy of Family Physicians. A combination drug treatment for acute common migraine. Gawel MJ. Wall EM. 92. 84. Acute treatment of migraine attacks: efficacy and safety of a non-steroidal anti-inflammatory drug. 35:65–69. Jansen JP. Massiou H. Rozen TD. Weiner M. Headache 2001. Garcia-Acosta S. Headache 1995. Cephalalgia 2004. 91. double-blind. Diener HC. Comparison of singledose meperidine. Ann Emerg Med 1992. 17:222–236. A randomized. 8(suppl 7):1–96. Weber M. American College of Physicians-American Society of Internal Medicine. Drug Treatment of Migraine and Other Headaches. Weiss K. Bi-Profenid Migraine Study Group. . Prescott JE. Ling LJ. 85. ed. COZAM Study Group. DiSerio F. et al. Mottur-Pilson C. 97. The Multinational Oral Sumatriptan and Cafergot Comparative Study Group. Couch JR. Szalai JF. 102. Eur Neurol 1991. Eur Neurol 2002. 38:25–27. double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. Schleevogt MB. 24:321–332. Urban G. comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Geraud G. 41:391–398. 47(2):88–98. Yehuda S. 39:590–592. Clin Pharmacol Ther 1990. 100. Sheehan DV. Neurology 2002. 21:919–924. Transnasal butorphanol in the treatment of migraine headache pain. Neurology 1989. Tramadol HCl/acetaminophen versus placebo in the treatment of acute migraine pain [abstr]. Comparative study of isometheptene mucate. Silberstein SD. In Diener HC. 86. Dib M. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind. randomized. Headache Classification Committee of the International Headache Society. Silberstein SD. Ann Intern Med 2002. Opioids. 95. Snow V. 137(10):840–849. Br J Clin Pract 1984. dichlorphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine. 101. Cady R. Bigal ME. Henry P. Headache 2004. A double-blind randomized clinical trial. Double-blind clinical trials of oral triptans vs other classes of acute migraine medication–a review. Stiglick A. Headache 1986. cranial neuralgias and facial pain. et al. Uzogara E. OSAM (Oral Sumatriptan and Aspirin Plus Metoclopramide Comparative Study Group). Migraine treated with an antihistamine-analgesic combination. Freitag FG. Ruiz E. Manschreck TC. DSMSG (Diclofenac-K/Sumatriptan Migraine Study Group). Carasso RL. Evaluation of analgesic agents in recurring headache compared with other clinical pain models. Practitioner 1973. Monogr Clin Neurosci 2000. 26:231–236. Freitag FG. et al. three-attack study. 93. 19:232–240. 94. Transnasal butorphanol in the treatment of acute migraine. 96. 31(5):314–322. 3:164–171. Bousser MG. diclofenac-potassium in comparison to oral sumatriptan and placebo. Aimola N. 98. Reches A. Diamond S. 47:504–508. Diamond ML.Nonspecific Migraine Acute Treatment 287 83. A randomized. Cephalalgia 1999. Headache Quart 1992. 89. and dihydroergotamine in the treatment of vascular headache. Jones KJ. 99. Diamond S. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. 87. Lipton RB. Ettinger MG. tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicenter. General Practitioner Research Group. 88. Hoffert MJ. 58:1660–1665. The prevention and treatment of migraine with an analgesic combination. Eur Neurol 1992. Pharmacologic management of acute migraine and prevention of migraine headache. Efficacy. et al. butorphanol. 211:357–361. McCrory DC. 32:177–184. Rossi A. Goadsby PJ. Classification and diagnostic criteria for headache disorders. Cephalalgia 1988. 47(2): 99–107. 103.288 Krymchantowski and Tepper randomized. Lipton RB. Liberman JN. Migraine practice among neurologists. Neurology 2004. double-blind. Yekonsky J. Bartleson JD. Stewart WF. Rush S. . Eur Neurol 2002. Lipton RB. The Disability in Strategies of Care (DISC) Study. Stratified care vs. 284: 2599–2605. step care strategies for migraine. et al. 62(11):1926–1931. Stone AM. placebo-controlled comparison. 104. JAMA 2000. Bigal ME. but not on tension-type headache or other conditions such as tooth pain or general pain (although several case reports show that these drugs can also be effective to some extent in a gamut of other secondary headache syndromes). Essen. however. ERGOTAMINE Ergotamine and dihydroergotamine (DHE) have been available for a long time. The standard dose of oral ergotamine is 1 to 2 mg.3).21 Specific Acute Migraine Treatment: Ergotamine and Triptans Hans-Christoph Diener Department of Neurology. A comparison between antimigraine drugs is only possible in randomized controlled trials (RCTs) with head-to-head comparisons. University of Duisburg-Essen. Cologne City Hospitals. The most recent recommendations of the International Headache Society. ‘‘Specific’’ means that these drugs theoretically only work on migraine (and on cluster headache). indirect. and no recurrence) as the appropriate end points for clinical trials in migraine treatment (4). The primary end point in most headache trials is the improvement from severe or moderate head pain to mild or no pain after 120 minutes. Moderate or severe migraine attacks should be treated with specific migraine drugs. no rescue medication. Germany INTRODUCTION This chapter summarizes the results of treatment trials with ergots and 5-HT1B/Dagonists (triptans) for the treatment of acute migraine attacks. propose two-hour pain-free and 24-hours sustained pain-free (pain-free after two hours. DHE is available as 289 . Ergotamine is also available in some countries in suppository form at a dose of 2 mg. University of Cologne. Cologne. Another way to indirectly compare the different triptans is a meta-analysis (2. information can be gained by comparing net therapeutic gain. These include ergot alkaloids (also called ergots) and triptans. although less reliable. Germany Volker Limmroth Department of Neurology. Therapeutic gain is the difference in efficacy between active drug and placebo (1). When direct comparisons are not available. diclofenacpotassium reduced pain more effectively than ergotamine plus caffeine at one hour after treatment and. double-dummy. In the trial.001) (Fig. double-blind. no reporting of baseline criteria and the randomization procedure. ERGOTAMINE VS. ORAL TRIPTANS The effect of oral ergotamine in the acute treatment of migraine has been compared to that of oral triptans in randomized controlled clinical trials. tolfenamic acid. or oral ergotamine plus caffeine (5).  Ergotamine (1–5 mg) was superior to placebo for some parameters in seven trials and no better than placebo in three studies using a dose of 2 to 3 mg (6). and vomiting ( p < 0. Despite the limited number of studies with contemporary methodology that involve ergotamine. and in several trials. whereas ergotamine served as the standard comparative drug in eight other trials without placebo control. and this is summarized briefly below. there is evidence for the efficacy of ergotamine. parallel-group trial (9). The reported parameters for efficacy were not all validated and varied considerably from benefit based on a clinical interview to use of changes on a verbal headache scale. provided a summary of 18 controlled double-blind trials of oral ergotamine. and superiority claims without appropriate statistics (5). 580 patients were treated. ergotamine was compared with placebo.  In two comparative trials. repeated intake of ergotamine was used. 1). Other methodological flaws in these trials include the lack of clearly stated inclusion criteria. and pirprofen were generally found comparable to ergotamine. Tfelt-Hansen et al. naproxen sodium.001). In 10 of these trials. This chapter will concentrate on the oral form of ergotamine. in contrast to the comparator. The dose of ergotamine varied from 1 to 5 mg with a median of 2 mg. nausea ( p < 0. whereas recurrence of migraine headache within 48 hours was lower with ergotamine plus caffeine. Sumatriptan was also significantly more effective at reducing the incidence of photophobia/phonophobia ( p < 0. The onset of headache resolution was more rapid with sumatriptan. 66% (145/220) of those treated with sumatriptan improved in this way by two hours.  The combination of lysine-acetylsalicylate (equivalent to 900 mg aspirin) plus metoclopramide (10 mg) was superior to the combination of ergotamine and caffeine (2 mg ergotamine and 200 mg caffeine) for most of the outcome parameters assessed (8).  Drugs such as ergocristine. unusual design of some of the crossover trials with a variable number of attacks per patient. Sumatriptan was significantly more effective than the ergotamine–caffeine combination at reducing the intensity of headache from severe or moderate to mild or none.001). dextropropoxyphene. was also significantly different compared with placebo. The number of good clinical trials incorporating ergotamine is rather small. However. there was no significant difference in measures of pain relief at two hours between oral ergotamine 2 mg plus 200 mg caffeine and oral diclofenac-potassium 50 or 100 mg (7).01) two hours after treatment. and fewer patients on .290 Diener and Limmroth tablet and in some countries as nasal spray. randomized. compared with 48% (118/246) of those treated with ergotamine plus caffeine ( p < 0. The first study performed without placebo investigated the efficacy and tolerability of oral sumatriptan 100 mg and oral ergotamine 2 mg plus caffeine 200 mg in a multicenter. with response rates at one hour of 29% and 39% for 40 and 80 mg eletriptan. 9. The overall incidence of patients reporting adverse events was 45% after sumatriptan and 39% after ergotamine plus caffeine.005) to ergotamine plus caffeine in terms of functional response and the incidence of accompanying symptoms at two hours. p < 0. 80 mg. The onset of headache relief was more rapid in eletriptan groups. patients (n ¼ 773) took up to two doses of study medication to treat an acute migraine attack. The patients were randomized to receive 40 mg eletriptan. and 34% in the eletriptan 40 mg.001) required other medication after two hours (9). or placebo (in the ratio 2:2:2:1) as the first dose (Fig. In a more recent study. The incidence of treatment-related adverse events for patients based on the first dose of study medication was 32%.002). Both doses of eletriptan were significantly more effective than ergotamine plus caffeine in terms of headache response (54% and 68% vs. rizatriptan 10 mg was preferred to ergotamine and caffeine (11). randomized placebo-controlled trial. It is noteworthy that ergotamine plus caffeine was not superior to placebo for the primary outcome parameter. parallel-group. 2).Specific Acute Migraine Treatment: Ergotamine and Triptans 291 Figure 1 Selected end points from a trial comparing sumatriptan 100 mg versus ergotamine (2 mg) plus caffeine. 43%. 33%. in a crossover preference study. p < 0. Source: From Ref. compared to 13% for ergotamine plus caffeine and placebo (p < 0. respectively. 80 mg eletriptan. ergotamine 2 mg plus caffeine 200 mg. the efficacy and tolerability of oral ergotamine was compared with that of eletriptan in the acute treatment of migraine (10). respectively. 10%.0001) and pain-free response (28% and 38% vs. the difference was not significant. In a double-blind. Eletriptan was also significantly superior (p < 0. 34%.0001) at two hours after treatment. sumatriptan (24%) than on ergotamine plus caffeine (44%. . p < 0. ergotamine plus caffeine and placebo groups. Finally. Oral sumatriptan was well tolerated and was more effective than ergotamine plus caffeine in the acute treatment of migraine. The only patients who might benefit from the longer duration of action of ergotamine are those with short action of triptans or multiple recurrences when taking triptans. cerebrovascular disease [stroke and transient ischemic attack (TIA)]. Patients who show a good response when treating migraine attacks with ergotamine can remain on this drug. called medication-overuse headache (12–15). which is the number of patients needed to be treated in the active drug group in order to obtain significant relief (which would not have been obtained with placebo). which is the number of patients needed to be exposed to . and 20 mg intranasal sumatriptan was written by Tfelt-Hansen (16). hepatic or renal disease. Source: From Ref. Sumatriptan The most comprehensive review about the efficacy and adverse events of 6 mg subcutaneous. Patients who do not respond should be switched to a triptan. TRIPTANS The available triptan medications are listed in Table 1. 100 mg oral. ergotamine either as monosubstance or in combination with caffeine is only slightly more effective than placebo and is clearly inferior to sumatriptan. or eletriptan. The too-frequent intake of ergotamine can lead to an increase of migraine frequency and diffuse headaches. and during pregnancy. He calculated the numbers needed to treat (NNT). and numbers needed to harm (NNH). 10. Ergotamine has vasoconstrictive properties and is therefore contraindicated in uncontrolled hypertension. and eletriptan 80 mg. peripheral vascular disease. rizatriptan.292 Diener and Limmroth Figure 2 Selected end points from a trial comparing ergotamine (2 mg) plus caffeine. In summary. coronary heart disease. eletriptan 40 mg. 4). 50. In a large dose-finding trial. NNH. numbers needed to harm. Twelve RCTs were performed with 100 mg oral sumatriptan.8) were achieved.2 hour and orally Table 2 Numbers Needed to Treat and Numbers Needed to Harm in a Meta-Analysis of Sumatriptan Trials Formulation Sumatriptan tablet 100 mg Sumatriptan nasal spray Sumatriptan injection Number of trials analyzed 12 6 12 NNT (95% confidence interval) 3.8–3.3 (95% CI 6. sumatriptan was developed in intranasal and suppository formulations for patients unable to take tablets and unwilling to inject themselves.1) and a NNH of 3. and 100 mg 10 and 20 mg 6 mg 25 mg 2.5 and 5 mg 5 and 10 mg 5 and 10 mg 1 and 2. Finally.8) at 2 hr 2. numbers needed to treat. and a success rate after two hours of 61% (563/917).0 (1.2) (Table 2).Specific Acute Migraine Treatment: Ergotamine and Triptans Table 1 Available Triptan Medications Generic Sumatriptan Formulations Tablets Nasal spray Subcutaneous injection Suppositories Tablets Orally disintegrating tablet Nasal spray Tablets Orally disintegrating tablet Tablets Tablets Tablets Tablets Doses 293 Zolmitriptan Rizatriptan Naratriptan Almotriptan Frovatriptan Eletriptan 25. These data clearly indicate that subcutaneous sumatriptan is the most effective treatment but causes more side effects than oral sumatriptan.4) and a NNH of 8.5 mg 2.9–2.5 and 5 mg 2. The 50 mg dose had fewer side effects than the higher dose and therefore is the preferred initial dose (17).7–3. The success rate was 58% (1067/1854) for sumatriptan compared to 25% (256/1036) for placebo resulting in a NNT of 3. For subcutaneous sumatriptan.7–3.3–12.5 and 5 mg 2. compared to 30% (149/503) for placebo.9–2.7–3.3–12.0 (2.1 (2.8–3.5 mg 20 and 40 mg 80 mg in some countries but not in the United States a drug in order to have more side effects than placebo.1) at 1 hr NNH (95% confidence interval) 8. six trials were performed with intranasal sumatriptan. sumatriptan has a tmax of one hour (subcutaneously 0. 12 RCTs were available.0 (95% CI 2. 50 and 100 mg oral sumatriptan were equally effective and superior to 25 mg sumatriptan.1 (2. In the intranasal formulation. and an NNT of 3.2) at 2 hr Not reported 3.7–3.0 (1. Following more than 80 international trials of oral and subcutaneous application. The success rate of sumatriptan after one hour was 69% (1337/1927) and of placebo 19% (226/1200) resulting in a NNT of 2.3 (6.4) at 1 hr Abbreviations: NNT. to evaluate side effects.0 (2.4) at 2 hr 3.5 mg 12. .0 (2. and 100 mg. 10. Dosages of 12.5 mg and 25 mg sumatriptan suppositories with placebo. 50.5. reported significant improvement of headache (22). 47% with 12. A randomized double-blind. 46%. The approved doses for the nasal spray are 10 and 20 mg.407 migraine sufferers treating over 130. and migraine prophylaxis on the success rates (21). and 70% of the patients receiving 12.5. Predictors included the following:  Moderate pain at baseline (was the strongest predictor. 5. respectively. the better. 12. Relief rates two hours postdose were 68% in the high-dose group. and 64% of the patients.11  10À18)  Absence at baseline of vomiting. pulsating pain. or photophobia/ phonophobia  Onset of headache during daytime hours Logistic regression confirmed that treatment with sumatriptan was the strongest predictor of headache relief. 72%. and 20 mg reduced the headache within two hours significantly in 49%. Dosages of 5.32  10À35)  Absence of a disability requiring bed rest (second strongest predictor. . A total of 24 possible univariate predictors of headache response in 3706 patients (18 years and older) receiving sumatriptan tablets 100 mg or placebo in a double-blind study were tested using recursive partitioning and logistic regression techniques.5 mg and upwards showed a significant improvement of headache within two hours. Predictors for the Response to Sumatriptan The determinants for optimal response to sumatriptan were unknown. and presence or absence of vomiting. A retrospective analysis of four pooled trials performed between 1993 and 1994 including 2395 patients showed no influence of sex. and 25% with placebo (23). Two additional trials comparing 10 and 20 mg with placebo (n ¼ 409 and 436) showed a significant relief of headache within two hours in 43% to 54% of the patients receiving the 10 mg dose and in 62% to 63% receiving 20 mg compared to 29% to 35% with placebo (20).5 hour) and a half-life of two hours (18). 66%. 25.000 attacks (24). It should be noted that only a small proportion of sumatriptan is absorbed through the nasal mucosa. pretreatment headache duration. The Sumatriptan Naratriptan Aggregate Patient database was introduced and contained data from 128 clinical trials including 28. This analysis showed that pretreatment pain severity is the most important predicting factor for response to sumatriptan in migraine attacks: the lower the baseline severity. 10. weight. there were no statistical differences between these dosages. placebo-controlled trial including 431 patients with dosages of 6. and 100 mg.294 Diener and Limmroth 1. dosages of 2. Sumatriptan as a suppository was tested in a double-blind. nausea. age. In a dose-finding study (n ¼ 544). Two hours following the drug administration. with significant baseline covariates being pain severity. respectively.5 mg. A similar pattern of results was reported for predictors of pain-free response two hours after taking sumatriptan. 25. However. 50. 65%. migraine type (with or without aura). adjusted p ¼ 3. These data were analyzed to identify factors predicting response (headache relief and pain-free response) to sumatriptan. with an adjusted p ¼ 3. The major side effect is taste disturbance. The approved dose of the sumatriptan suppository is 25 mg. parallel-group. level of disability. Seven predictors of headache relief two hours postdose were identified (25).5. and 20 mg were compared (19). placebo-controlled trial in 184 patients compared 12. Moreover.32).0 for 50 and 100 mg oral sumatriptan.5 hours). who are unable to tolerate the side effects of oral sumatriptan or another triptan. which reaches peak plasma levels earlier. Systemic sumatriptan exposure is increased in patients who are treated with monoamine oxidase inhibitors (MAOIs). however. the tmax is reached only after three hours (sumatriptan 1. Other Triptans Following sumatriptan. Pharmacokinetic and clinical studies revealed no interaction of sumatriptan with DHE. On the other hand. The pharmacokinetic profile offers interesting improvements compared to oral sumatriptan. this could indicate that the blood–brain barrier becomes leaky during a migraine attack. frovatriptan. which reduces the effective dosage to 2.8 compared with 3. The 1 mg dose of naratriptan is available in the United States. in some aspects. It should be noted that recurrence can only occur in patients who initially have a positive response to a headache drug. Most of the new drugs have already been studied extensively in clinical trials.33). a better pharmacokinetic profile than sumatriptan: the bioavailability of the oral formulation is almost 60% (sumatriptan ¼ 14%). The low penetration. flunarizine. and fluoxetine (28. Sumatriptan has a poor oral bioavailability (14%) and a low penetration of the blood–brain barrier.5 mg. seems not to affect the efficacy of sumatriptan. Naratriptan has a low recurrence rate after initial efficacy (36).Specific Acute Migraine Treatment: Ergotamine and Triptans 295 Recently. treated 28 patients who were on MAOIs with 6 mg sumatriptan and found no increase in adverse events but observed a lower recurrence rate (30). The further development of new 5-HT1B/D-agonists was motivated by the intention to improve the pharmacological and pharmacokinetic properties of sumatriptan. or drugs used for migraine prophylaxis such as propranolol. If a central mechanism is indeed crucial for the clinical efficacy of triptans. which indicated a slow onset of action. pizotifen. and zolmitriptan are approved in most countries. naratriptan. rizatriptan.29). naratriptan. In patients who do not respond to oral sumatriptan. the half-life is about five hours. however. eletriptan. which might speed up the gastric passage (27). Publications initially reported only four-hour efficacy data.5 mg (32. Zolmitriptan Zolmitriptan was the second triptan to enter the market. paroxetine. two to three times longer than the half-life of oral sumatriptan. a fast soluble tablet of sumatriptan. The low dose of oral naratriptan was chosen based on tolerability. Direct comparisons with the normal tablet in terms of onset of action are not yet available. several new 5-HT1B/D-agonists have been developed and introduced. Dose-finding trials with doses of naratriptan between 0. Naratriptan should be used in patients with moderate migraine attacks. which may account for a reduced percentage of patients with headache recurrence in some studies (31. Naratriptan Naratriptan has.5 mg. it might be worthwhile to combine sumatriptan with an antiemetic drug such as metoclopramide. At an oral dose of 2.1 and 10 mg showed the best relationship between efficacy and side effects to be at doses of 2. naratriptan has a favorable side-effect profile and is undistinguishable from placebo (35). One study. was developed (26).5 mg of 4. Goadsby (34) had access to two-hour data and calculated NNT for naratriptan 2. Almotriptan. With an oral . butorphanol. 5 mg zolmitriptan.. Zolmitriptan has been evaluated over a wide range of doses (1–25 mg) and has shown a consistently high headache response rate across placebo-controlled trials (39–42). In contrast to sumatriptan.000 migraine attacks using 5 mg of oral zolmitriptan. the 5 mg dose was introduced. Zolmitriptan has no interactions with DHE. no difference was seen between the three treatment groups in terms of the primary endpoint. no additional side effects were seen when combining it with propranolol.38). Due to the small number of patients in the placebo group resulting in large confidence intervals. zolmitriptan has a central mode of action (37. In addition to its vascular effects. Headache response rate for the 2. The rate of pain-free response after two hours across all dose-finding studies was 25% (N ¼ 438) (44). ergotamine. complete headache response. 3) (48).5 mg dose at two hours was 62% (N ¼ 219) compared to 36% for placebo (N ¼ 108) (43). In a long-term safety and efficacy trial including more than 2200 patients with over 20.5 mg dose.g. The rate of headache recurrence (27–33%) was comparable to that of sumatriptan. . The decision was made to market the oral 2. One placebo-controlled study compared zolmitriptan 5 mg with sumatriptan 100 mg (42). With a dose of 2. it would be prudent to limit the total daily dose should Figure 3 Uptake of labeled Zolmitriptan from the nasal mucosa and the subsequent increase of zolmitriptan serum levels. although zolmitriptan can cross the blood–brain barrier (49). Later. the necessary clinically effective dosage could be significantly reduced. Zolmitriptan nasal spray (5 mg) has a higher efficacy than oral application and an earlier onset of action (46). paracetamol. This study employed an unusual skewed randomization ratio (1:8:8) for placebo. MAO-A inhibitors (moclobemide) result in increased plasma levels of zolmitriptan and its metabolites. neither safety nor efficacy was affected when the drug was used in up to 30 consecutive attacks (45). Coadministration of propranolol resulted in a 56% increase in the area under the plasma concentration–time curve of zolmitriptan (51). e. pizotifen. fluoxetine. The two-hour response rate of the 5 mg spray was 70% compared to 30% with placebo (47). Therefore. zolmitriptan. or selegeline (50). and sumatriptan. nasal zolmitriptan is absorbed via the nasal mucosa (Fig. Side effects and central nervous system adverse events of oral zolmitriptan are similar to those of oral sumatriptan.296 Diener and Limmroth bioavailability of almost 50% (sumatriptan 14%). zolmitriptan is effective. The oral bioavailability of rizatriptan is about 40% versus 14% for oral sumatriptan. rizatriptan 10 mg had a success rate of 71%. and vice versa (52. 2. Rizatriptan 10 mg was also superior to sumatriptan 100 mg on pain-free response and reduction in functional disability. and 40 mg rizatriptan. and 60% reported relief from headache at two hours in one out of three. respectively. time to pain-free and pain-free after two hours. Rizatriptan was clearly Figure 4 Dose-finding trial of rizatriptan. Two clinical dosefinding studies have been carried out including 865 patients. suggesting the potential for a faster onset of action in favor of rizatriptan. 47%. is about three hours. In another comparative trial. 10. however. 5.Specific Acute Migraine Treatment: Ergotamine and Triptans 297 several doses be required (50). the efficacies of zolmitriptan and rizatriptan were identical for the two-hour headache response (59). and three out of three attacks. 96%. rizatriptan 5 mg 62%. 21%. Some patients who do not respond to 2. Two placebo-controlled studies compared rizatriptan to oral sumatriptan and found that rizatriptan 10 mg had earlier onset of headache relief than sumatriptan 100 and 50 mg (56.5 mg zolmitriptan will show a response to the 5 mg dose. The half-life. A dosage of 5 mg of zolmitriptan is equivalent to 100 mg sumatriptan. 52%. 20. Percentage of patients with headache relief two hours following drug administration. with 10 mg being the most effective dosage with reasonable side effects. Dosages were tested between 2. respectively. 86%.57). Rizatriptan Rizatriptan also has an improved pharmacokinetic profile compared to sumatriptan. In a large placebocontrolled trial (N ¼ 1473). Concerning the end points. and placebo 35% (55).53). and 64% of the patients receiving 2. 4) (54). and sumatriptan 100 mg 46%) reported relief from headache (Fig. 56%. Dosages of 5 mg and above were effective. Source: From Ref. 54. (placebo 18%. Of the 252 patients who treated three attacks with rizatriptan. In some patients who do not respond to sumatriptan. In clinical practice. Rizatriptan’s tmax is one hour. Rizatriptan 10 mg demonstrated consistent response across four migraine attacks (58). rizatriptan was superior to zolmitriptan. two out of three.5 mg zolmitriptan is at least equivalent to 50 mg sumatriptan. .5. Two hours following the administration of the drug.5 and 40 mg. eletriptan has an improved oral bioavailability (almost 50%). Side effects increased dose dependently and were typical for drugs of this class. rizatriptan is available in a wafer that dissolves instantly on the tongue without liquid. In some countries. the 80 mg dose is also approved. The fast dissolving wafer is preferred by patients. The rate of adverse events in Figure 5 Dose-finding trial of eletriptan in comparison with sumatriptan and placebo: percentage of patients with headache relief two hours following drug administration. is rapidly absorbed. rizatriptan 10 mg has a slightly faster onset of action and is somewhat more effective than oral sumatriptan. 65%. however. In a dose-finding trial with 857 migraine patients.61). In summary.298 Diener and Limmroth superior to naratriptan (60. Rizatriptan has an interaction with propranolol (not with metoprolol). 40.5 mg naratriptan (n ¼ 213) and 8% with placebo (n ¼ 107). 5). . 20. that sumatriptan was encapsulated in the comparative trials. respectively (placebo 24%) (66). 40. and sumatriptan 100 mg. Forty-five percent of patients were pain-free two hours after intake of 10 mg rizatriptan (n ¼ 201) compared to 21% with 2. à Sumatriptan was encapsulated. Source: From Ref. In addition to oral tablets. One should note. and 80 mg of eletriptan were evaluated against 100 mg of sumatriptan and placebo (Fig. Rizatriptan has comparable recurrence to oral sumatriptan (57). Patients who are on propranolol prophylaxis for their migraine should only take rizatriptan 5 mg. which might have affected absorption (67. 77%. Like the other new 5-HT1B/D-agonists. and has a half-life of four to five hours (65). 65. and 56% of the patients receiving 20. 80 mg of eletriptan.68). Eletriptan Eletriptan has been approved recently in oral doses of 20 and 40 mg. Headache response two hours following the administration of the drug could be observed in 55%. Trial results with this application form indicate that the efficacy is comparable to that of the tablet but that patients prefer the wafer (62–64). Headache recurrence was identical in the three treated attacks and ranged between 28.5% with 12. however.75). 6). In all other treatment groups. Almotriptan In dose-finding studies. few adverse events.5 mg almotriptan were used to treat three consecutive migraine attacks (76). Because there are no direct comparative trials with other triptans (except sumatriptan). Another comparative trial compared 12.5 mg almotriptan after two hours was 64% compared to 35% of placebo. Headache response after two hours was 58. the rate of adverse events was significantly lower. Pascual performed a meta-analysis of 2294 patients treated with almotriptan (75). The compound has a higher affinity to 5-HT1B/1D-receptors than sumatriptan. Eletriptan was effective in migraine patients who had a poor response to rizatriptan (72) or a combination analgesic drug (73). but is an agonist of 5-HT7-receptors as well (81).Specific Acute Migraine Treatment: Ergotamine and Triptans 299 the group receiving 80 mg eletriptan was higher compared with the rate in the group receiving 100 mg sumatriptan. This is interesting because activation of 5-HT7-receptors (in higher dosages) might cause vasodilatation. In another placebo-controlled trial with 722 patients.5 mg frovatriptan compared to 5% with placebo resulting in a therapeutic gain of 10% only.5..1% for the two almotriptan doses. the so-called ‘‘Glaxo’’ criterion.5 mg almotriptan compared to 32.83). and a low number of dropouts due to adverse events (79. The pharmacokinetic properties.25. The results for pain-free after two hours were 36% versus 14% (Fig.25 mg onward. Headache relief after two hours was reported by 62% and 65% of the patients in the active treatment groups and 19% of patients on placebo. Of those patients with a headache response at two hours after 80 mg eletriptan. 6. dosages of 2.5 mg almotriptan. In oral dose-finding studies (1–40 mg). Results for pain-free after two hours are 15% for 2. The efficacies of sumatriptan and almotriptan were identical (77). 40 and 80 mg eletriptan were significantly better effective than cafergot (2 mg ergotamine plus 200 mg caffeine) (10).5 and 25 mg almotriptan. and 100 mg sumatriptan. The efficacy rate for frovatriptan 2. 21% had a headache recurrence after a mean time of 19 hours.25 and 12. and 25 mg almotriptan were compared to placebo. In comparative trials. the drug is relatively slowly absorbed and reaches its tmax after two hours. almotriptan showed identical efficacy with the exception of the two-hour pain-free rate. Almotriptan had fewer side effects.80). an . Efficacy in two out of three migraine attacks was 64% for the lower and 75% for the higher dose. The efficacy of 12.25 mg almotriptan.g. are similar to those of naratriptan. Long-term trials showed sustained efficacy.7% and 30.5 mg is between 38% and 42%. 60% for 6. eletriptan was superior to naratriptan (70) and zolmitriptan (71).5% with placebo. The second best outcome parameter is improvement of headache from severe or moderate to mild or no headache. 2. The pain-free rates after two hours were 38% with 12. Almotriptan was superior to placebo from a dose of 6. Efficacy after two hours was 38% for placebo. Frovatriptan Frovatriptan has an interesting receptor profile. 12. on coronary vessels (possibly indicating no cardiovascular side effects due to vasoconstriction). In another comparative trial. A second trial compared 40 mg eletriptan (n ¼ 452) with 80 mg (n ¼ 461) and placebo (n ¼ 238) (69). 6. e.5 mg almotriptan and 11% with placebo (74. and 70% for 12. In another comparative trial including 1173 patients with 50 mg sumatriptan. which was higher for sumatriptan (78).5 mg and above were effective (82. 29% for zolmitriptan (2. The analysis was based on data from 24. double-blind.5 mg frovatriptan ranges from 15% to 26% compared to 33% for sumatriptan (100 mg). Oral sumatriptan 100 mg was taken as the reference drug. 12 of which had not yet been published (2). frovatriptan offers no advantages over the other triptans. Lowest recurrence rates have been reported for naratriptan (25%) and eletriptan 80 mg (24%). 36% for rizatriptan (10 mg). and compared one triptan to placebo or another triptan. however. Four-hour data. One has to keep in mind that recurrence can occur only after initial improvement of headache. The rate of headache recurrence varies between 25% and 40% for the other triptans. Frovatriptan therefore ranges at the low end of efficacy. also will have a low recurrence rate. These data are not yet reported for frovatriptan. at least at two-hour–time points. and no intake of rescue medication. therefore. Studies were included if they were randomized. In summary. 75. A total of 59% of patients . Therapeutic gain for 2. such as naratriptan and frovatriptan. Other end points were headache recurrence and consistency in two out of three treated migraine attacks. because patients want a fast onset of action. Source: From Ref.089 patients. End points for the analysis were headache response (improvement of headache from severe or moderate to mild or no headache) two hours after intake of study medication and pain-free response.5 mg). and 42% for eletriptan (40 mg) (84).5 mg). The Triptan Meta-Analysis Ferrari et al.300 Diener and Limmroth Figure 6 Selected end points from a meta-analysis assessment of trials comparing almotriptan and placebo. 22% for naratriptan (2. indirect way to compare triptans is by calculating therapeutic gain (16). no recurrence for the next 24 hours. The only way to get around this problem is to report sustained pain-free data: pain-free after two hours. appear to be less important. performed a meta-analysis of 53 triptan trials. drugs with a low efficacy. 40. At the end of the 1980s. It is unclear whether the ‘‘nonresponders’’ have a variant of migraine or a different 5HT-receptor profile. Consistency was 67%. These studies showed either no or only a minor difference in efficacy measured as improvement of headache. and in some countries in an 80 mg dose. pain-free after two . Sumatriptan 50 mg is as effective as the 100 mg dose. but has fewer side effects. If this also is not effective. Improvement of headache from severe or moderate to mild or no headache was achieved in 33.4% of patients in the zolmitriptan group and in 32. A more recent study compared 2. it is worthwhile to try another triptan (52).88). Almotriptan has a good side-effect profile.5 mg is as effective as sumatriptan for headache response and seems to be superior for painfree.9% in the aspirin group. were 20% of patients. although with a slightly longer time interval (83. Most 5-HT1B/D-agonists have a ceiling effect where higher doses do not lead to improved efficacy. Central sensitization may play a role (see below). up to 40% of all attacks and up to 25% of all patients do not respond to any of these substances. If a patient with migraine does not respond to a particular triptan on three attacks.5 mg zolmitriptan with 900 mg lysinated aspirin in combination with 10 mg metoclopramide (89). Shortcomings of Triptans Even the new 5-HT1B/D-agonists will not solve the problems of this class of substances. Some patients may suffer from tension-type headache with migraine features and are likely to not respond to a triptan. Zolmitriptan 2. which means pain-free after two hours. Drugs with longer half-lives than sumatriptan also show headache recurrence. is no longer the case. and no intake of rescue medication. two trials compared oral sumatriptan 100 mg with lysinated aspirin in combination with metoclopramide (87. This. Doses of 20 mg are inferior to sumatriptan and 40 mg are equivalent. Naratriptan and frovatriptan are less effective than sumatriptan but show a lower recurrence rate. Comparison with Nonsteroidal Anti-inflammatory Drugs An interesting aspect of the treatment of acute migraine attack is the fact that triptans up to now have not convincingly been shown to be superior to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Longer half-lives of new migraine drugs were supposed to decrease headache recurrence (85). SC sumatriptan should be tested. A significant difference was found for a secondary end point. no recurrence. If a patient does not respond to three oral triptans. Rizatriptan 10 mg is more effective than 100 mg sumatriptan. Despite improved pharmacokinetics and pharmacodynamics. however. Eletriptan 80 mg is more effective than sumatriptan and has a lower recurrence rate but more side effects. Eletriptan is the exception—20. This difference was statistically not significant. Almotriptan 12.Specific Acute Migraine Treatment: Ergotamine and Triptans 301 had a headache response after two hours and 29% were pain-free. and 80 mg have a linear dose–efficacy relationship. when therapeutic gain is calculated.86). but has a higher recurrence rate. Eletriptan is available in doses of 20 and 40 mg.5 and 5 mg are as effective as sumatriptan and have a similar side effect profile. the patient is either a ‘‘triptan-nonresponder’’ or does not suffer from migraine. Sustained painfree. Six hundred sixty-six patients were included in the study and treated for two migraine attacks. Rizatriptan has the best consistency. 302 Diener and Limmroth hours (10.7% for zolmitriptan and 5.3% for aspirin). In another double-blind, placebocontrolled, crossover study, patients received either 75 or 150 mg ketoprofen (NSAID), 2.5 mg zolmitriptan, or placebo. Two hundred thirty-five patients who were treated for 838 migraine attacks were available for the intention-to-treat analysis. Improvement of headache two hours after administration of study drug was reported in 62.6% of patients receiving 75 mg ketoprofen, 61.6% after 150 mg ketoprofen, 66.8% following zolmitriptan, and 27.8% after placebo. The difference between the three active treatments was not significant (90). We performed two placebo-controlled trials comparing 50 mg sumatriptan with 1000 mg aspirin without antiemetics. In both trials, aspirin was equivalent to sumatriptan in terms of efficacy, and both drugs were superior to placebo (91,92). The results of these studies indicate that it is worthwhile to try aspirin or a NSAID in de novo migraine patients. Patients in whom this approach has failed in the past should receive a triptan. Triptans Taken When Headache Is Mild In patients with established diagnosis of migraine, treatment effects are better when a triptan is used while the headache is mild (93–96). This approach should only be used in patients with infrequent migraine attacks and in patients who can distinguish migraine from tension-type headache. Otherwise, the triptan may be used too frequently and lead to medication-overuse headache (see below). Nonresponders About 20% to 30% of patients are nonresponders to triptans. Burstein et al. (97) observed that some patients developed allodynia in the head and face region, which they explained as central sensitization. In an elegant series of experiments, Burstein could show that patients who do not develop allodynia during a migraine attack almost always respond to treatment with SC sumatriptan, while 80% of patients who had allodynia at the time of injection did not respond (98). This result indicates that triptans might have a peripheral mode of action and will not be effective once central sensitization has taken place. This observation may have major implications for the treatment of migraine attacks in clinical practice. Nonresponders to a particular triptan should be asked if they are hypersensitive to nonpainful stimuli in the face and on the head. If this is the case, they should be treated as early as possible. Recurrence Triptans and ergots have a limited time of efficacy. Therefore, in about 15% to 40% of all migraine attacks, the symptoms recur after initial improvement (85). In these cases, a second dose of triptan can be taken. Some patients, however, do not want to take a second dose. In these patients, headache recurrence can be prevented by giving a slow-release NSAID either together with the triptan or a few hours before the expected recurrence (99). Use of Triptans During the Aura The aura is unaffected by treatment with a triptan. This has been shown for sumatriptan (100) and eletriptan (101). Therefore, triptans should only be given when the Specific Acute Migraine Treatment: Ergotamine and Triptans 303 aura symptoms have disappeared. In addition, triptans do not prevent the occurrence of headache when given during the aura. Migraine in the Emergency Room Patients coming to the emergency room with a severe migraine attack usually expect to receive a potent treatment. The treatment options here are aspirin IV (1000 mg) (102), sumatriptan SC (103), DHE IV (1–2 mg) (104), metamizole (dipyrone) IV (100 mg) (105), and, as recently shown, IV valproic acid (106). Medication-Overuse Headache All new 5-HT1B/D-agonists taken too often will decrease the time interval between migraine attacks, which results in medication-overuse headache such as has been observed in conjunction with ergotamine, DHE, and sumatriptan (107–111). A population-based study in Denmark indicated that a small number of patients use sumatriptan on a daily or almost daily basis (109). Whether these patients had chronic cluster headache or were abusing sumatriptan is not known. We observed medication-overuse headache after use of zolmitriptan and naratriptan (112). Of this group, five patients using zolmitriptan only (who had never taken ergotamine derivatives or other triptans before) developed drug-induced headache after a period of six months, partly with a dosage of 7.5 mg a week (i.e., three tablets weekly). This indicates that second-generation triptans with their improved pharmacological profile cause drug-induced chronic daily headache faster and at lower dosages than expected or that a pronounced central effect of action supports the development of drug-induced chronic daily headache. Safety All 5-HT1B/D-agonists have vasoconstrictive activity. Using human coronary arteries, there was no difference; the vasoconstriction was almost identical between the triptans (113,114). Therefore, all triptans are contraindicated in patients with vascular disease. Postmarketing surveillance studies and case reports indicate that sumatriptan, albeit rarely, is associated with serious cardiovascular events including myocardial infarction (MI), cardiac arrhythmia, TIA, stroke, and ischemic colitis. The frequency of serious adverse events is about 1:1 million treated attacks (115). Almost all serious adverse events occurred in patients with contraindications or other diseases than migraine. A positron emission tomography study in healthy volunteers showed that 6 mg sumatriptan SC had no influence on myocardial perfusion (116). Another trial observed no changes in myocardial blood flow in migraineurs after the use of naratriptan (117). Large-scale epidemiological studies confirmed that migraine patients have an increased risk of stroke. The risk of stroke and MI is not increased in patients treating their migraine attacks with a triptan compared with analgesics or NSAIDs (118,119). GlaxoSmithKline established a pregnancy register to obtain data from patients and newborns, when sumatriptan was taken during pregnancy (although not recommended). Up to now, the data from almost 300 pregnancies are available and indicate that there is no increased risk of major birth defects (120–122). Two other observational studies found no increase in fetal malformations (123,124). 304 Diener and Limmroth CONCLUSIONS The introduction of the first triptan in the early 1990s revolutionized the acute treatment of migraine and provided new insights into the pathophysiology and pharmacology of migraine. A decade later, seven triptans in over 20 different preparations are available and allow the physician to customize the treatment of acute attacks according to the patient’s needs. With over 200 clinical trials and long-term safety results from several thousand patients, triptans can be considered as safe and well tolerated. Comparative trials showed that triptans are superior to ergotamine derivatives in both clinical efficacy and tolerability. Triptans, however, are not the final answer for the acute treatment of migraine attacks, because a significant percentage of migraine patients do not respond to this group. But it will take at least a decade for new drug entities to challenge the triptan family as drugs of first choice in the acute treatment of migraine. REFERENCES 1. Tfelt-Hansen P. Preliminary analysis of randomized placebo-controlled clinical trials with newer 5-HT1D receptor agonists for the treatment of migraine attacks. In: Olesen J, Tfelt-Hansen P, eds. Headache Treatment: Trial Methodology and New Drugs. New York: Lippincott-Raven 1997:6:253–256. 2. Ferrari MD, Roon KI, Lipton RB, Goadsby P. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358:1668–1675. 3. Belsey JB. Reconciling effectiveness and tolerability in oral triptan therapy: a qualitative approach to decision making in migraine management. J Clin Res 2001; 4:105–125. 4. Tfelt-Hansen P, Block G, Dahlof C, et al. for the International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20:765–786. 5. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of ¨ migraine. A review and European consensus. Brain 2000; 123:9–18. 6. Dahlof C. Placebo-controlled clinical trials with ergotamine in the acute treatment of ¨ migraine. Cephalalgia 1993; 13:166–171. 7. McNeely W, Goa KL. Diclofenac-potassium in migraine. Drugs 1999; 57:991–1003. 8. Titus F, Lainez J, Leira R, Diez E, Monteiro P, Dexeus I. Double-blind, multicentric, comparative study of lysin acetylsalicylate (1620 mg equivalent to 900 mg aspirin) þ metoclopramide (10 mg) versus ergotamine (2 mg) þ caffeine (200 mg) in the treatment of migraine. Cephalalgia 1999; 19:371. 9. The Multinational Oral Sumatriptan Cafergot Comparative Study Group. A randomized, double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. Eur Neurol 1991; 31:314–322. 10. Diener HC, Reches A, Pascual J, Jansen J-P, Pitei D, Steiner T. on behalf of the Eletriptan Cafergot Comparative Study Group. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicenter, randomized, double-blind, placebo-controlled comparison. Eur Neurol 2002; 47:99–107. 11. Christie S, Gobel H, Mateos V, Allen C, Vrijens F, Shivaprakash M. Rizatriptan¨ Ergotamine/Caffeine Preference Study Group. Crossover comparison of efficacy and preference for rizatriptan 10 mg versus ergotamine/caffeine in migraine. Eur Neurol 2002; 49:20–29. Specific Acute Migraine Treatment: Ergotamine and Triptans 305 12. Horton BT, Peters GA. Clinical manifestations of excessive use of ergotamine preparations and management of withdrawal effect: report of 52 cases. Headache 1963; 3:214–226. 13. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol 2004; 3:475–483. 14. Olesen J, Bousser M-G, Diener H, et al. for the International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(suppl 1):1–160. 15. Diener HC, Katsarava Z. Medication overuse headache. Curr Med Res Opin 2002; 17:17–21. 16. Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia 1998; 18:532–538. 17. Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efficacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the acute treatment of migraine: defining the optimum doses of oral sumatriptan. Headache 1998; 38:184–190. 18. Moore KHP, Hussey EK, Shaw S, Fuseau E, Duquesnoy C, Pakes GE. Safety, tolerability, and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses. Cephalalgia 1997; 17:541–550. 19. Becker WJ. on behalf of the Study Group. A placebo-controlled, dose-defining study of sumatriptan nasal spray in the acute treatment of migraine. Cephalalgia 1995; 15(suppl 14):271–276. 20. Ryan R, Elkind A, Baker CC, Mullican W, DeBussy S, Asgharnejad M. Sumatriptan nasal spray for the acute treatment of migraine. Neurology 1997; 49:1225–1230. 21. Ashford E, Salonen R, Saiers J, Woessner M. Consistency of response to sumatriptan nasal spray across patient subgroups and migraine types. Cephalalgia 1998; 18:273–277. 22. Gobel H. on behalf of the Study Group. A placebo-controlled, dose defining study of ¨ sumatriptan suppositories in the acute treatment of migraine. Cephalalgia 1995; 15(suppl 14):232. 23. Tepper SJ, Cochran A, Hobbs S, Woessner M. on the behalf of the S2B351 Study Group. Sumatriptan suppositories for the acute treatment of migraine. Int J Clin Pract 1998; 52:31–35. 24. Barrows C, Saunders W, Austin R, Putnam G, Mansbach H, for the SNAP Study Group. The sumatriptan/naratriptan aggregated patient (SNAP) database: aggregation, validation and application. Cephalalgia 2004; 24:586–595. 25. Diener HC, Ferrari M, Mansbach H. for the SNAP Database Study Group. Predicting the response to sumatriptan: the Sumatriptan Naratriptan Aggregate Patient Database. Neurology 2004; 63:520–524. 26. Walls C, Lewis A, Bullman J, et al. Pharmokinetic profile of a new form of sumatriptan tablets in healthy volunteers. Curr Med Res Opin 2004; 20:803–809. 27. Schulman E, Dermott K. Sumatriptan plus metoclopramide in triptan-nonresponsive migraineurs. Headache 2003; 43:729–733. 28. Perry CM, Markham A. Sumatriptan. An updated review of its use in migraine. Drugs 1998; 55:889–922. 29. Joffe RT, Sokolov ST. Co-administration of fluoxetine and sumatriptan: the Canadian experience. Acta Psychiatr Scand 1997; 95:551–552. 30. Freitag FG, Diamond S, Diamond M, Urban G, Pepper B. Subcutaneous sumatriptan in patients treated with monoamine oxidase inhibitors and other prophylactic agents. Headache Q 1998; 9:165–171. 31. Klassen A, Elkind A, Asharnejad M, Webster C, Laurenza A. on behalf of the Naratriptan S2WA3001 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, parallel-group study. Headache 1997; 37:630–645. 306 Diener and Limmroth 32. Mathew NT, Asgharnejad M, Peykamian M, Laurenza A. on behalf of the Naratriptan S2WA3001 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. Neurology 1997; 49:1485–1490. 33. Gunasekara NS, Wiseman LR. Naratriptan. CNS Drugs 1997; 8:402–408. 34. Goadsby PJ. Treatment of acute migraine attacks with naratriptan. In: Diener H-C, ed. Drug Treatment of Migraine and other Frequent Headaches. Basel: Karger AG, 2000:134–140. 35. Heywood J, Bomhof MAM, Pradalier A, Thaventhiran L, Winter P, Hassani H. Tolerability and efficacy of naratriptan tablets in the acute treatment of migraine attacks for 1 year. Cephalalgia 2000; 20:470–474. 36. Sheftell F, O’Quinn S, Watson C, Pait D, Winter P. Low migraine headache recurrence with naratriptan: clinical parameters related to recurrence. Headache 2000; 40:103–110. 37. Goadsby PJ, Knight YE. Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. Cephalalgia 1997; 17:153–158. 38. Ellrich J, Messlinger K, Chiang CY, Hu JW. Modulation of neuronal activity in the nucleus raphe magnus by the 5-HT1-receptor agonist naratriptan in rat. Pain 2001; 90:227–231. 39. Ferrari MD. 311C90: increasing the options for the therapy with effective acute antimigraine 5HT1B/D receptor agonists. Neurology 1997; 48(suppl 3):21–24. 40. Rapoport AM, Ramadan NM, Adelmann JU, et al. on behalf of The 017 Clinical Trial Study Group. Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose-finding study. Neurology 1997; 49:1210–1218. 41. Dahlof C, Diener HC, Goadsby PJ, et al. Zolmitriptan, a 5-HT1B/D receptor agonist ¨ for the acute oral treatment of migraine: a multicenter, dose-range finding study. Eur J Neurol 1998; 5:535–543. 42. Geraud G, Olesen J, Pfaffenrath V, et al. on behalf of the Study Group. Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design. Cephalalgia 2000; 20:30–38. 43. Solomon GD, Cade RK, Klapper JA, Earl NL, Saper JR, Ramadan NM. on behalf of The 042 Clinical Trial Study Group. Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. Neurology 1997; 49:1219–1225. 44. Schoenen J, Sawyer J. Zolmitriptan (Zomig, 311C90), a novel dual central and peripheral 5HT1B/1D agonist: an overview of efficacy. Cephalalgia 1997; 17(suppl 18):28–40. 45. The International 311C90 Long-Term Study Group. The long-term tolerability and efficacy of oral zolmitriptan (Zomig, 311C90) in the acute treatment of migraine. An international study. Headache 1998; 38:173–183. 46. Becker WJ, Lee D. Zolmitriptan nasal spray is effective, fast-acting and well tolerated during both, short- and long-term treatment. Cephalalgia 2001; 21:271. 47. Dowson AJ, Boes-Hansen S, Farkkila AM. Zolmitriptan nasal spray is fast-acting and highly effective in the acute treatment of migraine. Eur J Neurol 2000; 7(suppl 3):82. 48. Sorensen J, Bergstrom M, Antoni A, et al. Distribution of 11C-zolmitriptan nasal spray assessed by positron emission tomography (PET). Eur J Neurol 2000; 7(suppl 3):82. 49. Edmeads JG, Millson DS. Tolerability profile of zolmitriptan (Zomig; 311C90), a novel dual central and peripherally acting 5HT1B/1D agonist. Cephalalgia 1997; 17:41–52. 50. Rolan P. Potential drug interactions with the novel antimigraine compound zolmitriptan (Zomig (R), 311C90). Cephalalgia 1997; 17(suppl 18):21–27. 51. Peck RW, Seaber EJ, Dixon RM, et al. The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women. Clin Pharmacol Ther 1998; 63(3):342–353. 52. Stark S, Spierings ELH, McNeal S, Putnam GP, Bolden-Watson CP, O’Quinn S. Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan. Headache 2000; 40:513–520. Specific Acute Migraine Treatment: Ergotamine and Triptans 307 53. Pascual J, Munoz R, Leira R. An open preference study with sumatriptan 50 mg and zolmitriptan 2.5 mg in 100 migraine patients. Cephalalgia 2001; 21:680–684. 54. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. for the Dutch/U.S. Rizatriptan Study Group. Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Arch Neurol 1997; 53: 1132–1137. 55. Teall J, Tuchmann M, Cutler N, et al. on behalf of the Rizatriptan 022 Study Group. Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Headache 1998; 38:281–287. 56. Tfelt-Hansen P, Teall J, Rodriguez F, et al. on behalf of the Rizatriptan 030 Study Group. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache 1998; 38:748–755. 57. Goldstein J, Ryan R, Jiang K, et al. and the Rizatriptan Protocol 046 Study Group. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 and 50 mg in migraine. Headache 1998; 38:737–747. 58. Kramer MS, Matzura-Wolfe D, Polis A, et al. Rizatriptan Multiple Attack Study Group. A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Neurology 1998; 51:773–781. 59. Pascual J, Vega P, Diener HC, Allen C, Vrijens F, Patel K. and the RizatriptanZolmitriptan Study Group. Comparison of rizatriptan 10 mg vs. zolmitriptan 2.5 mg in the acute treatment of migraine. Cephalalgia 2000; 20:455–461. 60. Bomhof M, Paz J, Legg N, Allen C, Vandormael K, Patel K. Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Eur Neurol 1999; 42:173–179. 61. Goadsby PJ. Rizatriptan in acute treatment of migraine: update on new comparative data. Cephalalgia 2000; 20(suppl 1):10–15. 62. Ahrens SP, Farmer MV, Williams D, et al. Rizatriptan Wafer Protocol 049 Study Group. Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Cephalalgia 1999; 19:525–530. 63. Adelman JU, Mannix LK, Seggern von RL. Rizatriptan tablet versus wafer: patient preference. Headache 2000; 40:371–372. 64. Klapper JA, O’Connor S. Rizatriptan wafer-sublingual vs. placebo at the onset of acute migraine. Cephalalgia 2000; 20:585–587. 65. Diener HC, McHarg A. Pharmacology and efficacy of eletriptan for the treatment of migraine attacks. Int J Clin Pract 2000; 54:670–674. 66. Goadsby PJ, Ferrari MD, Olesen J, et al. for the Eletriptan Steering Committee. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000; 54:156–163. 67. Milton KA, Kleinermans D, Scott N, Cooper JDH. The bioequivalence of standard sumatriptan tablets and two encapsulated forms of sumatriptan. Int J Pharm Med 2001; 15:21–26. 68. Salonen R, Kori S, Scott A, Richardson MS. Encapsulated sumatriptan is not bioequivalent to commercial sumatriptan. Headache 2003; 43:923–924 [comment]; 924–928 [author reply]. 69. Diener HC. Eletriptan therapy. In: Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Basel: Karger, 2000:184–189. 70. Garcia-Ramos GME, Hilliard B, Bordini CA, Leston J, Hettiarachchi J. Comparative efficacy of eletriptan vs. naratriptan in the acute treatment of migraine. Cephalalgia 2003; 23:869–876. 71. Steiner T, Diener H, MacGregor E, Schoenen J, Muirhead N, Sikes C. Comparative efficacy of eletriptan and zolmitriptan in the acute treatment of migraine. Cephalalgia 2003; 23:942–952. 72. Goldstein J, Tiseo P, Denaro J, Sikes C. Efficacy of eletriptan in migraine patients reporting unsatisfactory response to rizatriptan. Poster presentation at the 7th Biennial European Headache Federation Congress, 2004. 308 Diener and Limmroth 73. Diamond M, Hettiarachchi J, Hilliard B, Sands G, Nett R. Effectiveness of eletriptan in acute migraine: primary care for Excedrin nonresponders. Headache 2004; 44:209–216. 74. Cabarrocas X, Zayas JM. on behalf of the Almotriptan Oral Study Group. Efficacy data on oral almotriptan, a novel 5-HT1B/D agonist. Headache 1998; 38:377. 75. Pascual J. Therapy with other triptans: almotriptan. In: Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Basel: Karger, 2000:197–205. 76. Pascual J, Falk RM, Piessens F, et al. Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia 2000; 20:588–596. 77. Cabarrocas X, Zayas JM, Suris M. on behalf of the Almotriptan Oral Study Group. Equivalent efficacy of oral almotriptan, a new 5-HT1B/D agonist, compared with sumatriptan 100 mg. Headache 1998; 38:377–378. 78. Spierings E, Gomez-Mancilla B, Grosz D, Rowland C, Whaley F, Jirgens K. Oral almotriptan vs. oral sumatriptan in the abortive treatment of migraine: a double-blind, randomized, parallel-group, optimum-dose comparison. Arch Neurol 2001; 58:944–950. 79. Mathew NT. for the Oral Almotriptan Study Group. A long-term open-label study of oral almotriptan 12.5 mg for the treatment of acute migraine. Headache 2002; 42:32–40. 80. Cabarrocas X, Esbri R, Peris F, Ferrer P. Long-term efficacy and safety of oral almotriptan: interim analysis of a 1-year open study. Headache 2001; 41:57–62. 81. Brown AM, Ho M, Thomas DR, Parson AA. Comparison of functional effects of frovatriptan, sumatriptan and naratriptan on human recombinant 5-HT1 and 5-HT7 receptors. Headache 1998; 38:376. 82. Goldstein J, Elkind A, Keywood C, Klapper J, Ryan R. A low dose range-finding study of frovatriptan: a potent selective 5-HT1B/D agonist for the acute treatment of migraine. Headache 1998; 38:382–383. 83. Goldstein J, Keywood C. and the 251/96/14 Study Group. Frovatriptan for the acute treatment of migraine: a dose-finding study. Headache 2002; 42:41–48. 84. Ferrari MD. How to assess and compare drugs in the management of migraine: success rates in terms of response and recurrence. Cephalalgia 1999; 19(suppl 23):2–8. 85. Visser WH, Jaspers N, de Vriend RHM, Ferrari MD. Risk factors for headache recurrence after sumatriptan: a study in 366 migraine patients. Cephalalgia 1996; 16:264–269. 86. McDavis HL, Hutchison J. Frovatriptan Phase III Investigators. Frovatriptan- a review of overall clinical efficacy. Cephalalgia 1999; 19:363–364. 87. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. Eur Neurol 1992; 32:177–184. 88. Tfelt-Hansen P, Henry P, Mulder LJ, Schaeldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995; 346:923–926. 89. Geraud G, Compagnon A, Rossi A. The COZAM Study Group. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomized, three-attack study. Eur Neurol 2002; 47:88–98. 90. Dib M, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser M. Bi-Profenid Migraine Study Group. Efficacy of oral ketoprofen in acute migraine: a double-blind randomized clinical trial. Neurology 2002; 58:1660–1665. 91. Diener HC, Eikermann A, Gessner U, et al. Efficacy of 1,000 mg effervescent acetylsalicylic acid and sumatriptan in treating associated migraine symptoms. Eur Neurol 2004; 52:50–56. 92. Diener HC, Bussone G, de Liano H, et al. The EMSASI Study Group. Placebocontrolled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004; 24:947–954. 93. Ryan RE, Diamond S, Giammarco RAM, Aurora SK, Reed RC, Fletcher PE. Efficacy of zolmitriptan at early time points for acute treatment of migraine and treatment of recurrence. CNS Drugs 2000; 13:215–226. Specific Acute Migraine Treatment: Ergotamine and Triptans 309 94. Pascual J, Cabarrocas X. Within-patient early versus delayed treatment of migraine attacks with almotriptan: the sooner the better. Headache 2002; 42:28–31. 95. Cady RK, Sheftell F, Lipton RB, et al. Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Clin Ther 2000; 22:1035–1048. 96. Mathew N. Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003; 43:1075–1079. 97. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614–624. 98. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against development of cutaneous allodynia. Ann Neurol 2004; 55:19–26. 99. Krymchantowski AV, Adriano M, Fernandes D. Tolfenamic acid decreases migraine recurrence when used with sumatriptan. Cephalalgia 1999; 19:186–187. 100. Bates D, Ashford E, Dawson R, et al. Subcutaneous sumatriptan during the migraine aura. Neurology 1994; 44:1587–1592. 101. Olesen J, Diener HC, Schoenen J, Hettiarachchi J. No effect of eletriptan administration during the aura phase of migraine. Eur J Neurol 2004; 11:671–677. 102. Diener HC. for the ASASUMAMIG Study Group. Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. Cephalalgia 1999; 19:581–588. 103. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325:316–321. 104. Silberstein S, Douglas C, McCrory D. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 2003; 43:144–166. 105. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous dipyrone in the acute treatment of migraine without aura and migraine with aura: a randomized, double blind, placebo controlled study. Headache 2002; 42(9):862–871. 106. Leniger T, Pageler L, Stude P, Diener H, Limmroth V. Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine. Headache 2005; 45:42–46. 107. Diener HC, Tfelt-Hansen P. Headache associated with chronic use of substances. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven Press, 1993:721–727. 108. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308:1573. 109. Gaist D, Tsiropoulus I, Sindrup SH, Hallas J, Rasmussen BK, Kragstrup J. Inappropriate use of sumatriptan: population based register and interview study. Br J Med 1998; 316:1352–1353. 110. Gaist D. Use and overuse of sumatriptan. Pharmaco-epidemiological studies based on prescription register and interview data. Cephalalgia 1999; 19:735–761. 111. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener H. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002; 59:1011–1014. 112. Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of new 5-HT agonists zolmitriptan and naratriptan. Lancet 1999; 353:378. 113. Maassen van den Brink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998; 98:25–30. 114. Maassen van den Brink A, Broek vdRWM, Vries dR, Bogers AJJC, Avezaat CJJ, Saxena PR. Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels. Neurology 2000; 55:1524–1530. 115. Welch KMA, Mathew NT, Stone P, Rosamond W, Saiers J, Gutterman D. Tolerability of sumatriptan: clinical trials and post-marketing experience. Cephalalgia 2000; 20:687–695. 310 Diener and Limmroth 116. Lewis PJ, Barrington SF, Marsden PK, Maisey MN, Lewis LD. A study of the effects of sumatriptan on myocardial perfusion in healthy male migraineurs using 13NH3 positron emission tomography. Cephalalgia 1997; 48:1542–1550. 117. Gnecchi-Ruscone T, Bernard X, Pierre P, et al. Effect of naratriptan on myocardial blood flow and coronary vasodilator reserve in migraineurs. Neurology 2000; 55:95–99. 118. Hall G, Brown M, Mo J, MacRae K. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004; 62:563–568. 119. Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache 2004; 44:642–651. 120. Shuhaiber S, Pastuszak A, Schick B, et al. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998; 51:581–583. 121. Kallen B, Lygner PE. Delivery outcome in women who used drugs for migraine during ¨ pregnancy with special reference to sumatriptan. Headache 2001; 41:351–356. 122. Fox AW, Chambers CD, Anderson PO, Diamond ML, Spierings ELH. Evidence-based assessment of pregnancy outcome after sumatriptan exposure. Headache 2002; 42:8–15. 123. Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. Pregnancy outcome following prescription for sumatriptan. Headache 2000; 40:20–24. 124. O’Quinn S, Ephross SA, Williams V, Davis RL, Gutterman DL, Fox AW. Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study. Arch Gynecol Obstet 1999; 263:7–12. 22 Preventive Treatment for Migraine Stephen D. Silberstein Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. INTRODUCTION—WHY AND WHEN TO USE MIGRAINE-PREVENTIVE MEDICATIONS Migraine is a common episodic headache disorder characterized by attacks that consist of various combinations of headache and neurologic, gastrointestinal, and autonomic symptoms. It has a one-year prevalence of approximately 18% in women, 6% in men, and 4% in children (1,2). The second edition of the International Classification of Headache Disorders (ICHD-2) (3) subclassifies migraine into migraine without aura (1.1) and migraine with aura (1.2), the aura being the complex of focal neurologic symptoms that most often precede or accompany an attack (3). Migraine varies widely in its frequency, severity, and impact on the patient’s quality of life. A treatment plan should consider not only the diagnosis, symptoms, and any coexistent or comorbid conditions the patient may have, but also the patient’s expectations, needs, and goals (4). The pharmacologic treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment attempts to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used for a maximum of two to three days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability. There is a possibility that preventive treatment may also prevent episodic migraine’s progression to chronic migraine and result in health-care cost reductions. Silberstein et al. (5) retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second six months after the initial preventive medication, as compared with the six months preceding preventive therapy, office and other outpatient visits with a migraine diagnosis decreased by 51.1%; emergency department (ED) visits with a migraine diagnosis decreased by 81.8%; computed tomography (CT) scans with a migraine diagnosis decreased by 75.0%; magnetic resonance 311 312 Silberstein Box 1 U.S. Evidence-Based Guidelines for Migraine—Preventive Treatment 1. Recurring migraine that significantly interferes with the patient’s daily routine despite acute treatment (e.g., two or more attacks a month that produce disability that lasts three or more days, or headache attacks that are infrequent but produce profound disability) 2. Failure of, contraindication to, or troublesome side effects from acute medications 3. Overuse of acute medications 4. Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurologic injury 5. Very frequent headaches (more than two a week), or a pattern of increasing attacks over time, with the risk of developing medication overuse headache 6. Patient preference, that is, the desire to have as few acute attacks as possible imagings (MRIs) with a migraine diagnosis decreased by 88.2%; and other migraine medication dispensements decreased by 14.1% (5). According to the U.S. Evidence-Based Guidelines for Migraine (6), circumstances that might warrant preventive treatment are shown in Box 1. These rules are stricter during pregnancy—severe disabling attacks accompanied by nausea, vomiting, and possibly dehydration are required for preventive treatment to be prescribed (7). It is clear that preventive therapy is not being utilized to nearly the extent it should be. Results from the American Migraine Study I and II and the Philadelphia phone survey II demonstrated that migraine preventive therapy is underutilized. In the American Migraine Study II, 25% of all people with migraine, or more than seven million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest (2). However, only 5% of all migraineurs currently use preventive therapy to control their attacks (8). The major medication groups for preventive migraine treatment (Table 1) include anticonvulsants, antidepressants, b-adrenergic blockers, calcium channel Table 1 Preventive Prescription Drugs ACE inhibitors/angiotensins Receptor antagonist Anticonvulsants Valproate, gabapentin, topiramate Antidepressants TCAs, SSRIs, MAOIs b-adrenergic blockers Propranolol/nadolol/metoprolol/atenolol Calcium channel antagonists Verapamil/flunarizine Neurotoxins Serotonin antagonists Methysergide/methergine Others NSAIDs, riboflavin, magnesium, feverfew, butterbur root, neuroleptics Abbreviations: ACE, angiotensin-converting enzyme; TCA, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitor; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug. such as blood vessel pulsations. Stress can also activate meningeal plasma cells via a parasympathetic mechanism. MECHANISM OF ACTION OF PREVENTIVE MEDICATIONS The migraine aura is probably due to cortical spreading depression (CSD). The neuropeptides interact with the blood vessel wall. and platelet activation (10). calcitonin gene–related peptide (CGRP).Preventive Treatment for Migraine Table 2 Migraine Comorbid Diseases Cardiovascular Hyper-/hypotension Raynaud’s Mitral valve prolapse Angina/myocardial infarction Stroke Psychiatric Depression Mania Panic disorder Anxiety disorder Neurologic Epilepsy Essential tremor Positional vertigo GI Irritable bowel syndrome Other Asthma Allergies Abbreviation: GI. serotonin antagonists. the pain of migraine. gastrointestinal. plasma protein extravasation. causing. Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization). and others (including riboflavin. the agent should be preferentially chosen from one of the first-line categories. neurotoxins. 313 antagonists. nonsteroidal anti-inflammatory drugs (NSAIDs). Brainstem activation also occurs in migraine without aura. The migraine aura can trigger headache: CSD activates trigeminovascular afferents. . CS may play a key role in maintaining the headache. Headache and its associated neurovascular changes are subserved by the trigeminal system. based on the drug’s side-effect profile and the patient’s coexistent and comorbid conditions (Table 2) (9). Trigeminal sensory neurons contain substance P. which now respond to previously innocuous stimuli. in part due to increased activity of the endogenous antinociceptive system. leading to nociceptor activation (11). and herbs). If preventive medication is indicated. Stimulation results in the release of substance P and CGRP from sensory C-fiber terminals and neurogenic inflammation (NI). Headache probably results from activation of meningeal and blood vessel nociceptors combined with a change in central pain modulation. Central sensitization (CS) of trigeminal nucleus caudalis neurons can also occur. a decrease in electrical activity that moves across the cerebral cortex at a rate of 2 to 3 mm/min. minerals. and neurokinin A. producing dilation. in part.  Therapy must be reevaluated: Migraine headaches may improve. blocking NI. Most migraine preventive drugs were designed to treat other disorders. and others may not require it at all. the ceiling dose for the chosen drug is reached. inhibiting peripheral sensitization and CS. or side effects become intolerable. and modulating sympathetic. block CSD (12). mitral valve prolapse. In controlled clinical trials. modulates the trigeminal nucleus caudalis and prevents CS.  A woman of childbearing potential must be made aware of potential risks and the medication that will have the least adverse effect on the fetus must be picked (13).  Interfering. parasympathetic.  Each treatment must be given an adequate trial. overused. enhancing antinociception. The aura is triggered in the hypersensitive cortex (CSD). Decreased antinociceptive system activity and increased peripheral input may be present. Headache is generated by central pain facilitation and NI. Antidepressants downregulate 5-HT2 and b-adrenergic receptors. Principles of Preventive Therapy The following principles are useful regardless of the chosen preventive medication:  The chosen drug should be started at a low dose and increased slowly until therapeutic effects develop. must be considered. Moskowitz has recently shown that preventive medications given chronically.  Patients must be made to involve themselves in their care to maximize compliance. and certain psychological disorders. independent of treatment. or ergot derivatives. The rationale for a particular treatment.314 Silberstein Migraine may be a result of a change in processing of pain and sensory input. triptans. when and how to use it. Potential mechanisms of migraine preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system. The expected benefits of therapy and how long it will take to achieve them must be discussed with the patients. Oshinsky has shown that descending control from the upper brainstem. through serotonergic and noradrenergic systems. Anticonvulsant medications decrease glutamate and enhance gamma-aminobutyric acid (GABAA). and contraindicated drugs must be avoided. opioids. the drug dosage must be slowly tapered and. Raynaud’s syndrome. which is the presence of two or more disorders whose association is more likely than chance. and what are the likely side effects must be discussed. Conditions that are comorbid with migraine include stroke. inhibiting CSD. anxiety. in part. Many patients experience continued relief with a lower dose of the medication. Patient preferences must be taken into account when deciding between drugs of relatively equivalent efficacy. or serotonergic tone. The patient’s expectations must be addressed. mediated by supraspinal facilitation. A full therapeutic trial may take two to six months. including depression. mania. but not acutely. epilepsy. the patient should not overuse analgesics. discontinued. . if possible. If the headaches are well controlled. CS can occur. and panic (Table 2) (14–17). Serotonin antagonists were developed based on the concept that migraine is due to excess 5-hydroxytryptamine (5-HT). efficacy is often first noted at four weeks and continues to increase for three months.  Comorbidity. To obtain maximal benefit from preventive medication. b-Blockade inhibits norepinephrine (NE) release by blocking prejunctional b-receptors. in the superior cervical ganglia. Four trials comparing metoprolol with placebo had mixed results (27–30). it results in a delayed reduction in tyrosine hydroxylase activity.Preventive Treatment for Migraine 315 SPECIFIC MIGRAINE-PREVENTIVE AGENTS b-Adrenergic Blockers b-blockers. a delayed reduction of the locus ceruleus neuron–firing rate has been demonstrated after propranolol administration (55). Metoprolol was similar to propranolol (28. One trial comparing propranolol and amitriptyline suggested that propranolol is more efficacious in patients with migraine alone. Overall. The only factor that correlates with the efficacy of b-blockers is the absence of partial agonist activity (31. but it appears that their antimigraine effect is due to inhibition of b1-mediated mechanisms (55). and amitriptyline has a superior effect on patients with the phenotypes of migraine and tension-type headache (26). Headache Consortium (21) analyzed 74 controlled trials of b-blockers for migraine prevention. the most widely used class of drugs in prophylactic migraine treatment. No absolute correlation has been found between propranolol’s dose and its clinical efficacy (22). In addition.43. Timolol (37–39). and pindolol) are not effective for migraine prevention (45–50). Evidence consistently showed propranolol to be effective for migraine prevention with a daily dose of 120 to 240 mg. atenolol (40–42). the ratelimiting step in NE synthesis.S. Mechanism of Action The mechanism of action of b-blockers is not certain. This could explain the delay in the prophylactic effect of the b-blocker.44) are also likely to be beneficial based on comparisons with placebo or with propranolol. the 26 placebocontrolled trials showed clear short-term effects of propranolol over placebo. Linde and Rossnagel (24) in a Cochrane analysis included randomized and quasi-randomized clinical trials of at least four weeks’ duration. One meta-analysis revealed that. A total of 58 trials with 5072 participants met the inclusion criteria. (ii) interaction with 5-HT receptors (but not all b-blockers bind to the 5-HT receptors). In the rat brainstem. are approximately 50% effective in producing a greater than 50% reduction in attack frequency. b-Blockers with intrinsic sympathomimetic activity (acebutolol. oxprenolol. The action of b-blockers is probably central and could be mediated by (i) inhibiting central b-receptors interfering with the vigilance-enhancing adrenergic pathway. Propranolol was more effective than placebo in the short-term interval treatment of migraine (25).41.31–33). and a variety of other drugs did not yield any clear-cut differences. The Agency for Healthcare Policy and Research (AHCPR) Technical Report (20) and the U. one out of six patients discontinued propranolol treatment (23). and nadolol (14–17.51–54). flunarizine (34. other beta-blockers. (18) serendipitously discovered propranolol’s effectiveness in headache treatment in patients who were being treated for angina (19).35). Rabkin et al. comparing the clinical effects of propranolol with placebo or another drug in adult migraineurs. propranolol yielded a 44% reduction in migraine activity compared with a 14% reduction with placebo. on average. Overall. Propranolol inhibits nitric oxide (NO) production by blocking inducible NO . alprenolol. and pizotifen (36). The 47 comparisons with calcium antagonists. and (iii) cross-modulation of the serotonin system (56). because stopping them abruptly can cause increased headache (29) and the withdrawal symptoms of tachycardia and tremulousness (64). sleep disorders. The short-acting form can be given three to four times a day. Clinical Use Propranolol [approved by the Food and Drug Administration (FDA) for migraine] is a nonselective b-blocker with a half-life of four to six hours. asthma. suggesting that the CNV may predict the response to b-blocker treatment (58). lethargy. impotence.316 Silberstein synthase. b-Blockers are not absolutely contraindicated in migraine with aura unless a clear stroke risk is present. and aggravation of intrinsic muscle disease. significant bradycardia. Schoenen et al. Common AEs include gastrointestinal complaints and decreased exercise tolerance. given once daily or in split doses. and the long-acting form. nausea. The dose ranges from 20 to 160 mg/day. which is consistent with central adrenergic hyperactivity in migraine. Some authors have commented on continued improvement (61) and lack of rebound (62) after discontinuing propranolol. indicating that they all affect the central nervous system (CNS). fatigue. is significantly increased and its habituation reduced in patients with untreated migraine without aura. but the actual risk is uncertain. and insomnia. once or twice a day. an event-related slow negative scalp potential. with no correlation between propranolol and 4-hydroxypropranolol plasma levels and headache relief (67). However. centrally mediated secretion of epinephrine after exposure to light (59). The reported adverse reactions to propranolol may be either coincidental or idiosyncratic. (58) have shown that contingent negative variation (CNV). it seems more reasonable to slowly taper b-blockers. Migraineurs exhibit an enhanced. Nadolol is a nonselective b-blocker with a long half-life. An advantage of the regular propranolol is its greater dosing flexibility. It is less lipid soluble than propranolol and has fewer CNS side effects. memory disturbance. It is also available in a long-acting formulation (65. such as drowsiness. AEs most commonly reported in clinical trials with b-blockers were fatigue. which reduce neuronal activity and has membrane-stabilizing properties (57). Whether this includes prolonged aura is uncertain. depression. These symptoms appear to be fairly well tolerated and were seldom the cause of premature withdrawal from trials (20). CNV normalizes after treatment with b-blockers. Congestive heart failure. The dose in children is 1 to 2 mg/kg/day (Table 3). Propranolol has been reported to have an adverse effect on the fetus (60). nightmares. . Migraineurs who have elevated CNV scores have a much better response to b-blocker therapy (80% effective) than migraineurs who have a low or normal score (22% effective). All b-blockers can produce behavioral adverse events (AEs). Less common are orthostatic hypotension. dizziness. Some authorities prefer it to propranolol because it has fewer side effects (68). Propranolol should be started at a dose of 40 mg/day in divided doses and slowly increased to tolerance. Propranolol also inhibits kainate-induced currents and is synergistic with N-methyl D-aspartate blockers. although we recommend twice a day. Others have found no carry-over effects (63). depression.66). and insulin-dependent diabetes are contraindications to the use of nonselective b-blockers. this returns to normal after treatment with propranolol. and hallucinations. The therapeutically effective dose ranges from 40 to 400 mg/day. Antidepressants Antidepressants consist of a number of different classes of drugs with different mechanisms of action. and serotonin NE–reuptake inhibitors increase synaptic NE or serotonin (5-HT) by inhibiting high-affinity .i. 1–2 mg/kg in children The dose should be divided Short half-life 10–400 10–300 10–150 Starting dose of 10 mg at bedtime Starting dose of 10 mg at bedtime Starting dose of 10–25 mg at bedtime If insomnia present.d.d. Atenolol is a selective b1-blocker with fewer side effects than propranolol.i.i. Metoprolol is a selective b1-blocker with a short half-life.5–225 Mirtazapine tablets 15–45 Monoamine oxidase inhibitors Phenelzine 30–90 Strict diet considerations Timolol (approved by the FDA for migraine) is a nonselective b-blocker with a short half-life. The long-acting preparation may be given once a day.i. or t.d. The dose ranges from 100 to 200 mg/day in divided doses.d.Preventive Treatment for Migraine Table 3 b-Blockers and Antidepressants in the Preventive Treatment of Migraine Agent b-blockers Atenolol Metoprolol Nadolol Propranolol 50–200 100–200 20–160 40–400 Daily dose (mg) Comment 317 Timolol Antidepressants Tertiary amines Amitriptyline Doxepin Secondary amines Nortriptyline 20–60 Can be used q. Mechanism of Action TCAs. we cover the newer components for completeness and reader interest. The dose ranges from 50 to 200 mg/day once daily. Less side effects than propranolol The short-acting form should be used b.d. The long-acting form must be used q.d.d. must be given early in the morning Starting dose of 10–25 mg at bedtime Protriptyline 5–60 Selective serotonin reuptake inhibitors Fluoxetine tablets 10–80 Evidence in the treatment of migraine is controversial Sertraline tablets 25–100 Some may worsen the migraine pattern Paroxetine tablets 10–30 May be used as an adjuvant in the treatment of migraine and severe depression Venlafaxine tablets 37. Less side effects than propranolol Short-acting form must be used b. or b. The long-acting form can be used q. Only tricyclic antidepressants (TCAs) have proven efficacy in migraine.d. Can be used q. The dose ranges from 20 to 60 mg/day in divided doses. selective serotonin-reuptake inhibitors (SSRIs). or hippocampal infusions of BDNF in rats reduce learned helplessness behavior and reduce immobility in the forced swim and inescapable shock models. and electroconvulsive therapy) is a decrease in b-adrenergic receptor density and NE-stimulated cyclic adenosine monophosphate (cAMP) response. there may be enhanced physiologic responsiveness. augments serotonin synthesis and turnover. Adenosine A1 receptor activation results in antinociception mediated by inhibition of adenylate cyclase. TCAs and electroconvulsive shocks (ECS) enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors. BDNF binds to and phosphorylates its high-affinity tyrosine kinase receptor and activates intracellular signaling pathways including microtubule-associated protein kinase and cAMP (76). Serotonergic axon densities are decreased in the prefrontal cortex of suicide patients with major depressive disorder (77). long-term antidepressant treatment actually enhances the efficacy of 5-HT synaptic transmission. Adenosine A3 receptors facilitate pain due to release of histamine and 5-hydroxytryptamine from mast cells (72. whereas lesions of the NE system block the decrease in 5-HT2–receptor binding (69). whereas selective 5-HT reuptake blockers reduce the function of terminal 5-HT autoreceptors. that produce learned helplessness in animals and precipitate depression in humans decrease BDNF mRNA (79). thereby increasing the amount of 5-HT released per stimulation-triggered action potential (70). The most consistent neurochemical finding with antidepressant treatment (including the TCAs. such as immobilization. In the neocortex and hippocampus. The decrease in 5-HT2 receptor–binding sites does not correlate with a decrease in function. and increases serotonergic axon fiber density. BDNF mRNA and protein are highly expressed (78). neurotrophin-3 (NT-3). downregulate the histamine receptor. Long-term antidepressant treatment decreases 5-HT2–receptor binding and imipramine-binding sites (related to the 5-HT uptake system) but does not change 5-HT1–receptor binding. TCAs upregulate the GABA-B receptor.73). Some are more potent inhibitors of NE. Neurotrophic factors may also be candidates for mediating the long-term effects of antidepressants. others of 5-HT reuptake. outgrowth. and NT-6] positively modulate monoaminergic neurotransmission (74) and CNS neuron survival. BDNF promotes serotonin neuron development. BDNF mRNA increases in animals treated with antidepressant drugs and . Antidepressant treatment b-receptor downregulation is dependent on an intact 5-HT system. and neuroprotection (75). indicating an antidepressant-like effect. In fact. TCAs also interact with endogenous adenosine systems. MAOIs. dorsal raphe. A strong interaction exists between the NE and 5-HT systems. The mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Environmental stressors. Intraventricular. whereas adenosine A2 receptor activation is pronociceptive due to stimulation of adenylate cyclase within the sensory nerve terminal (71). brain-derived neurotrophic factor (BDNF). Increased a1-receptor system sensitivity is not seen as consistently with antidepressant treatment. NT-4/5. and enhance the neuronal sensitivity to substance P. They inhibit adenosine and augment its electrophysiologic actions contributing to antinociception.318 Silberstein reuptake. The neurotrophins [a protein class comprising nerve growth factor. Some TCAs are 5-HT2–receptor antagonists. SSRIs. Bupropion is both a dopamine and NE-reuptake inhibitor. and these regions are widely implicated in the pathophysiology of depressive disorders. Monoamine oxidase inhibitors (MAOIs) block the degradation of catecholamines. and three weeks of treatment increased it by 18% in the frontal cortex and 29% in the neostriatum.Preventive Treatment for Migraine 319 following seizures (80). Another trial reported that amitriptyline was significantly more efficacious than propranolol for patients with mixed migraine and tension-type headache. BDNF protein levels were measured with a two-site enzyme-linked immunosorbent assay in six brain regions of adult male rats that received daily ECS or daily injections of antidepressant drugs. and is the only antidepressant with fairly consistent support for efficacy in migraine prevention. The evidence was insufficient to support the efficacy of clomipramine (27. Antidepressants increase BDNF mRNA in the brain via 5-HT2A and b-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA.85–99). stratified by severity. Clinical trials are currently evaluating the antidepressant activity of small molecules that increase BDNF mRNA and protein release from cultured cells (76). TR-DHE was significantly better than amitriptyline at reducing the number of hours of extremely severe and severe migraine-like pain. BDNF protein immunoreactivity was elevated compared with subjects who were not so treated at the time of death (80). Fluoxetine was significantly better than placebo in one (85) but not a second (95) migraine prevention trial. and the response occurs sooner than the expected antidepressant effect (81. fluoxetine. whereas propranolol was significantly better for patients with migraine alone (26). The antidepressants that are clinically effective in headache prevention either inhibit noradrenaline and 5-HT reuptake or are antagonists at the 5-HT2 receptors (84). One trial found no significant difference between amitriptyline and propranolol (97). In the hippocampus of depressed patients treated with unspecified antidepressants.97). Three placebo-controlled trials found amitriptyline significantly better than placebo at reducing headache index or frequency (88–90. However. including headache. Two weeks of daily injections with the MAO-A and MAO-B inhibitor tranylcypromine (8–10 mg/kg. antidepressants potentiate the effects of coadministered opioids (83). independent of the presence of depression. Tranylcypromine. and desmethylimipramine did not elevate BDNF in the hippocampus. with a peak response by the fourth day of ECS. BDNF increased gradually in the hippocampus and frontal cortex. Amitriptyline has been more frequently studied than the other agents. showed that amitriptyline was significantly better than TR-DHE at reducing the number of hours of moderate and mild tensiontype headache-like pain. a trial conducted in a group of patients with mixed migraine and tension-type headache found that amitriptyline was significantly better than timed-released dihydroergotamine (TR-DHE) at reducing headache index (87). In contrast.27. . Antidepressants are useful in treating many chronic pain states. Increases peaked at 15 hours after the last ECS and lasted at least three days thereafter. an analysis of the data on headache duration. IP) increased BDNF by 15% in the frontal cortex. The mechanism by which antidepressants work to prevent headache is uncertain but does not result from treating masked depression.82).94) and fluvoxamine (99) for migraine prevention. In animal pain models. Similarly. Clinical Trials and Use A total of 16 controlled trials have investigated the efficacy of the TCAs amitriptyline and clomipramine and the SSRIs fluoxetine and fluvoxamine (26. Elevations in BDNF protein in the brain are consistent with greater treatment efficacy of ECS and MAOIs in drugresistant major depressive disorder and may be predictive for the antidepressant action of the more highly efficacious interventions (80).  With the exception of protriptyline. dizziness. Adrenergic activity is responsible for the orthostatic hypotension.320 Silberstein Tricyclic Antidepressants Pharmacology of the TCAs. Ten percent of patients develop tremors.5 mg/kg body weight. palpitations. . particularly in older patients who are more vulnerable to the muscarinic side effects. have a high volume of distribution. the TCAs have not been vigorously evaluated. A useful rule of thumb is to start low and aim for a dose of 1 to 1. and urinary retention.  If the TCA is too sedating. The following principles are useful when using a TCA. their use is based on anecdotal or uncontrolled reports. and avidly bind to plasma proteins. which contributes to weight gain. None have been approved for migraine. doxepin. Antidepressant treatments may also reduce the seizure threshold (101). With the exception of amitriptyline. nortriptyline. They are less sedating than the TCAs and some patients may require a hypnotic for sleep induction. which should be administered in the morning. although this is not generally a problem in antimigraine treatment. constipation. Treatment should be started with a low dose of the chosen TCA taken at bedtime. AEs are common with TCA use. The AEs of TCA are due to its interaction with multiple neurotransmitters and their receptors. The dose ranges from 10 to 400 mg/day (Table 3). tachycardia.  Bipolar patients can become manic on antidepressants.  SSRIs can be given as a single dose in the morning. Imipramine and desipramine have been used at times.  The TCA dose range is wide and must be individualized. The antimuscarinic AEs are most common. with a 10. Amitriptyline and other TCAs rarely cause inappropriate secretion of antidiuretic hormone. reflex tachycardia. but this has been evaluated only for nortriptyline for treatment of depression. There is wide individual variation in the absorption. epigastric distress. and confusion or delirium may occur. a metallic taste. The antihistamine and antimuscarinic activity of the TCAs account for many of their side effects (100). the tertiary TCA (amitriptyline and doxepin) should be switched over to a secondary TCA (nortriptyline and protriptyline). blurred vision. and palpitations that patients may experience. There may exist a therapeutic window above which the TCAs are ineffective. Antihistaminic activity may be responsible for carbohydrate cravings. TCAs are sedating. TCAs are lipid soluble. Clinical Use Tertiary Amines. The TCAs most commonly used for headache prophylaxis include amitriptyline. distribution. Patients with coexistent depression are more tolerant and require higher doses of amitriptyline. except in the case of protriptyline. Amitriptyline is a tertiary amine tricyclic that is sedating and has antimuscarinic activity. Principles of TCA Use. and excretion of the TCAs.to 30-fold variation in individuals’ drug metabolism. Any antidepressant treatment may change depression to hypomania or frank mania (particularly in bipolar patients). Administration of the drug should be started at a dose of 10 to 25 mg at bedtime. TCA should be given in the morning. and protriptyline. although rigorous evidence for activity in migraine is lacking. mental confusion. If a patient develops insomnia or nightmares. they include dry mouth. the drug must be given earlier in the day or in divided doses. The dose of phenelzine ranges from 30 to 90 mg/day in divided doses.9% of patients on placebo (103). resistant cases of migraine. double-blind. which preferentially deaminates dopamine. The drug is started at a dose of 10 to 25 mg at bedtime. parallel study of fluoxetine showed a significant reduction (p < 0. vomiting. fatigue.05) beginning from the third month of treatment in the fluoxetine group and no significant reduction in the placebo group. nausea.3% of patients on fluoxetine. All patients on MAOI-A must be on a restricted diet and avoid certain medications to prevent hypertensive crisis. randomized. Fluoxetine. paroxetine. Monoamine Oxidase Inhibitors MAOIs exist in two subtypes: MAO-A. A recent single-center. If insomnia develops. The drug should be started at a dose of 10 mg at bedtime. Headache was noted in 20. L-Deprenyl is a selective MAO-B inhibitor that may be effective in the treatment of Parkinson’s disease.Preventive Treatment for Migraine 321 Doxepin is a sedating tertiary amine TCA. as early as one month after initiation of therapy (105). The MAOI phenelzine at a dose of 15 mg TID was effective in an open study (108). The most common AEs include anxiety. sertraline. The combination may require dose adjustment of the TCA because levels may significantly increase. and dizziness or lightheadedness. The dose ranges from 10 to 150 mg/day. double-blind trials exist. They are helpful for patients with comorbid depression because their tolerability profile is superior to tricyclics. Meperidine. fluvoxamine. however. The dose ranges from 10 to 300 mg/day. anorexia. The dose ranges from 10 to 80 mg/day. Nortriptyline is a major metabolite of amitriptyline. These drugs produce less weight gain (and in some cases produce weight loss) and have fewer cardiovascular side effects than the TCAs (102). Some researchers have reported that fluoxetine does not improve or may worsen headache (107). drowsiness. alcohol. Evidence for the use of SSRIs is poor. The dosage should be started at 5 mg/day. Anecdotal reports (106) and our experience seem to indicate its benefit in migraine prophylaxis where coexistent depression is a prominent issue. Monoamine-Reuptake Inhibitors Selective Serotonin-Reuptake Inhibitors. Nortriptyline is a secondary amine that is less sedating than amitriptyline. The dose ranges from 5 to 60 mg/day. Phenelzine is a nonspecific inhibitor of MAO-A and MAO-B. The efficacy analysis summarized in the AHCPR Evidence Report did not indicate a clear benefit of the racemic mixture of fluoxetine over placebo. sweating. and foods with a high . tremor. sympathomimetics (including Midrin). The combination of an SSRI and a TCA can be beneficial in treating refractory depression (104) and. insomnia. and citalopram are specific SSRIs that have minimal antihistaminic and antimuscarinic activity. and MAO-B. but no placebo-controlled. Protriptyline is a secondary amine similar to nortriptyline. which preferentially deaminates NE and 5-HT. In contrast. a recent randomized controlled trial of S-fluoxetine indicated a possible clinical benefit in migraine prevention. Secondary Amines. as measured by a reduction in migraine frequency. nervousness. Fluoxetine should be administered starting at a dose of 10 mg in the morning. it was also noted in 19. in our experience. including muscle contraction. inhibition of ejaculation or reduced libido. and activation and inactivation properties (116). Voltage-gated calcium channels mediate calcium influx in response to membrane depolarization and regulate intracellular processes such as contraction.5-triphosphate receptors (116). There are six functional subclasses of voltage-gated calcium (Ca2þ) channels. The most common AEs of MAOIs include insomnia. and gene expression. They fall into two major categories: high-voltage–activated channels and the unique low-voltage– activated T-type. When stimulated. The concentration gradient is established by membrane pumps and the intracellular sequestering of free calcium. it incorporates the conduction pore. as gut MAO activity rapidly returns to normal (113). The a1 subunit of 190 to 250 kDa is the largest. Its extracellular concentration is high. in combination with a calcium-binding protein such as calmodulin or troponin. sauerkraut. and a cytoplasmic b subunit that modifies the channel’s current amplitude. Pharmacology of the Calcium-Channel Blockers Two types of calcium channels exist: calcium entry channels. drugs.000-fold smaller. opened by depolarization. and R. these are named T. its intracellular free concentration is 10. secretion. and toxins. and other soybean condiments) must be avoided (108–112). which allow extracellular calcium to enter the cell. which allow intracellular calcium (in storage sites in organelles) to enter the cytoplasm. and enzyme activity. including a membrane-spanning a2-d complex that increases the amplitude of calcium currents and binds the anticonvulsant gabapentin. tap beers. They are members of a gene superfamily of transmembrane ion channel proteins that includes voltage-gated potassium and sodium channels. banana peel. P. less commonly. the voltage sensor and gating apparatus. increased perspiration. N. Sublingual nifedipine has been used to treat hypertensive crisis when it occurs in MAOI users (114). and subunit isoforms give rise to distinct channel subtypes. fava beans. Insomnia can be reduced by giving most of the medication early in the day. The risk of hypertensive crisis may be reduced by having the patient take the MAOI three to four hours before or after eating or taking the entire dose at bedtime. Q. constipation. yeast extract. and the known sites of channel regulation by second messengers. L. Calcium entry channel subtypes include voltage-gated. These subunits have different functions. opened by chemical messengers (such as glutamate) and capacitative. which are activated at negative potentials (117).322 Silberstein tyramine content (cheddar cheese. voltage dependence. neurotransmitter and hormone release. which are encoded by multiple genes. The a1 subunit of voltage-gated calcium channels is organized in four homologous domains (I–IV) with six transmembrane segments . ligand-gated. Marmite and Veggie-Mite concentrated. activated by depletion of intracellular calcium stores. weight gain. Calcium-Channel Antagonists Calcium. and calcium release channels. Voltage-gated calcium channels are heteromers composed of four or five distinct subunits. neurotransmission. soy sauce. and. regulates many functions. The a1 subunit is associated with auxiliary subunits. orthostatic hypotension. peripheral edema. They are modulated by ryanodine and inositol 1.4. the cell can open calcium channels in the plasma membrane or release intracellular stores of calcium (115). Calcium channels are named using the chemical symbol of the principal permeating ion (Ca) with the principal physiological regulator (voltage) indicated as a subscript (CaV). the pharmacologic and electrophysiological diversities of calcium channels arise primarily from the existence of multiple a1 subunits (118). The CaV2 subfamily (CaV2. They are expressed primarily in neurons. and a1F. The CaV2. The CaV2 family of calcium channels is relatively insensitive to dihydropyridine calcium channel blockers. Calcium currents have diverse physiological and pharmacologic properties. The CaV1 channels are the molecular targets of the organic calcium channel blockers used widely in the therapy of cardiovascular diseases. P/Q-type. An intracellular b subunit and a transmembrane. are thought to act allosterically to shift the channel toward the open or closed state. The CaV3 family of calcium channels is insensitive to both the dihydropyridines that block CaV1 channels and the spider and cone snail toxins that . and related subunits are expressed in heart and brain. These peptide toxins are potent blockers of synaptic transmission because of their specific effects on the CaV2 family of calcium channels. where they initiate neurotransmission at most fast synapses and also mediate calcium entry into cell bodies and dendrites.3 channels are blocked specifically by the synthetic peptide toxin SNX-482 derived from tarantula venom. receptor sites. which mediate T-type Ca2þ currents (118). respectively. which mediate P/Q-. Diltiazem and related benzothiazepines are thought to bind to a third receptor site (118). The CaV2. L-type calcium currents require a strong depolarization for activation and are long lasting (117). and IV will convert a sodium channel to calcium selectivity. These drugs are thought to act at three separate.1 to CaV1. Dihydropyridines can be channel activators or inhibitors and.1 to CaV2. and a1E. Phenylalkylamines are intracellular pore blockers. N-type. a1C. They are the main calcium currents recorded in muscle and endocrine cells. and a1I. rather than by occluding the pore. Although these auxiliary subunits modulate the properties of the channel complex. The CaV2. a1D. N-.3) includes channels containing a1G. The CaV3 subfamily (CaV3. A g subunit has also been found in skeletal muscle calcium channels. and R-type calcium currents also require strong depolarization for activation. The pore loop between transmembrane segments S5 and S6 in each domain determines ion conductance and selectivity. T-type calcium currents are activated by weak depolarization and are transient. a1B.Preventive Treatment for Migraine 323 (S1–S6) in each.1 channels are blocked specifically by o-agatoxin IVA from funnel web spider venom. and R-type Ca2þ currents. disulfide-linked a2d-subunit complex are components of most types of calcium channels. The S4 segment serves as the voltage sensor. which mediate L-type Ca2þ currents.4) includes channels containing a1S. therefore.3) includes channels containing a1A. but allosterically coupled. III.2 channels are blocked specifically by o-conotoxin GVIA and related cone snail toxins.1 to CaV3. and changes of only three amino acids (aa) in the pore loops in domains I. but these calcium channels are specifically blocked with high affinity by peptide toxins of spiders and marine snails (119). where they are involved in shaping the action potential and controlling patterns of repetitive firing (118). According to this nomenclature. the CaV1 subfamily (CaV1. where they initiate contraction and secretion. Mammalian a1 subunits are encoded by at least 10 distinct genes. a1H. The numerical identifier corresponds to the CaV channel a1 subunit gene subfamily (1–3 at present) and the order of discovery of the a1 subunit within that subfamily (1 through m). The pharmacology of the three families of calcium channel is distinct. They are expressed in a wide variety of cell types. Mechanism of Action in Migraine The mechanism of action of the calcium channel antagonists in migraine prevention is uncertain. nifedipine (5 trials).146). Our conclusion is that nifedipine is ineffective as a migraine preventive. Two comparisons with placebo yielded similar effect sizes that were statistically insignificant. cyclandelate (3 trials). but suggested that differences in the effects of the two treatments were small.131). controlled trial evidence to support the use of verapamil in migraine. and inhibition of the Ca2þ-dependent enzymes involved in prostaglandin formation. One trial comparing flunarizine and dihydroergocryptine (DEK) (137) reported mixed results. randomized.324 Silberstein block the CaV2 channels. and placebo (54. This trial reported no significant difference between verapamil.139). One trial found that metoprolol was significantly better than nifedipine at reducing headache frequency (32). The discovery that an abnormality in an a1A subunit (P/Q channel) can produce familial hemiplegic migraine (121) has led to a search for more fundamental associations.149). Three placebo-controlled studies suggested no significant differences (138. showed no significant differences between flunarizine and these b-blocking agents. Our interpretation and our clinical experience is that nimodipine is ineffective in migraine prevention.145). nimodipine (11 trials).147). They were introduced into the treatment of migraine on the assumption that they prevent hypoxia of cerebral neurons. including flunarizine (25 trials). interfere with neurovascular inflammation. Diltiazem (60–90 mg QID) was effective in two small open studies (148. whereas two reported relatively large and statistically significant differences in favor of nimodipine (140). verapamil (3 trials). A meta-analysis of these seven heterogeneous trials was statistically significant in favor of flunarizine. Nimodipine had mixed results in placebocontrolled trials. but the 95% confidence intervals associated with these estimates were large and did not exclude either a clinically important benefit or harm associated with nifedipine (143). Five comparisons of flunarizine with propranolol (130. or interfere with the initiation and propagation of spreading depression that is critical (120). or between flunarizine and methysergide (136). rendering the findings uncertain (54. Flunarizine was compared with placebo in eight migraine prevention trials and effect sizes could be calculated for seven studies (122–128).119). propranolol. and two with metoprolol (35. There are no widely useful pharmacological agents that block T-type calcium currents (118. but both positive trials had high dropout rates. pizotifen (133) or propranolol (142). There were no significant differences between flunarizine and pizotifen (133–135). . Nimodipine was not different than flunarizine (141). Similarly ambiguous results were reported in one comparison with flunarizine (144) and two comparisons with propranolol (32. The single negative placebo-controlled trial included a propranolol treatment arm. The evidence for nifedipine was difficult to interpret. Verapamil was more effective than placebo in two of three trials. contraction of vascular smooth muscles. but not the eighth study (129). and nicardipine (1 trial) (20). These studies are insufficient to recommend the use of diltiazem. Clinical Trials The AHCPR Technical Report identified 45 controlled trials of calcium antagonists.132). Our conclusion is that there is no rigorous. Perhaps it is their ability to block 5-HT release. The drug can be started at a dose of 40 mg two to three times a day. 80. Peak plasma levels occur in five hours. hypotension. topiramate. with a maximum of 640 mg/day in divided doses. Anticonvulsants Anticonvulsant medication is increasingly recommended for migraine prevention. not weight gain Starting dose of 250–500 mg/day Levels should be monitored if compliance is an issue Maximum dose is 60 mg/kg day Selected calcium channel blockers Verapamil 120–640 mg Flunarizine 5–10 mg Selected anticonvulsants Carbamazepine 600–1200 mg Gabapentin 600–1200 mg Topiramate 100 mg Valproate/Divalproex 500–1500 mg/day Adverse Events AEs of the Ca2þ antagonists are dependent on the drug. dry mouth. anticonvulsants . and exacerbation of depression.d. The most prominent AEs include weight gain. hypotension. double-blind trials.5 hours (Table 4). at bedtime Weight gain is the most common side effect t.i. headache. With the exceptions of valproic acid. dizziness.d. Headache improvement frequently requires weeks of treatment. 180. The elimination half-life of flunarizine is 19 days.5 to 7. The sustained-release preparation of verapamil can be given once or twice a day. headache. somnolence. Clinical Use Verapamil is available as a 40. flushing. and mental symptoms (143). Side effects with nifedipine were frequent (54%) and included dizziness. Sustained release can be given q. Flunarizine is not available in the United States. dizziness. but unreliable absorption reduces reliability. The absorbed drug is tightly protein bound. It is given at a dose of 5 to 10 mg/day. and zonisamide. q. or 120 mg tablet or as a 120. the half-life ranges from 2. Patients frequently report an initial increase in headache. and edema are less common.d.i.Preventive Treatment for Migraine 325 Table 4 Selected Calcium-Channel Blockers and Selected Anticonvulsants in the Preventive Treatment of Migraine Agent Daily dose Comment Starting dose of 80 mg b. nausea. or 240 mg sustained-release preparation.i. edema.d. Dose can be increased up to 3000 mg Starting dose of 15–25 bedtime Can be increased by 15–25 mg/wk Reaching a dose of 50–100 mg must be attempted Can be increased further if necessary Associated with weight loss. because it was proved to be effective by placebo-controlled. Two trials of verapamil and one of nifedipine reported high dropout rates due to AEs (20). occasional extrapyramidal reactions.d. or b. The most common AE is constipation. Bioavailability is 20%.i.d. or t. Valproate turns off the firing of the 5-HT neurons of the dorsal raphe. Another trial. The two treatment groups were comparable with respect to treatment-limiting AEs. gabapentin. at lower concentrations. have an anticonvulsant effect and cause GABA accumulation in vivo (163). Valproic acid possesses anticonvulsant activity in a wide variety of experimental epilepsy models. with an elimination half-life between 8 and 17 hours.165). may be effective in preventive migraine treatment (Table 4).326 Silberstein may interfere substantially with the efficacy of oral contraceptives (150. although differences from clonidine were not statistically significant (157). and. Imbalance in the plasma concentrations of GABA. one of which (2-en-valproic acid) accumulates in the brain. an inhibitory aa. Valproate also attenuates plasma extravasation in the Moskowitz model of NI by interacting with the GABAA receptor. and directly enhancing its postsynaptic effects. Relatively high patientwithdrawal rates due to AEs were reported in some trials (20) (Table 4). 600 to 1200 mg/day.151). Valproic Acid Valproic acid is a simple eight carbon. inhibition of kindling. Carbamazepine The only placebo-controlled trial of carbamazepine suggested a significant benefit. Valproate enhances GABA activity within the brain by inhibiting its degradation. perhaps by inhibiting its degradation. and reduction of excitatory neurotransmission by the aa aspartate by blocking its release (164. comparing carbamazepine with clonidine and pindolol. However. it increases potassium conductance. Disordered GABA metabolism during migraine has been reported (161). Other potential mechanisms of action include direct effects on neuronal membranes (it suppresses induced and spontaneous epileptiform activity).02). suggested that carbamazepine had a weaker effect on headache frequency than either comparator treatment.162). Gabapentin was not effective in one placebocontrolled. which are implicated in controlling head pain. double-blind study (159). was superior to placebo in reducing the frequency of migraine attacks. it enhances the postsynaptic response to GABA. has also been observed (153–156. The valproate concentration required to inhibit GABA transaminase is greater than that which occurs during therapy. The responder rate was 36% for gabapentin and 14% for placebo (p ¼ 0. Carbamazepine (Tegretol). active metabolites. two chain fatty acid with 80% bioavailability after oral administration. The mechanism of action of valproate in migraine prevention may be related to facilitation of GABA-ergic neurotransmission (163–165). The relevant . producing neuronal hyperpolarization. In a more recent randomized. but this trial was inadequately described in several important respects (155). Nine controlled trials of five different anticonvulsants were included in the AHCPR Technical Report (53. double-blind trial (160). It is highly protein bound. Valproate at high concentrations increases GABA levels in synaptosomes. placebo-controlled. and glutamic acid. an excitatory aa.152–156). Limited data were reported on AEs—the most common were dizziness or giddiness and drowsiness. at a dosage of 1800 to 2400 mg. stimulating its synthesis and release. Gabapentin Gabapentin (600–1800 mg) was effective in episodic migraine and chronic migraine in a 12-week open-label study (158). however. Five studies provided strong and consistent support for the efficacy of divalproex sodium (approved by the FDA) (153. however. One hundred seven patients were randomized to divalproex sodium or placebo (2:1 ratio). Hering and Kuritzky (169) evaluated sodium valproate’s efficacy in migraine treatment in a double-blind. Sorensen (172) performed a prospective open trial of valproate. Jensen et al. and duration of attacks in 86. in a multicenter.169). showed almost identical AE rates for the placebo and active treatment arms. placebo-controlled investigation. single-blind. In addition. crossover study. Mathew et al. A single study compared divalproex sodium with propranolol and found differences favoring divalproex sodium. He studied 22 patients with severe migraine that was resistant to previous prophylactic treatment.162. whose attacks were reduced from 15. crossover study of slow-release sodium valproate. In 1988.Preventive Treatment for Migraine 327 receptor may be on the parasympathetic nerve fibers projecting from the sphenopalatine ganglia. with 70 receiving divalproex sodium and 37 receiving placebo.168. and weight gain.and dose-controlled.167.2% of 29 patients. During the last four weeks of valproate treatment. In 1995. No significant treatmentgroup differences were observed in average peak severity or duration of individual . Thirty-two patients were divided into two groups and given either 400 mg of sodium valproate twice a day or placebo for eight weeks. but not significantly different compared with propranolol. The most common AEs (33% valproate and 16% placebo) were intensified nausea and dyspepsia.001). studied 43 patients with migraine without aura in a triple-blind. the statistical significance of these results could not be determined (open-label study with high dropout rates) (153). Forty-eight percent of the divalproex sodium–treated patients and 14% of the placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from baseline (p < 0. in 1994 (152). it attenuates nociceptive neurotransmission (163). In 1992. tiredness. Follow-up in 3 to 12 months revealed that 11 patients were migraine-free. eight-week maintenance). The AE profile in the clinical trial. prompted by his clinical observations of valproate’s benefits. Fifty percent of the patients had a reduction in migraine frequency to 50% or less for the valproate group compared with 18% for placebo. placebo.8 a month. one had no change. in so doing. valproate-induced increased central enhancement of GABAA activity may enhance central antinociception (166). and were usually mild or moderate. randomized. severity. An extended release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation (171).6 to 8. for prevention of migraine in patients without aura (170). double-blind.168) and sodium valproate (162. Fifty-eight percent of the patients had no AEs. six had a significant reduction in frequency. A more recent study (not included in the AHCPR Technical Report) found divalproex sodium more effective compared with placebo. Sodium valproate was effective in preventing migraine or reducing the frequency. 65% responded. Two placebo-controlled trials of each of these agents showed them to be significantly better than placebo at reducing headache frequency (154. Thirty-four patients completed the trial. Valproate also interacts with the central 5-HT system and reduces the firing rate of midbrain serotonergic neurons (166). (154) compared the effectiveness and safety of divalproex sodium and placebo in migraine prophylaxis. increased appetite. placebo-baseline phase was followed by a 12-week treatment phase (four-week dose adjustment. After a four-week medication-free run-in period. the patients were randomized to sodium valproate (n ¼ 22) or placebo (n ¼ 21). randomized. Clinical Trials.169). and four had dropped out (Table 5).. A four-week. 9 Patient Population (diagnostic criteria) Design Dosage (mg/day)/ other medication Duration Plasma levels (mg/mL) No.000 mg/ sodium valproate Mean 73.4 Migraine 29 Jensen et al. (2002) Migraine with or without aura 234 12 Weeks 21% placebo 30% divalproex 24% placebo Silberstein .328 Table 5 Divalproex/Valproate Clinical Trials Study 800 mg (400 mg b.1–91. Results Hering and Kuritzky (1992) 1.i. (1995) Migraine with or without aura 107 16 Weeks 18% placebo 48% divalproex Klapper (1995) Migraine with or without aura 176 10 Weeks 14% placebo 43% divalproex Freitag et al.000–15.) 31.2% of patients responded better to valproate 50% valproate Mathew et al.d. (1994) Migraine without aura 43 Double-blind/ placebo-controlled crossover Double-blind/ placebo-controlled crossover Double-blind/ placebo controlled Double-blind/ placebo-controlled Double-blind/ placebo-controlled 500–1000 mg/ Divalproex 500–1600 or 1500 mg/ Divalproex ? 500–1500 mg/ Divalproex 70–120 8 Weeks each. total of 16 weeks 32 Weeks 86. Overall. was observed for both overall reduction in attack frequency and a 50% or more reduction in attack frequency. because of intolerance (p. including data from the double-blind study. randomized. and gastrointestinal distress are the most common AEs of valproate therapy. valproate . alopecia (31%). The primary efficacy variable was four-week headache frequency during the experimental phase. The proportion of subjects achieving at least 50% reduction in experimental phase migraine headache rate was higher in the extended-release divalproex sodium group (36/119. In an open-label study. and 1500 mg.Preventive Treatment for Migraine 329 migraine headaches. to permanently decrease the dose to 500 mg during the second week. placebo-controlled studies. the overall percentage of patients reporting AEs with divalproex sodium or sodium valproate was not higher than with placebo.251). 500. Reasons for premature discontinuation (67%) included administrative problems (31%). In three of four placebo-controlled trials. tremor. represented 198 patient-years of divalproex exposure. but the difference was not significant (p ¼ 0. 24%). placebocontrolled study. if intolerance occurred. The most frequently reported AEs were nausea (42%).6 (from a baseline mean of 4. drug intolerance (21%). The results. AEs were similar in all groups (divalproex sodium 24%.2) in the placebo group (p ¼ 0.2 (from a baseline mean of 4. Treatment was stopped in 13% of the divalproex sodium–treated patients and 5% percent of the placebo-treated patients. p ¼ 0.4) in the extendedrelease divalproex sodium group and 0. 1000. Nausea. With the exception of nausea. asthenia. or placebo. double-blind. 30%) than in the placebo group (28/115. vomiting. dyspepsia (25%).015) and most AEs were mild or moderate in severity. not significant). The mean reductions in the fourweek migraine headache rate were 1. compared with 21% of placebo-treated patients. and alopecia with divalproex sodium. Klapper et al. The fourth trial found significantly higher rates of nausea. Freitag et al. somnolence. On rare occasions. During the experimental phase.5 attacks per four weeks in the placebo group. the incidence of gastrointestinal symptoms decreases. Treatment was initiated by administering a dose of 500 g once daily for one week. and treatment ineffectiveness (15%). A statistically significant (p < 0. 1000. tremor (28%). (171) evaluated the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment. Divalproex was found to be safe and initial improvements were maintained for periods more than 1080 days. asthenia (25%). with an option. or 1500 mg. When therapy is continued.05) dose–response effect across the dose range placebo. Patients with two or more migraine attacks during the baseline phase were randomized to a daily divalproex sodium dose of 500. (168) evaluated the efficacy and safety of divalproex sodium as prophylactic monotherapy in a multicenter. particularly after six months. These are generally self-limited and are slightly less common with divalproex sodium than with sodium valproate.006).8 migraines per four weeks compared with a mean reduction of 0. placebo 7%. 43% of divalproex sodium–treated patients achieved 50% or more reduction in their migraine attack rates. vomiting. No unexpected AEs or safety concerns unique to the use of divalproex in the prophylactic treatment of migraine were found. infection (39%). The average dose was 974 mg/day. Silberstein and Collins (173) evaluated the long-term safety of divalproex sodium in patients who had completed one of two previous doubleblind. and somnolence (25%). reductions with extended-release divalproex sodium were significantly greater than with placebo in all three four-week segments of the treatment period. and the dose was then increased to 1000 mg once daily. the mean reduction in the combined daily divalproex sodium groups was 1. Divalproex sodium is a stable coordination complex comprising sodium valproate and valproic acid in a 1:1 molar ratio. . thereby blocking gluconeogenesis. Because of valproate’s potential idiosyncratic interactions with barbiturates (severe sedation and coma). and the patient’s general state of health. Monitor serum levels if there is a question of toxicity or compliance. ovarian cysts. Other important contraindications are hematologic disorders. but it has no hypoglycemic activity. An enteric-coated form of divalproex sodium is available as 125. The relative risk of hepatotoxicity from valproate is low in migraineurs. the patient’s age. An extended release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation. Valproic acid is available as 250 mg capsules and as a syrup (250 mg/5 mL). and bleeding disorders. resulting from elevated testosterone levels.) The maximum recommended dose is 60 mg/kg/day. and the presence of genetic and metabolic disorders. and 500 mg capsules and a sprinkle formulation. Topiramate was originally marketed for the treatment of epilepsy (179). Start with 250 to 500 mg/day in divided doses and slowly increase the dose. Topiramate Topiramate is a structurally unique anticonvulsant that was discovered serendipitously. The risk of valproate hepatotoxicity is highest in children under the age of two years. The frequency of these AEs varies with the number of concomitant medications used. It is not extensively metabolized and is eliminated predominantly unchanged in the urine. the patient’s age and general state of health. is of particular concern in young women with epilepsy who use valproate (177). Topiramate is a derivative of the naturally occurring monosaccharide D-fructose and contains a sulfamate functionality. pancytopenia. Valproate has little effect on cognitive functions and rarely causes sedation. they should be given with caution and at a low dose. It is uncertain if valproate can cause these symptoms in young women with migraine or mania. 250.330 Silberstein administration is associated with severe AEs such as hepatitis and pancreatitis. If these drugs are used. The structural resemblance of its O-sulfamate moiety to the sulfonamide moiety in acetazolamide prompted an evaluation of possible anticonvulsant effects. and obesity. The AE profile in the clinical trial showed almost identical adverse effect rates for the placebo and active treatment arms (178). migraine patients who are on valproate should not be given barbiturate-containing combination analgesics for symptomatic headache relief. it is now FDA approved for migraine. especially those treated with multiple antiepileptic drugs.6bisphosphatase. Absolute contraindications to valproate are pregnancy and a history of pancreatitis or a hepatic disorder such as chronic hepatitis or cirrhosis of the liver. those with metabolic disorders. (The usual therapeutic level is from 50 to 100 mg/mL. The frequency of these adverse reactions varies with the number of concomitant medications used. Topiramate is rapidly and almost completely absorbed (180). These idiosyncratic reactions are unpredictable (175). Hyperandrogenism. and those with severe epilepsy accompanied by mental retardation and organic brain disease (176).6-diphosphate capable of inhibiting the enzyme fructose-1. Valproate is potentially teratogenic and should not be used by pregnant women or women considering pregnancy (174). including thrombocytopenia. It was originally synthesized as part of a research project to discover structural analogs of fructose-1. the presence of genetic and metabolic disorders. The consensus peptide sequence at the protein kinase A–mediated phosphorylation site exhibits homology. In a pharmacokinetic interaction study with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE). Topiramate reduced SSS-evoked firing of neurons in the trigeminocervical complex in a dose-dependent fashion. and possibly CA2þ/CaMactivated kinases. and AMPA/kainate receptors are all regulated by protein phosphorylation (187–190). Topiramate can influence the activity of some types of voltage-activated Naþ and Ca2þ channels. as measured by whole-cell current-clamp recordings (186). the concentration in whole brain was approximately one-third of that in blood plasma one hour after oral dosing (181). use-dependent manner (185). At doses above 200 mg/day. topiramate at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure [area under the curve (AUC)] to either component of the oral contraceptive. Topiramate readily enters the CNS parenchyma. the GluR6 subunit of the AMPA/ kainate receptor contains an RRQS. threonine. Its inhibition is a plausible mechanism of the action of migraine or cluster headache preventive medicines. Activation of neurons within the trigeminocervical complex is likely to be the biological substrate for pain in migraine and cluster headache. Topiramate also inhibits some isozymes of carbonic anhydrase (CA) and exhibits selectivity for CA II and CA IV (179. Thus. arginine. A. Storer and Goadsby (191) studied the effect of topiramate on trigeminocervical activation in the anesthetized cat. topiramate may bind to the membrane channel complexes at phosphorylation sites in the inner loop and thereby allosterically modulate ionic conductance through the channels (182). and the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate subtype of glutamate receptors. asparagine). protein kinase C. i.183).. in rats. the b subunit of the GABAA receptor contains RRAS. over time. The effects of topiramate on voltage-activated Naþ channels. The superior sagittal sinus (SSS) was isolated and electrically stimulated. there may be a dose-related reduction in exposure to the estrogen component of oral contraceptives.Preventive Treatment for Migraine 331 The average elimination half-life is approximately 21 hours (180). Topiramate can reduce the amplitude of tetrodotoxin-sensitive voltage-gated Naþ currents in rat cerebellar granule cells. secondarily. Topiramate is therefore not associated with significant reductions in estrogen exposure at doses below 200 mg/day. GABAA receptors. .e. topiramate could exert either a positive or a negative allosteric modulatory effect. and is not affected by food (182). respectively (R. S. Units linked to SSS stimulation were recorded in the most caudal part of the trigeminal nucleus. The anticonvulsant activity of most antiepileptic drugs is thought to be due to a state-dependent blockade of voltage-dependent Naþ or Ca2þ channels or an ability to enhance the activity of GABA at GABAA receptors (181. One or more subunit of each complex is phosphorylated by protein kinase A.184). and N. glutamine. serine. T. which. alanine. thereby preventing phosphorylation. The bioavailability of topiramate from the tablet formulation is about 80%. GABAA receptors. Immediately upon binding to the site. and some subtypes of the primary subunit of Naþ and Ca2þ channels contain RRNS and RRPT. voltage-activated calcium channels. topiramate would prevent protein kinase A from accessing the serine hydroxyl site. Q. Topiramate blocks Naþ channels in a voltage-sensitive. would shift a population of channels toward the dephosphorylated state (182). In a preliminary safety and efficacy study (195). anorexia.001). or placebo. In addition. Brandes et al. and 200 mg/day) in migraine prevention in a 26-week. 213 patients were randomized (2:1) to topiramate or placebo and were titrated to either 200 mg/day or maximum tolerated dose over an eight-week period. 100. The primary efficacy measure was the change in mean monthly migraine frequency between baseline and the double-blind phase.04). 54% with topiramate 100 mg (p < 0. For each protocol. 100. Patients who completed the baseline period and met the entry criteria were randomized to one of four treatment groups: 50 mg/day topiramate. Patients then continued on that dose for 18 weeks. The 200 mg dose was not significantly more effective than the 100 mg dose. Topiramate has been shown to be effective in a number of open-label and pilot studies (192–194). The most common AEs were paresthesias.04) and migraine days (p ¼ 0.05). randomized. which was followed by a prospective baseline period of 28 days. Body weight was reduced by an average of 3. but was sensitive to demonstrate superiority of topiramate versus placebo for patients completing the trial (n ¼ 155. migraine days. topiramate . Eligible subjects entered a washout period of up to 14 days. A weighted regression analysis also demonstrated a statistically significant reduction in migraine rate for topiramate patients versus placebo patients (p ¼ 0. not weight gain (a common reason to discontinue preventive medication). Silberstein et al. and abnormal taste. nausea. Pivotal Phase III trials—Efficacy. p ¼ 0. ANCOVA was insensitive for detection of drug–placebo differences in the ITT population. and percent reduction in migraine frequency for the intent-to-treat (ITT) population (n ¼ 211) were assessed by an analysis of covariance (ANCOVA) with baseline migraine rate as covariate and last observation carried forward. whichever was lower. A disproportionately high number of topiramate patients dropped out during the first four weeks of the study. However.8% in the 100 and 200 mg groups. 100 mg/day topiramate. the monthly migraine rate.001).039). The responder rate (patients with 50% or more reduction in monthly migraine frequency) was 52% with topiramate 200 mg/day (p < 0. multicenter.4–3. the daily dose was increased by 25 mg weekly (for a total of eight weeks) until patients reached either their assigned dose or maximum tolerated dose. A total of 483 patients were randomized to the four treatment groups (placebo. In the group treated with topiramate 100 mg/day. Patients randomized to topiramate started at a dose of 25 mg/day.3).1 monthly migraine episodes (5. (196) assessed the efficacy and safety of topiramate (50. 120. double-blind. 200 mg/day topiramate. and percent reduction in migraine episodes (p ¼ 0. compared with 23% with placebo (Table 6). in the first pivotal placebo-controlled clinical trial of 487 patients. Topiramate treatment was also associated with reduced consumption of acutetreatment medications. assessed the efficacy and safety of topiramate (50. followed by a 12-week maintenance period. multicenter.03). 36% with topiramate 50 mg/day (p ¼ 0. (195). fatigue. placebo-controlled study (MIGR-001).8 for placebo. double-blind. a repeated measured analysis using the ITT population demonstrated statistically significant reductions in monthly migraine rate (p ¼ 0.02) for topiramate patients versus placebo patients.332 Silberstein Clinical Profile Pilot Studies. there was a mean reduction of 2. The onset of efficacy was observed within the first month of treatment. placebo-controlled study (MIGR-002). and 200 mg/day) in the prevention of migraine headaches in the second 26-week. randomized. The primary and secondary efficacy measures were identical to MIGR-001. its chronic use has been associated with weight loss. compared with 0. (2004) Migraine with and without aura 487 Double-blind/ placebo-controlled crossover Brandes et al. Preventive Treatment for Migraine Silberstein et al. (2004) Migraine with or without aura 483 Double-blind/ placebo controlled Diener et al. 8 wks titration 18 wks maintenance 4 wk baseline. (2004) Migraine with or without aura 176 Double-blind/ placebo-& propranolol controlled placebo 23% topiramate 50 mg: 36% topiramate 100 mg: 54% tiouranate 200 mg: 49% placebo 23% topiramate 50 mg: 39% topiramate 100 mg: 49% topiramate 200 mg: 49% placebo 23% topiramate 100 mg: 37% topiramate 200 mg: 35% propranolol 160 mg: 43% 333 . 8 wks titration 18 wks maintenance Dosage (mg/day)/ other medication Duration Results Study Patient population (Diagnostic criteria) No.Table 6 Topiramate Clinical Trials Design 50 mg (25 BID) 100 mg (50 BID) 200 mg (50 BID) 50 mg (25 BID) 100 mg (50 BID) 200 mg (50 BID) 4 wk baseline. 8 wks titration 18 wks maintenance 4 wk baseline. 8 to 3. Significant reductions were evident as early as the first month of treatment. or 200 mg of topiramate. Topiramate 100 mg/day was superior to placebo as measured by average monthly migraine period rate. In this second pivotal study. double-blind studies. The ITT population consisted of 468 patients. nausea. and anxiety. The percentages of subjects who discontinued due to AEs were 17%. and were treatment limiting in only 8% of these subjects. and 10% in the placebo group. topiramate 100 mg/day. and was comparable to propranolol (responder rate 43%). and 200 mg/day of topiramate (47%. 100 mg/day of topiramate (49%. difficulty with memory. Patients treated with 200 mg/day of topiramate lost an average of 4. Safety and Tolerability. taste perversion. 100. Paresthesias were rated as mild-to-moderate in the majority of patients. and topiramate 200 mg/day. p ¼ 0. mood problems. multicenter trial of 575 subjects conducted in 68 centers in 13 countries. Topiramate 200 mg/day failed in the primary end point compared to placebo but had a significantly higher responder rate (35% vs. average monthly migraine days. The most common CNS AEs were somnolence. when bothersome. difficulty with concentration. placebo 22%).009). and 29% in the TPM 50. diarrhea. Topiramate 100 mg/day (responder rate 37%) was better tolerated than topiramate 200 mg/day. There were no clinically important changes in clinical laboratory tests of liver function.9. In the study that included both topiramate and propranolol. and 200 mg groups. 121). The topiramate 100 mg/day and propranolol groups were similar in change from baseline to the core double-blind phase in average monthly migraine period rate and other secondary efficacy variables. weight decrease. renal function. rate of rescue medication use. the overall incidence of treatment-emergent and treatment-limiting AEs for topiramate 100 was comparable to propranolol 160 mg/day. These findings provide clear evidence that topiramate is effective in migraine prophylaxis.5. The other most common AEs were fatigue. who received total daily doses of 50. The mean monthly number of migraine periods decreased significantly for those patients on 100 mg/day of topiramate (from 5. insomnia. or hematologic parameters. or abnormalities in vital sign measurements or neurologic examinations.334 Silberstein 50 mg/day. 100.5). 25%. topiramate was associated with significant improvement in migraine at doses of 100 or 200 mg/day in each efficacy measure assessed. and abdominal pain. and 49% in the topiramate 200 mg group compared with 6% in the placebo group. they can be controlled with potassium supplementation (198). .1 to 2.6 to 4. which occurred in 35% of subjects in the topiramate 50 mg group. parallel-group.001) versus placebo (from 5. language problems. respectively. Most dropouts were due to side effects that occurred early in the trial. Diener et al.008) or 200 mg/day of topiramate (from 5.001). 51% in the topiramate 100 mg group. The onset of efficacy was observed as early as the first month of treatment. p ¼ 0. 120. p ¼ 0. The 100 mg dose offers the best relationship between efficacy and tolerability. A major shortcoming of this trial is the high dropout rate of patients in the topiramate 200 mg group due to adverse effects. 122.001). hypoesthesia. (197) compared two doses of topiramate (100 or 200 mg/day) to placebo or propranolol (160 mg/day) in a randomized. and percentage of patients with a 50% or greater decrease in average monthly migraine period rate (responder rate 37%).8% of body weight from baseline through the double-blind phase. Data for safety and tolerability in migraine is based on the experience of 1135 patients in multicenter. A significantly greater proportion of patients exhibited at least a 50% reduction in mean monthly migraines in the groups treated with 50 mg/day of topiramate (39%. The most common AE was paresthesia. p ¼ 0. p ¼0. decreased appetite. double-blind. This high dropout rate resulted in the nonsuperiority of topiramate 200 mg over placebo (Table 7). or t.201).d.d. such as monotherapy in epilepsy. Patients who take topiramate for epilepsy have weight loss that occurs early in the treatment and is maximal by 15 to 18 months (203). utilizing topiramate as a single antiepileptic treatment. The activity of lipoprotein lipase is reduced in adipose tissue in topiramate-treated rats (108). Most of these AEs were seen during the first two months of the initial titration period. or t. with most changes not persisting after maintenance treatment (201). Most patients faced with this problem do not need surgery and go on to continue treatment with topiramate once they pass the stone (202). somnolence. In clinical practice.i.d. Renal calculi can occur with the use of topiramate. Other investigators suggest that topiramate inhibits fat deposition. ataxia. Useful in children Weight gain in most patients t.05–0. and corticosterone (205). The most common of these AEs were dizziness. and had resolved in 60% to 90% of patients with continued use of topiramate.Preventive Treatment for Migraine Table 7 Miscellaneous Medication in the Preventive Treatment of Migraine Agent Daily dose Comment 335 Serotonin antagonists Methysergide 2–8 mg Cyproheptadine 12–36 mg Pizotifen a2-agonists Clonidine Guanfacine Miscellaneous Lisinopril Candesartan Feverfew Petasites Riboflavin Coenzyme Q Magnesium 1. the incidence of CNS AEs can be reduced with a low starting dose and a slower dose-escalation rate. Rats treated with stopiramate showed decreased body fat as well as acutely reduced food intake and an increased metabolic rate. and impaired concentration (199). The reported incidence is about 1.d.5–3 mg Higher doses are given b. representing a two to fourfold increase over the estimated occurrence in the general population (202).i. Dose started at 1 mg and increased by 1 mg every three days Should not be taken continuously for long periods b. slowed thinking. fatigue.i. Two studies have prospectively evaluated neuropsychometric changes with adjunctive topiramate treatment in patients with epilepsy (200. leptin.5%. . These studies support clinical observations that AEs occur most prominently during titration.i. The mechanism is unclear.3 mg/ day 1 mg 10–40 mg 16 mg 50–82 mg 50–100 mg 400 mg 100–150 mg 400–600 mg Neurobehavioral AEs occurred at rates comparable to those seen for studies of other conditions. confusion. Weight gain and drowsiness are common side effects Limited evidence in migraine Limited evidence in migraine Positive small controlled trial Positive small controlled trial Controversial evidence 75 and 100 mg better than placebo in independent trials Positive small controlled trial Two positive controlled trials Controversial evidence 0. The weight loss appears to be greatest in patients who are heavier at the onset and is most commonly seen in female patients (204). These animals also had decreased levels of total insulin.id. Other measures. Mydriasis may or may not be present. Topiramate administration should be started with a dose of 15 to 25 mg at bedtime and the dose should be increased by 15 to 25 mg/week. secondary angle-closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. with secondary angle closure glaucoma. and increased intraocular pressure. may be helpful (206). infrequently resulting in hospitalization. The dose can be increased to 600 mg/day or higher. which many believe is the basis of the migraine aura. anterior chamber shallowing. 3. Patients on propranolol gained 2.6%) responders. has been reported in association with an elevation in body temperature. with 12 dropping out because of AEs. There were 17 (48. Glutamate is essential in the propagation of CSD. prospective. Topiramate is effective for migraine prophylaxis. and together represent the largest controlled trials of a migraine preventive. Treatment with topiramate was also associated with reduced use of acute medications (207). which is rare in patients under 40 years of age. The dose should not be increased if bothersome AEs develop. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Only 35 patients were compliant with treatment to warrant inclusion in the analysis.3% in the 50 mg group. Most of the reports have been in children. and 3. migraine days. in conjunction with discontinuation. Topiramate was associated with improvements in each of the efficacy measures presented. MIGR-002. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible. It is our experience that patients who tolerate the lower doses with only partial improvement often have increased benefit with higher doses. and number of migraine attacks per month. Some of the cases were reported after exposure to elevated environmental temperatures. most of whom had chronic migraine (208). at a mean dose . Lamotrigine has been studied as combination therapy for headache prevention in one relatively large.3% of their baseline body weight. Symptoms typically occur within one month of initiating topiramate therapy. according to the judgment of the treating physician. ocular hyperemia. and MIGR-003 trials represent the largest controlled clinical trials of topiramate in migraine prevention to date.336 Silberstein In the migraine trials. There were no cases of this condition reported in the clinical studies. The 100 mg dose seems to have the best efficacy/tolerability ratio. then increased by a lower dose more slowly. Treatment with topiramate 100 or 200 mg/day was associated with significant reductions in migraine frequency. Lamotrigine Lamotrigine blocks voltage-sensitive sodium channels. one must wait until they resolve (they usually do). Ophthalmologic findings can include myopia. If they do not resolve. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported infrequently in patients receiving topiramate. leading to inhibition of neuronal glutamate release of glutamate. The MIGR-001. the dosage of the drug should be decreased to the last tolerable dose. open-label trial of 65 patients. The aim should be to reach a dose of 50 to 100 mg/day given twice a day. Oligohidrosis (decreased sweating). Cognitive side effects are of less concern with doses of 100 mg or less. Conclusion.8% in the 200 mg group. In contrast to primary narrow-angle glaucoma. body weight was reduced by an average of 2. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris.2% in the 100 mg group. The primary end point was reduction in frequency of severe headaches. Improvements were greater on placebo. whereas ketanserin. Headache data were obtained from patient headache diaries and telephone reports. induces migraine hours after the immediate pharmacologic response to the drug . cyproheptadine. a 50% reduction in headache duration. after a one-month placebo run-in period. The drug was titrated to a mean dose of 244 mg/day. placebo responders and noncompliers were excluded. (209) reported two patients with migraine with persistent aura-like visual phenomena for months to years. is not (217. Zonisamide was also examined as monotherapy in a small. parallel-groups trial. to 3. migraine-preventive drugs are potent 5-HT2B– and 5-HT2C–receptor antagonists. lamotrigine therapy was begun at the full dose of 200 mg/day. 34 patients with refractory migraine with or without aura were treated adjunctively with zonisamide at doses as high as 400 mg/day (211). randomized. Chen et al. open-label studies of zonisamide in the preventive treatment of episodic migraine have been reported (211. Initially.4 on placebo. mCPP. In the study conducted by Drake et al.218). Serotonin Antagonists The antiserotonin. following a high incidence of skin rashes. most commonly rash. during the last month of treatment. a major metabolite of the antidepressants trazodone and nefazodone. Zonisamide Two retrospective. open-label study of nine patients with episodic migraine with or without aura (213). leaving 77 to be treated with lamotrigine (n ¼ 37) or placebo (n ¼ 40) for up to three months. not statistically significant. (210) compared the safety and efficacy of lamotrigine and placebo in migraine prophylaxis in a double-blind. After two weeks of lamotrigine treatment. Four patients (12%) discontinued the drug because of AEs and nine stopped the medicine because they believed it was not working. and investigator efficacy ratings were made for all patients who remained on a stable dose of the drug for six weeks. and pizotifen. both had resolution of the visual symptoms. prospective. and these changes. A total of 110 patients entered.6 per month on lamotrigine and 4. Another open-label study assessed the impact of lamotrigine on aura itself. Steiner et al. including four of eight whose headaches were chronic. and found that the drug significantly reduced both the frequency and duration of aura (208). It was effective or very effective in 6 of 9 (67%) patients.0. There were more AEs on lamotrigine than on placebo. Methysergide. are 5-HT2B– and 5-HT2C–receptor antagonists.212).Preventive Treatment for Migraine 337 of 55 mg/day. (211). whereas metachlorophenyl piperazine (mCPP). a selective 5-HT2A– and a poor 5-HT2B– and 5-HT2C–receptor antagonist. a slow dose-escalation was introduced: 25 mg/day for two weeks. their frequency was reduced and the rate of withdrawal for AEs was similar in both treatment groups. Attack rates were reduced from baseline means of 3. Those who had migraine with aura had a better response rate (12/18 or 67%).2 and 3. With slow dose-escalation. effective migraine prophylactic drugs. respectively. 50 mg/day for two weeks. indicate that lamotrigine was ineffective for migraine prophylaxis. and then 200 mg/day. a 5-HT2B– and 5-HT2C– receptor agonist. but. A 40% reduction in headache severity. induces migraine in susceptible individuals (214–216). with four dropouts due to AEs (212). and a 25% decrease in headache frequency were found at three months compared to baseline values. Krusz reported improvement in 14/33 (42%) of patients. or endocardial fibrosis (244. and hallucinations. dizziness. but has lower affinity for the 5-HT1– than for the 5-HT2–binding site (224). .245). which can be blocked by selective 5-HT2B antagonists (222). but there were highly significant associations between the cortisol responses and headache severity and duration. Chronic. but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with long-term. The difference between acute and chronic drug administration could be due to the accumulation of the active metabolite. It was probably the first drug developed for migraine prevention (229). but not acute. giddiness. Pizotifen and methylergometrine are potent rabbit jugular vein endothelial cell 5-HT2–receptor antagonists. Methysergide is also a 5-HT1–receptor agonist (223). The only trial that compared methysergide with metoprolol reported an unusually low response to metoprolol (6%) and thus a misleading relative increase in methysergide efficacy (242). drowsiness. Activation of 5-HT2B or 5-HT2C receptor by mCPP or endogenously released 5-HT could dilate cerebral vessels.220. Frightening hallucinatory experiences after the first dose are not uncommon (243). however. The AHCPR Technical Report identified 17 controlled trials of methysergide for migraine prevention (136. The duration of the trials reviewed here was too short to detect them. pulmonary. Four placebo-controlled trials suggested that methysergide was significantly better than placebo at reducing headache frequency (28. Methysergide (or methylergometrine) presynaptically could inhibit the release of CGRP from perivascular sensory nerves. treatment with methysergide attenuates dural plasma extravasation following electric stimulation of the rat trigeminal ganglion in the Moskowitz model (228). vomiting.220).221). gastrointestinal complaints (nausea. AEs noted in trials and clinical practice include transient muscle ache. (215) found that mCPP induced headache in both migraineurs (five of eight) and nonmigraine controls (four of 10). Methysergide was associated with a higher incidence of AEs than was placebo.338 Silberstein (monitored by elevation of plasma cortisol and prolactin) is over. and diarrhea). is neither necessary nor sufficient to cause headache (219. claudication.242). The major complication of methysergide is the rare (1/5000) development of retroperitoneal. Gordon et al.238). No significant differences were found between the migraineurs and normal subjects in terms of their neuroendocrine or headache responses to mCPP. AEs were no more common with methysergide than with pizotifen. abdominal pain. mCPP itself can produce extravasation in the dural membrane. Methysergide Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT2–receptor antagonist and 5-HT1B/D agonist. Vasodilation.240). Methysergide-induced contraction of the isolated saphenous vein of dog is also mediated by 5-HT1B receptors (225– 227). Two trials that directly compared methysergide and propranolol failed to demonstrate any statistically significant differences between these treatments (31. lassitude. hair loss. administration (230). which mediates pial artery vasodilation (114) and neurogenic inflammation (218. mostly uninterrupted. leg cramps. weight gain. Four comparison trials showed no statistically significant differences between methysergide and pizotifen (234. methylergometrine. but endotheliumderived NO can activate sensory trigeminovascular fibers resulting in CGRP release. paresthesia.231–241). no significant differences were demonstrated between pizotifen and flunarizine (133–135).246). or serious infection. Cyproheptadine is available as 4 mg tablets.232. peptic ulcer disease. naproxen sodium (251). and diarrhea are less common. stopped for one month. Curran and Lance (249) found cyproheptadine more effective than placebo but less effective than methysergide. Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically significant. without AEs and with higher efficacy (113). Cyproheptadine may inhibit growth in children (250) and reverse the effects of SSRIs.251. thrombophlebitis or cellulitis of the legs. Due to its AEs profile. and then restarted. Some authorities use methysergide on a continuous basis with careful monitoring (113). The total dose ranges from 12 to 36 mg/day (given two to three times a day or at bedtime).133– 135. the patient should be weaned off the drug over a one-week period. fibrotic disorders. Cyproheptadine Cyproheptadine. severe hypertension.247. Methysergide is an effective migraine preventive medication that is an appropriate consideration in resistant headaches with a high attack frequency.261–268). and abdominal MRI.) Methysergide. collagen disease. severe arteriosclerosis. which includes auscultation of the heart and yearly echocardiography.238.251–260) and 19 comparisons with other agents (36.S. an antagonist at the 5-HT2. In addition to being effective in reducing attack frequency. To avoid an increase in headache when methysergide is stopped. Patients who receive methysergide should remain under the supervision of the treating physician and be examined regularly for development of pulmonary/cardiac or peritoneal fibrosis or vascular complications. In direct comparisons with other agents known to be efficacious for migraine prevention. and muscarinic cholinergic receptors. (This can be accomplished by breaking the 2 mg tablets if 1 mg tablets are not available. up to 14 mg/day. with the higher doses being given two or three times a day. chest X-ray. Headache Consortium Guidelines (21) found that evidence was inconsistent for its efficacy from 11 placebocontrolled trials (239. lung diseases. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal fibrosis (113). a 5-HT2–receptor antagonist structurally similar to cyproheptadine. ankle edema. it should be reserved for severe cases in which other migraine-preventive drugs are not effective. valvular heart disease. because doing so may produce retroperitoneal fibrosis (230. Instead.167. nausea.258. To minimize early AEs. lightheadedness. Common AEs are sedation and weight gain. patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every two to three days.244.234. aching legs. liver or renal function impairment.Preventive Treatment for Migraine 339 Methysergide is indicated for the treatment of migraine and cluster headache. methysergide (232. in general. dry mouth.239). The dose ranges from 2 to 8 mg/day.239. coronary artery disease.234. peripheral vascular disorders. debilitation. is widely used in the prophylactic treatment of migraine in children (113. the drug should be given for six months. is not available in the United States. The U. Some clinicians find that they can use higher doses. Contraindications to methysergide use include pregnancy. All of the open and controlled studies attest to its efficacy.248). it often acts synergistically with ergotamine for breakthrough attacks. Pizotifen Pizotifen.238. or metoprolol . histamine H1. should not be taken continuously for long periods. The dose recommendation is 0. The treatment period was 12 weeks. Two comparative trials comparing clonidine with the b-blockers metoprolol (283) and propranolol yielded mixed results (284). Intention to treat analysis of data from 55 patients supported the differences in favor of lisinopril for the primary end points. and 20% (95% confidence interval 3–37%). and then two placebo tablets for 11 weeks. and not conclusively. placebo-controlled. Hours with headache. respectively. an angiotensin-converting enzyme inhibitor. tiredness. Days with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. or between clonidine and carbamazepine (157). days with migraine. Thirty patients were randomly assigned to receive one 16 mg candesartan cilexetil tablet daily in the first treatment period. in migraine prophylaxis. 3 found a significant difference in favor of the active agent. AEs occurred at similar rates for both interventions.271–284) and one of guanfacine (282). one to three times daily by titration. Tronvik et al. placebo-controlled crossover study of candesartan. an angiotensin II receptor blocker. The evidence from these trials suggests that a2 agonists are minimally. and/or drowsiness were frequently reported.S. One trial each found no significant differences between clonidine and pizotifen (167). crossover study of lisinopril. 21% (95% confidence interval 9–34%). Clonidine’s most commonly reported AEs were drowsiness and tiredness. Sixty patients aged 18 to 65 years with two to six migraine attacks per month were recruited. Controlled and uncontrolled studies in Europe (269) have shown this drug to be of benefit in 40% to 79% of patients. and pindolol (157). followed by one placebo tablet daily in the . days with headache.340 Silberstein (36). once daily for one week. (286) performed a randomized. with one 10 mg lisinopril tablet once daily for one week.167. Side effects include drowsiness and weight gain (270). In studies comparing clonidine with b-blockers. but the magnitude of the effect was small (275. practolol (275). in the 26 trials reviewed. Headache Consortium Guidelines and the AHCPR Technical Review included 17 controlled trials of a2 agonists for the prevention of migraine: 16 of clonidine (157. 17% (95% confidence interval 5–30%). in migraine prevention. Of the 11 placebo-controlled trials of clonidine. double-blind. Pizotifen was associated with a high rate of withdrawals due to AEs. followed by a two-week washout period. The second treatment period consisted of one placebo tablet. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists Schrader et al. and headache severity index were significantly reduced by 20% (95% confidence interval 5–36%). Two comparative trials showed no significant differences among clonidine. (285) conducted a double-blind. with lisinopril compared with placebo. pizotifen was generally poorly tolerated (20). Substantial weight gain. However.5 to 1 mg.280). A placebo run-in period of four weeks was followed by two 12-week treatment periods separated by four weeks of placebo washout. efficacious. then two 10 mg lisinopril tablets once daily for 11 weeks. Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and in 17 patients for active treatment versus run-in period. Other Drugs Alpha Antagonists The U.279. respectively. 42.Preventive Treatment for Migraine 341 second period. (289) found a 20% reduction in headache frequency. The 25 U botulinum toxin type A treatment group fared significantly better than the placebo group by the . and tolfenamic acid (291). AEs were similar in the two periods.S. Two major multicenter trials. We would use ASA only in patients who had prolonged or nonvisual aura. 41. Buring et al. and intensity of attacks to the same extent. ‘‘The British Physician Trial’’ showed that a daily dose of 500 mg ASA reduced the frequency of migraine by an average of 30% (288).4%) for days with migraine. One hundred twenty-three patients who had chronic International Headache Society (IHS)–defined migraine and a history of two to eight moderateto-severe migraine attacks during a one-month baseline were randomized to treatment with either 0. and 40 patients were randomized to 0. duration. The number of candesartan responders (reduction of 50% or greater compared with placebo) was 18 of 57 (31. (287) found that aspirin (ASA) (650 mg/day) decreased headache frequency. High-dose ASA use may lead to overuse and the development of rebound headaches. In a small open trial. and 75 U botulinum toxin type A treatment groups and had baseline frequencies of migraine of 4.6%) for days with headache and 23 of 57 (40.071 U.45. The remaining 30 patients received placebo followed by candesartan. Although NSAIDs are effective. both drugs were equally effective and reduced the frequency. ketoprofen. in practice.5 with placebo versus 13. it may not be clinically significant. fenoprofen.5 mg/kg) with propranolol (1. ASA is usually implicated with other compounds in combination analgesics. In 1988.001) in the intention-to-treat analysis (n ¼ 57). proved the efficacy of ASA in the prophylaxis of migraine. frontalis. Baldratti et al. although. however. Diaries were kept for three months postinjection. ASA in low doses is indicated for the prophylaxis of myocardial infarction and transient ischemic attacks. In a period of 12 weeks. (296) evaluated the safety and efficacy of pericranial botulinum toxin type A injections as prophylactic treatment of chronic moderate-to-severe migraine. In this trial. with a tolerability profile comparable with that of placebo.6 with candesartan (p ¼ 0. 25. Although this is statistically significant. male physicians (Physician Health Study). and temporalis muscles. Aspirin O’Neill and Mann (35) and Masel et al.41. they must be used with caution because of their gastrointestinal and renal function AEs (295). and 3. ASA (500 mg daily) was statistically less effective than 200 mg propranolol daily (34). 25. 4. Nonsteroidal Anti-inflammatory Drugs Some NSAIDs may be effective in migraine prophylaxis. In this study. In a double-blind trial of low-dose ASA (325 mg every other day) in 22. (290) compared the efficacy of ASA (13. or 75 U of botulinum toxin type A injected symmetrically into glabellar. the mean number of days with headache was 18.95 attacks per month. At 12 centers. In a double-blind crossover trial. Botulinum Toxin Type A (Botox1) Silberstein et al. These include sodium naproxen.8 mg/kg). the angiotensin II receptor blocker candesartan was effective. Some headache disorders (paroxysmal hemicrania and hemicrania continua) are defined by their responsiveness to indomethacin (292–294). Pericranial injection of botulinum toxin type A (25 U) showed significant differences compared with vehicle-induced type in reducing migraine frequency and associated symptoms during the 90 days following injection. the proportion of patients with a 50% reduction in days of headache. One trial was conducted in a self-selected group of feverfew users and showed that withdrawing feverfew led to a statistically significant increase in headache frequency (300). between 1990 and 1997. (298) evaluated the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine in a multicenter. Five trials were conducted. placebo-controlled. insect bites. i.304). has traditionally been used for fever.d. toothache. a medicinal herb. rheumatism. Feverfew (Tanacetum parthenium).342 Silberstein following measures: reduction in mean frequency of moderate-to-severe migraines during days 31 to 60. Leukotriene Receptor Antagonist (Montelukast) A previous. Those receiving placebo had a tripling in the frequency of migraine attacks. two that were reported in the AHCPR and three that were conducted after the report was published. No serious treatment-related AEs were reported. small. During the last decades. The end point response rate for lanepitant-treated patients (41. with and without aura.4% for montelukast versus 10. but high-dose botulinum toxin type A showed significantly more treatment-related AEs than placebo. The primary outcome measure was response rate. parallel-design study comparing the effect of 200 mg q.065) greater than that for placebo-treated patients (22. and improvement by patient global assessment for days 31 to 60 postinjection.3% for placebo (p ¼ 0. randomized. parallel-group study. a potent nonpeptide neurokinin-1 receptor antagonist that inhibits neurogenic dural inflammation in migraine prevention. Brandes et al. Over the three months of treatment. Medicinal Herbs. population increased by a staggering 480%. Patients on placebo reported increased nervousness. Further studies are currently underway. and stomachache. asthma. open-label study of migraine patients suggested prophylactic efficacy for montelukast. A pilot study of 17 migraineurs who ate fresh feverfew leaves daily was undertaken at the City of London Migraine Clinic.S. (297) studied lanepitant. the use of herbal medicinal products by the general U. Patients with IHS migraine. and Minerals (See Chapter 23) According to a national survey (299). women’s ailments. there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15. inflammatory conditions. an antagonist of the cysteinyl leukotriene receptor that is used to treat asthma.e.0%) was not statistically significantly (p ¼ 0. . Substance P Antagonist (Lanepitant) Goldstein et al. psoriasis. The 75 U botulinum toxin type A treatment group was significantly better than the placebo group on patient global assessment for days 31 to 60.. Botulinum toxin type A treatment was well tolerated. double-blind. but not other parameters.0%). it has also been used for migraine prophylaxis. Montelukast 20 mg was not an effective prophylactic for prevention of migraine. Patients were given capsules of freeze-dried feverfew or placebo. were enrolled in a 12-week. lanepitant (n ¼ 42) and placebo (n ¼ 42) on migraine frequency. Vitamins. double-blind. incidence of 50% reduction in mild-to-severe migraines at days 61 to 90. Three trials (301–303) were crossover trials. These studies have demonstrated that the plant has inhibitory effects on platelet aggregation and release of serotonin from blood platelets and leukocytes (307. The other trial reported no significant differences between feverfew. More clinical trials are needed. randomized crossover trial that tested the efficacy of feverfew compared with placebo. one used an alcoholic feverfew extract (303). both on a larger scale and with various feverfew extracts.301).005). while two (303.308).303). Feverfew may be effective in the prevention of migraine. insomnia.304) did not. The better quality studies were negative. In total. One trial that used feverfew extract with a standardized and constant concentration of parthenolides to treat migraine did not show any beneficial effect (303). Pittler and Ernst (305) conducted a new systematic review of the evidence from rigorous clinical trials of feverfew’s efficacy in migraine prevention. Feverfew’s AEs include mouth ulceration and a more widespread oral inflammation associated with loss of taste (20). 343 patients participated in the included studies. the clinical effectiveness of feverfew for migraine prevention has not been established beyond reasonable doubt. updating their older systematic review (306). Three trials were not included in the AHCPR report. This hypothesis was supported by in vitro experiments that emphasized its biological activity. while two (303.304). more conventional. Two studies were withdrawal studies (302.Preventive Treatment for Migraine 343 tension headaches.304) reported no such effect.304) showed no beneficial events. This trial reported a smaller difference between feverfew and the control treatment than did the other trial. two studies (301. powdered feverfew extract (300–302). the identity . given as an alcoholic extract. or joint stiffness constituting a ‘‘post-feverfew syndrome’’ (perhaps another example of rebound). Only mild and transient AEs were reported in the included trials. The biologic variation in the sesquiterpene lactone content and the long-term safety and effectiveness of feverfew are of concern (300). and three were treatment studies (301. and acetylcholine antagonist.304) used a parallel-group design. Pfaffenrath et al. three others (300–302) were in favor of feverfew. Among the four trials with an acceptable sample size.303. (304) found no difference between several doses of a new feverfew extract and placebo except in a small subset of patients with more than four migraine attacks a month. and reported that treatment with feverfew was associated with a significant reduction in pain intensity and nonheadache symptoms (nausea. The sesquiterpene lactone parthenolide has been suggested as the main active component of feverfew. The frequency of migraine was reduced by feverfew in two trials (300. Results from these trials were mixed and did not convincingly establish that feverfew is efficacious in preventing migraine.302) reported feverfew to be superior to placebo. While the two studies with the highest methodological quality (303. vomiting. and placebo in reducing the migraine frequency (303). Feverfew’s mechanism of action is uncertain. One was a doubleblind. most of whom (71%) had never used feverfew (301). Thus. and phonophobia) (302). but still found the difference to be statistically significant in favor of feverfew (p < 0. Thus. 5-HT. bradykinin. met the inclusion criteria. only three of five studies were positive. The same five trials. At present. trial was conducted in a larger group of migraineurs. including parthenolide-free sesquiterpene lactone chemotypes (309). Three trials administered dried. prostaglandin. quoted above. especially parthenolide. The other. which may be a nonspecific NE. It is rich in sesquiterpene lactones. and another used a CO2 extract (304). photophobia. whereas two (300. is more effective than placebo and is well tolerated as a preventive therapy for migraine.d.i. or placebo b. ‘‘responders. with or without aura. Over the four months of treatment. and 36% for petasites extract 50 mg b. (312) performed an independent reanalysis of a randomized. and the number-needed-to-treat for effectiveness was 2. placebo-controlled trial of Petasites’ efficacy in migraine prophylaxis. headache days (p ¼ 0. There were no side effects noted with coenzyme Q10. Based on the results of an open trial in migraine.i.e. To follow regulatory requirements. migraine attack frequency was reduced by 26% for placebo. Following a four-week baseline phase. coenzyme Q10 appears to be a good migraine preventive.i. .005).. 48% for petasites extract 75 mg b. Schoenen et al.3. 61..d.8 after three months (p ¼ 0.. (321) assessed the efficacy of coenzyme Q10 as a preventive treatment for migraine headaches in an open-label trial.012).s. Only three AEs occurred: two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps).i.012).).0012 vs. The responder rate (improvement of migraine frequency by more than 50%) was 45% in the active group and 15% in the placebo group. which are required for the activity of flavoenzymes involved in the electron transport chain.d. i.0024) in the active group and from 2. were treated with coenzyme Q10 at a dose of 150 mg/day. placebo-controlled. A mitochondrial dysfunction resulting in impaired oxygen metabolism may play a role in migraine pathogenesis (313–316).9 to 2. (311) conducted a randomized. The most frequently reported AE was mild gastrointestinal events. double-blind.6 in the placebo group (n. None was serious.3% of patients had a greater than 50% reduction in number of days with migraine headache. Lipton et al.d. Petasites.344 Silberstein of the principle active constituent(s) of feverfew remains unclear. Given to patients with MELAS or mitochondrial myopathies on the assumption that large doses might augment activity of mitochondrial complexes I and II. Riboflavin.127 vs. doubleblind trial of high dose of vitamin B2 (400 mg) was performed and showed significant benefit (320). Riboflavin (vitamin B2) is the precursor of flavin mononucleotide and flavin adenine dinucleotide. a placebo-controlled. Petasites hybridus root (butterbur) is a perennial shrub whose extracts have been used for therapeutic purposes in traditional medicine for centuries.002). 75 mg b. an independent reanalysis of the original data was performed. predominantly burping. placebo). Thirty-one of 32 patients completed the study. Riboflavin was significantly superior to placebo in reducing attack frequency (p ¼ 0.. Thirty-two patients with a history of episodic migraine. placebo). From this open-label investigation.i. The proportion of patients who improved by at least 50% in headache days.i.4 at baseline to 1. (p ¼ 0. petasites extract 75 mg b. and migraine index (p ¼ 0. It has recently been suggested that feverfew is a nuclear factor kappa B antagonist (310). Rozen et al. Diener et al. Two hundred forty-five eligible IHS migraine patients were randomized to one of three arms: petasites extract 50 mg b. Coenzyme Q. This study demonstrates that a standardized petasites extract. The mean monthly attack frequency decreased from 3. 33 patients were randomized to treatment with two 25 mg capsules of butterbur twice a day and 27 to placebo.’’ was 15% for placebo and 59% for riboflavin (p ¼ 0. (320) compared riboflavin (400 mg) with placebo in migraineurs in a randomized trial of three months’ duration. (p ¼ 0. riboflavin improved clinical as well as biochemical parameters (109.d.317–319). Butterbur was well tolerated and may be effective in the prophylaxis of migraine.d. parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex1) for the prophylaxis of migraine. Those differences may produce differences in bioavailability and efficacy and account for the reported difference. 20 mmol magnesium-L-aspartate-hydrochloride trihydrate given in divided doses was evaluated.05).7%) (323). which include SSRIs. gabapentin. There were 10 responders in each group (28. other b-blockers. (iv) drugs that either have documented high efficacy but significant AEs or are difficult to use. and NSAIDs. the drug’s side effects. improve responsiveness to acute attack treatment.6%) and gastric irritation (4. In another multicenter. 20 mmol) and in the salt (dicitrate vs. amitriptyline. and the presence or absence of coexisting or comorbid disease (Table 2).3% for placebo. The studies differed in the amount of magnesium (24 mmol vs. nifedipine. duration. SETTING TREATMENT PRIORITIES The goals of preventive treatment are to reduce the frequency. the patient’s preferences and headache profile. . One study enrolled 81 patients who had IHS migraine.8% in the placebo group compared with the baseline (p < 0.326). (ii) drugs that have lower documented efficacy and mild-to-moderate AEs. b-blockers should be used with caution.6% for coenzyme Q10 and 14. and reduce disability.6% magnesium and 29. AEs were diarrhea (18. Choice should be made based on a drug’s proven efficacy. placebocontrolled study. topiramate. placebo-controlled trial of coenzyme Q10 (100 mg TID) in 42 patients for three months. one would try to avoid these drugs in the overweight patient and consider the use of topiramate. but could use divalproex or topiramate. The medications used to treat migraine can be divided into four major categories: (i) drugs that have documented high efficacy and mild-to-moderate AEs. Patients received 600 mg (24 mmol) of oral magnesium (trimagnesium dicitrate) or placebo daily for 12 weeks. randomized. There was no benefit from magnesium compared with placebo in the number of migraine days or migraine attacks (324). double-blind.4% placebo). lithium. (B) mild-to-moderate AEs. 5 men). prospective. improve function. 35 had received magnesium and 34. or (C) major AEs or complex management. (iii) drugs used based on (A) opinion. in contrast. which include methysergide and MAOIs. the attack frequency was reduced by 41.Preventive Treatment for Migraine 345 Sandor et al. riboflavin. aspartate). The drug used should be the one that has the best risk-to-benefit ratio for the individual patient and takes advantage of the drug’s side-effect profile (325. such as a TCA. An underweight patient would be a candidate for one of the medications that commonly produce weight gain. and (v) drugs that have proven limited or no efficacy. which include cyproheptadine. An interim analysis was performed with 69 patients (64 women. Magnesium supplementation was effective in one of two trials. or severity of attacks. It may also prevent episodic migraine’s progression to chronic migraine and result in health-care cost reductions. The 50%-responder rate was 47. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs or calcium channel or b-blockers. placebo. nimodipine. (322) performed a double-blind. and divalproex.6% in the magnesium group and by 15. The number of days with migraine and symptomatic drug consumption also decreased significantly in the magnesium group. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. and phenytoin. Of these. calcium channel antagonists. which include some b-blockers. In the weeks 9 to 12. In the athletic patient. 326) (Table 8). amitriptyline. timolol. metoprolol. b-blockers should be used with caution in the depressed migraineur.329). nonsteroidal anti-inflammatory drugs. nadolol Calcium-channel blockers—Verapamil Anticonvulsants—Gabapentin Other—Fenoprofen. When individuals have more than one disease. nabumetone. nicardipine. b-blockers or calcium channel blockers may be effective for all conditions (295).346 Table 8 Preventive Drugs Silberstein High efficacy: low-to-moderate AEs Propranolol. protriptyline. TCAs or SSRIs may be especially useful (327). Fifty-six percent had a greater than 50% reduction in migraine days. carbamazepine. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. valproate. NSAIDs. For the patient with migraine and epilepsy (328) or migraine and bipolar illness (174. For example. two or more conditions may be treated with a single drug. clonazepam. Fifty-two patients (43 women) with a history of episodic migraine. certain categories of treatment may be relatively contraindicated. Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits (325. Although monotherapy is preferred. protriptyline. Antidepressants are often used with beta-blockers or calcium channel blockers and topiramate or divalproex sodium may be used in combination with any of these medications. This open trial supports the practice of combination therapy. venlafaxine. adverse events. fluvoxamine. whereas TCAs. ketoprofen. nifedipine. MAOIs Proven not effective or low efficacy Acebutolol. were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label fashion. sertraline. Comorbid and coexistent diseases have important implications for treatment. Pascual et al. For the patient with migraine and depression. naproxen sodium b-blockers—Atenolol. neuroleptics. and previously unresponsive to beta-blockers or sodium valproate monotherapy. When migraine and hypertension and/or angina occur together. . with or without aura. trazodone Major AEs or complex management Methergine. nortriptyline. flurbiprofen. topiramate Low efficacy: low-to-moderate AEs NSAIDs—Aspirin. monoamine oxidase inhibitors. Controlled trials are needed to determine the true advantage of this combination treatment in episodic and chronic migraine. divalproex and topiramate are the drugs of choice. feverfew. or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur. mirtazepine. MAOIs. paroxetine. clomipramine. indomethacin. it is sometimes necessary to combine preventive medications. pindolol Abbreviations: AEs. The pregnant migraineur who has a comorbid condition that needs treatment should be given a medication that is effective for both conditions and has the lowest potential for AEs on the fetus. In some instances. lamotrigine. (330) found that combining a beta-blocker and sodium valproate could lead to an increased benefit for patients with migraine previously resistant to either alone. imipramine. vitamin B2 Pizotifen Unproven efficacy: low-to-moderate AEs Antidepressants—Doxepin. 1999. Theoharides TC. Eberlein K. Lipton RB. Furberg B. Neurology 1972. Headache Classification Committee. 24(suppl 2):2–7. Migraine preventive medication reduces resource utilization. 2nd ed. The International Classification of Headache Disorders. Buzzi MG. Tulsky J. Headaches in pregnancy. 108:1156–1159. 10. Gheorghe D. 8. Lipton RB. . eds. 23:26–31. 16. 43:171–178. Priller J. Cephalalgia 2004. Moskowitz MA. 22:727–756. Stables DP. Headache 1983. 21. 9. Ramadan NM. 6. Practice Parameter—Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology for the United States Headache Consortium. Neurol Clin 2004. Silberstein SD. Sudilovsky A. Gustavsson CL. 22:366–369. Weber RB.org. Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-1 receptor knockout mice. Nadolol: its use in the prophylactic treatment of migraine. 18. et al. Migraine in the United States: epidemiology and patterns of health care use. London: Martin Dunitz Ltd. 2nd ed. 127953. 7. 13. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Olerud B. Neurology 2002. The Headaches. Silberstein SD. Goadsby PJ. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Nadolol and propranolol in migraine management. Silberstein SD. Kandere-Grzybowska K. 11. Am J Cardiol 1996:370–383. 290-94-2025. Reinmuth OM. Stern MA. Evidencebased guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. Headache 1986. 58:885–894. 14. 41:646–657. 20. Drug treatments for the prevention of migraine headache. 4. Accession No. Stewart WF. 2000:453–456. In: Olesen J. Prepared for the Agency for Health Care Policy and Research. Headache 2001. Neurologic Clinics 1997. Migraine and pregnancy. Silberstein SD.neurology. Nadolol: the benefits of an adequate trial duration in the prophylaxis of migraine. 48:187–203. Why study the comorbidity of migraine? Neurology 1994. 2002. 3. Welch KMA. Levin NW. Lipton RB. Ryan RE. New York: Lippincott Williams & Wilkins. Rabkin R. Scher AI. Am Heart J 1984. Neuroscience 1992. Migraine pathophysiology and its clinical implications. Suzman M. Silberstein SD. Gilbert TT. Hasselblad V. Dimitriadou V. Contract No. Cephalalgia 2004. 44:4–5. The prophylactic value of propranolol in angina pectoris. Kolodner K. Available at: http// www. Goslin RE. Silberstein SD. Winner PK. 15. Neurology 2000. 26:325. Diamond S. Diamond ML. Headache: J Head Face Pain 2003. Silberstein SD. Freitag FG. Headache 1986. Prioritizing acute pharmacotherapy of migraine. Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat aura mater and tongue following antidromic trigeminal stimulation. Silberstein SD. Lipton RB. Sudilovsky A. 17. The treatment of migraine with propranolol. 24:1–160. 2. McCrory DC. 19. 5. 55:754–762. Available from the National Technical Information Service. 15:209–231. 12. Chmiel JJ. Frishberg BM. 26:490–493. Steiner TJ. Tfelt-Hansen P. Liberman J. Headache in Clinical Practice. Brain Res 2003. Ryan RE.Preventive Treatment for Migraine 347 REFERENCES 1.. Stewart WF. Neurology 2000. 980:213–220. Gray RN. Meyer JH. Reed M. TfeltHansen P. Cephalalgia 1985. Nilsson LR. Headache 1987. Ogawa A. Kangasniemi P. Silberstein SD. 35. 1–4-(2-hydroxy-3-isopropylaminopropoxy) indol): an adrenergic beta-receptor blocking agent in migraine prophylaxis. ketoprofen (19. Lancet 2004. Coordingley GE. 29. Sjaastad O. Takase S. Johannsson V. 84:343–347. Hedman C. Prophylaxis of migraine and mixed headache. 19:379–381. Migraine prevention with timolol: a double-blind crossover study. Koletzki E. et al.583 r. Andersen AR. Briggs RS. Prophylactic treatment of classical and nonclassical migraine with metoprolol: a comparison with placebo. Andersson PG. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicenter study. Selective and nonselective beta-blockers: are both effective in prophylaxis of migraine? A clinical trial versus methysergide. Penzien DB. Bonuso S. 252:2576–2580. Standnes B. 21:105–109. 39. Gerber WG. Steiner TJ. Scharafinski HW. Widelius T. Langohr HD. Linde K. Hino M. Headache 1985. Ahrens SP. . Cochrane Database Systematic Rev 2004. Schroth G. Andersson PG. Drugs 1990. 28:15–23. Niederberger U. 12:15–17. Headache 1974. J Am Osteopath Assoc 1984. 30:639–641. 70: 160–180. Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine: a double-blind investigation. d-propranolol and placebo in migraine. et al. Dahl S. Migraine. Andersson K. Ichikawa N. et al. Headache 1990. 45. 26. Cephalalgia 1991. Classic migraine: effective prophylaxis with metoprolol. 36. 37. 7:231–238. 5:17–23. Mayer K. 27:372–374. Acta Neurol Scand 1984. Grotemeyer KH. Gerber WD. Stensrud P. 31. Lundberg PO. 34. 8101:1179–1181. 3:207–212. Atenolol in migraine prophylaxis: a double-blind crossover multicenter study. Acetylsalicylic acid vs metoprolol in migraine prophylaxis: a double-blind crossover study. Zbornikova V. Mathew NT. 14:96–100. Headache 1988. Behring HC. Short-term trial of propranolol in racemic form (Inderal). 44. Stensrud P. Acta Neurol 1982. Olsson JE. 39:355–373. Clinical trial of a new antibradykinin. DiStasio E. Aspirin prophylaxis in migraine. Acta Neurol Scand 1976. Lancet 1978. O’Neill BP. Tobita M. Reines SA. 23:188–190. Headache 1981. 31:333–340. 30.348 Silberstein 22. 32. et al. 42. 43. 3. Schlake HP. anti-inflammatory drug. Joseph R. Ekbom K. Mann JD. Stellar S. Diamond S. Diener H. Marano E. Headache 1987. Headache 1972. 28. Rossnagel K. 27. Propranolol for migraine prophylaxis. Atenolol for migraine prophylaxis. 11:37–45. 27:487–488. 33. Forssman B. Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging followup. Cephalalgia 1987. 23. 25:107–113. Nadolol and placebo comparison study in the prophylactic treatment of migraine.) in migraine prophylaxis. 38. 40. Holroyd KA. 4:196–204. Forssman B. Hansen JH. 363:381–391. Meibohm AR. Rose FC. Vilming S. Cephalalgia 1983. Vinge E. Clinical trial of LB-56 (d. A randomized controlled study. A case of hemiplegic migraine treated with flunarizine. Husstedt IW. 53:229–232. Headache 1991.p. Headache 1979. 25. Timolol in migraine prophylaxis. Responders and nonresponders to metoprolol. Steardo L. Millac PA. propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Freitag FG. JAMA 1984. Sjaastad O. Clomipramine and metoprolol in migraine prophylaxis: a double-blind crossover study. Scholz E. Lindblad CJ. Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine. Propranolol in the management of recurrent migraine: a meta-analytic review. 41. 24. Hedman C. Headache 1983. 7:457–458. Ann Neurol 1983. 50. Headache 1986. West J Med 1983. 55. Advances in headache research. Propranolol plasma levels and relief of migraine. 28:55–63. Curr Pain Headache Rep 2004. Br Med J 1974. Featherstone HJ. Blier P. Gray J. Comparative efficacy of nadolol and propranolol in the management of migraine. Solomon GD. Albani F. Psychopharmacology: The Third Generation of Progress. Stensrud P. 53. 25:61–62. Observations on the efficacy of propranolol for the prophylaxis of migraine. 62. Long-term study of propranolol in the treatment of migraine. Alprenolol for migraine prophylaxis. Long-acting propranolol in the prophylaxis of migraine. Mechanism of action of antidepressant treatments: implications for the etiology and treatment of depressive disorders. Ryan RE. 1987:161–166. Elkind AH. Fanchamps A. 27:421–426. Koella WP. Stern MA. et al. ed. 1987:535–544. 67. 6: 231–233. Headache 1987. Nanda RN. Melville ID. 48:124–128. Shanks RG. 59. Headache 1978. Solomon GD. 57. Headache 1994. ed. Charney DS. Heninger GR. Contingent negative variation and efficacy of b-blocking agents in migraine. A review of the relationship between beta-adrenoreceptor antagonists and their action in migraine. Wideroe TE. New York: Raven Press. 51. Timsit-Bertheir M. Neuropsychopharmacology 1991. Propranolol in the treatment of migraine. 13:92–93. 59:32F. London: John Libbey. Clinical trial of a beta-receptor blocking agent (LB46) in migraine prophylaxis. 30:19–22. 58. Acta Neurol Scand 1977. 2:699–701. Colard M. 70. 49. 34:476–478. Kudrow L. . 52. Cephalalgia 1986. Propranolol corrects the abnormal catecholamine response to light during migraine. 27:70–72. Saper JR. Vigander T. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. Oxprenolol in the treatment of migraine. 8:91–95. et al. Dahlof C. 47. Cephalalgia 1989. Rosen JA. Stevens J. Eur Neurol 1990. 54. Long-acting propranolol on migraine prophylaxis: results of a double-blind. Am J Cardiol 1987. 64. Verapamil and propranolol in migraine prophylaxis: a double-blind crossover study. 68. Cephalalgia 1987. Keugh HJ. Zetterman M. 56:181–184. Cephalalgia 1986. Cortelli P. 63. Sudilovsky A. Hering R. Serratrice G.Preventive Treatment for Migraine 349 46. 56. Ekbom K. 138:416–417. Johnson RH. placebo-controlled study. 9:247–253. 42:46–48. Beta adrenergic blocker withdrawal. 65. Migraine and b-blockade: modulation of sympathetic neurotransmission. 6:7–13. Maertens de Noordout A. 69. CNS-related (side-)effects of b-blockers with special reference to mechanisms of action. Diamond S. 18:379–381. In: Meltzer HY. Acta Neurol Scand 1972. Ekbom K. Pradalier A. Enulescu O. 22:268–271. Arch Neurol 1985. Low dose propranolol therapy for aborting acute migraine. 7:459–460. Prophylactic migraine therapy: mechanisms and evidence. Ablad B. deMontigny C. Ramadan NM. In: Rose FC. 26:325. 5:219–229. Schoenen J. A double-blind trial of acebutolol for migraine prophylaxis. Diamond S. Sacquegna T. Chaput Y. An in vivo electrophysiologic study in the rat. Shapiro DB. Sjaastad O. Headache 1982. Prophylactic treatment of migraine with long acting propranolol: a comparison with placebo. Eur J Clin Pharmacol 1985. Headache 1987. 66. Cephalalgia 1987. 60. No clear-cut long-term prophylactic effect of one month of treatment with propranolol in migraineurs. Mehta ND. Freitag FG. Stoica E. Kuritzky A. Meyer JH. Frishman WH. Dahlof C. Why do not all beta-blockers prevent migraine? Headache 1985. 48. 61. Timisit M. Chen R. Gomersall JD. BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. 710:11–20. Amitriptyline in migraine prophylaxis. Lewis DA. with augmentation by an adenosine deaminase inhibitor. Esser MJ. diStefano PS. Neuroscience 2002. Neurotrophic factors: from molecule to man. 72. Couch JR. Biol Psychiat 2003. Legutko B. Jacobs H. Austin MC. Pharmacol Res 2001. Migraine and depression: effect of amitriptyline prophylaxis. Sawynok J. 32:101–104. in migraine prophylaxis: a double-blind crossover study. 85. Acta Neurol Scand 1981. Wiegand SJ. Edgar CL. Siuciak JA. Headache 1992. Pain relief by antidepressants: possible modes of action. Fluoxetine prophylaxis of migraine. Barone P. 65: 1227–1236. DiStasio E. 23: 1–8. Altar CA. et al. Schafer SC. Monza G. Andersson PG. 64: 280–288. A trial of opipramol in the treatment of migraine. 79. Levine JD. Richelson E. Whitehead RE. Bymaster FP. 86. placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Changes in pattern of attacks during a controlled clinical trial. Adly C. 15:1768–1777. Antidepressants and brain neurochemistry. Kishore-Kumar R. Reid AR. Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide. Mayo Clin Proc 1990. Neuroscience 1991. . 91. Post RM.350 Silberstein 71. Lindsay RM. Trends Neurosci 1994. Panerai AE. 88. 36:695–699. Amitriptyline in migraine prophylaxis. J Neurol Neurosurg Psychiat 1972. Trans Am Neurol Assoc 1976. within-patient. 74. 76. Francussi BM. Petersen EN. 77. 36: 684–690. Pain 1998. Taiwo YO. Desipramine relieves post-herpetic neuralgia. Current perspectives on the development of non-biogenic amine-based antidepressants. 78. A randomized. a 5HT-uptake inhibitor. 90. Arch Neurol 1979. 114:807–815. Pain 1999. Whitehead RE. Peripheral antinociceptive effect of an adenosine kinase inhibitor. J Neurosci 1995. Altar CA. Brain Res 1996. Altar CA. 73. 101:234–237. Cephalalgia 1983. in the rat formalin test. Neurotrophins and depression. Lindsay RM. 3: 175–178. Tiengo M. Bianchi M. 84. 17:182–190. 47:305–312. Altar CA. Propranolol and femoxetine. 74:75–81. Steardo L. Straumanis J. Hassanein RS. Stuart A. Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. 20:59–61. J Neurol Neurosurg Psychiat 1973. Makino S. Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Reid A. Kvetnansky R. Acta Neurol Scand 1990. 81. Hassanein RS. 83. Max MB. Pain 1985. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. Bonuso S. Timed-release dihydroergotamine in the prophylaxis of mixed headache: a study versus amitriptyline. Fritsche M. Movilia P. 80. Feinmann C. 35:500–504. Wortwein G. 80:45–55. Janosky JE. Skolnick P. 54:703–709. Chesson A. 89. TiPS 1999. 43:411–423. Sawynok J. Smith MA. 87. Madsen TM. Boylan C. Clin Pharmacol Ther 1990. cross-over. Couch JR. Poon A. 44:131–135. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. 75. 82:34–38. Li X. 82. A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Tyramine content of pizzas and soy products. Zeeberg I. The treatment of MAOI hypertensive crisis with sublingual nifedipine. Ziegler DK. Schweitzer E. Scholte HR. J Int Med Res 1980. 59:330–337. Ahmed F. Luyt-Houwen IE. 99. Clary C. 50:447–449. . 100. Nyrke T. 44: 280–288. Petersen E. 1988. Markley ME. Physicians’ Desk Reference. Richard D. Orholm M. J Clin Psychiat 1983. Ferland J. Wilkinson M. Fluoxetine added to non-MAOI antidepressants converts nonresponders to responders: a preliminary report. 98. 45th ed. Headache Quart 1996. Silberstein SD. Femoxetine in the prophylaxis of migraine: a randomized comparison with placebo. A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Honor PF. Biochim Biophys Acta 1995. 16:961–966. Preskorn SH. Kangasniemi PJ. Migraine prophylaxis. Riboflavin-responsive complex I deficiency. Cephalalgia 1998. Swade C. Reynolds IJ. Weilburg JB. Nielsen JD. 101. Cephalalgia 1991. 108. 68:262–267. 72:98–103. 18:283–286. 113. A comparison of propranolol and amitriptyline. Solomon G. Tollefson GD. Ignacio R. Raskin NH. Saper JR. Mosniam A. 114. Freitag FG. Arch Neurol 1987. Pratt SM. Shulman KI. J Clin Psychiat 1999. Noone JF. Fluoxetine (Prozac) revisited [Medical Letter]. Nutrition 2000. Antidepressants: a clinical update for medical practitioners. Gasser PA. 96. 1990:383–435. Headache 1994. 115. 48:249–250. The Pharmacological Basis of Therapeutics. 30:301. Pollack MH. Acta Neurol Scand 1986. Kunkel R. Taylor P. Zeeberg I. Steiner TJ. MacGregor EA. Headache. Bakker HD. Kodanaz HA. Lalonde J. Calcium-antagonist drugs: receptor interactions that clarify therapeutic effects. Apparent lack of correlation between tyramine and phenylethylamines content and the occurrence of food precipitated migraine. Coppen A. Larsen JJ. 102. Biederman J. Abramowicz M. Clin Psychiat 1987. Kelly K. 106. Influence of topiramate in the regulation of energy balance. Orholm M. Lang AH. Drugs and the treatment of psychiatric disorders. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Winters ME. Mason J. Acta Neurol Scand 1981. 103. Bank J. J Clin Psychiat 1989. 97. 74:235–239. Clomipramine in the prevention of migraine. New York: Pergamon. Acta Psychiatr Scand 1985. Hurwitz A. Kuyt LP. Barnhart ER. 94. 8:49–52. et al. Rosenbaum JF. et al. Drugs Ther 1990:83–85. Oradell: Medical Economics Inc. 107. eds. 110. 1271:75–83. N Eng J Med 1985. Headache 1994. Mianserin in the prophylaxis of migraine: a doubleblind study. Sachs GS. Walker SE. Mayo Clin Proc 1984. Bogaard JM. Lake AE. 11:164–165. 34:476–478. Markley HG. Busch HF. 60:191–193. Refining the MAOI diet.Preventive Treatment for Migraine 351 92. Richelson E. 104. 313:995–1002. Richardson JW. 112. 44:486–489. Findley LJ. Nies AS. 8th ed. Double-blind trial of fluoxetine: chronic daily headache and migraine. Femoxetine—a new 5HT uptake inhibitor—and propranolol in the prophylactic treatment of migraine. 34:497–502. 105. 2nd ed. 95. New York: Churchill-Livingstone. 1991. Baldessarini RJ. Hassanein RS. 64:452–459. 7:239–249. 93. Snyder SH. 111. Monoamine oxidase inhibitors: a review. Monro P. Headache 1990. Rall TW. Acta Neurol Scand 1983.. Fluoxetine in prophylaxis of migraine: clinical experience. Effects of fluoxetine on premenstrual syndrome in chronic headache sufferers. In: Gilman AG. Honor PL. 109. . Bahou Y. Aldeeb SM. 5: 31–37. Aljaberi M. Calcium channels in neurological disease. Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. 124. Mailland F. Marranes R. The effects of flunarizine in experimental models related to the pathogenesis of migraine. Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. 26:83–85. 21:235–239. 132.352 Silberstein 116. a new preventive approach to migraine: a double-blind comparison with placebo. function. 6:7–14. Casacchia M. Gawel MJ. 127. Rolf LH. Montastruc JL. Cephalalgia 1985. Lucking CH. TiPS 1995. Oestreich W. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Vergouwe MN. Martucci N. Louis P. Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Headache 1986. 5: 173–175. Hansen K. Mikala G. Prophylaxis of migraine attacks with a calcium-channel blocker: flunarizine versus methysergide. 121. 136. Barone P. Kreeft J. Behari M. cross-over trial of flunarizine in common migraine. International Union of Pharmacology. 119. Annu Rev Pharmacol Toxicol 1995. Ashton D. Cephalalgia 1986. Sorensen PS. Perez-Reyes E. 131. Flunarizine in migraine: a double-blind placebo-controlled study (in a Saudi population). Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Flunarizine-pizotifen single-dose doubleblind cross-over trial in migraine prophylaxis. Sternieri E. J Clin Pharmacol 1986. 2:43–49. Greenberg DA. Agnoli A. Cephalalgia 1985. 86:17–20. Grotemeyer KH. Cephalalgia 1985. Schwartz A. 6:15–18. Ahuja GK. Compendium of voltage-gated ion channels: calcium channels. Nelson RF. Ferrari A. 130. 42: 275–282. 126. Miljanich GP. 55:579–581. Monteleone P. 31:613–615. Clin Neurol Neurosurg 1984. Schlake HP. Thomas M. Pharmacol Rev 2003. Flunarizine. A double-blind trial of flunarizine in migraine prophylaxis. Bussone G. Cardone G. Snutch TP. 133. Cephalalgia 1986. Antagonists of neuronal calcium channels: structure. 26:524–528. 19:340–345. Mendenopoulos G. Cerbo R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNLA4. Dihydroergokryptine vs flunarizine in the basic treatment of migraine without aura. 129. Husstedt IW. Cephalalgia 1982. 5:119–120. 137. 11:216–217. Ann Neurol 1997. and therapeutic implications. Simard D. 2:197–203. 120. Manzone GC. Catterall WA. 122. Denman DW. Formisano R. Pini LA. 134. Marano E. Cell Tiss Res 1996. 32: 461–462. Galetti G. Biary N. Khoja W. Rascol O. Cephalalgia 1988. Freitag FG. 125. Flunarizine in migraine prophylaxis: an Indian trial. Cephalalgia 1991. Striessnig J. Ophoff RA. Headache 1991. Cephalalgia 1987. 35:707–734. Wauquier A. Louis P. et al. Diamond S. Soyka D. Flunarizine vs propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Metoprolol versus flunarizine: a double blind crossover study. 128. Ramachandran J. Varadi G. 8:21–26. Headache 1981. Steardo L. 117. Nappi G. Molecular determinants of Ca2þ channel function and drug action. double-blind. Frenken CW. Arnott WS. Olesen J. Headache Quart 1993. Manafi T. Can J Neurol Sci 1992. 7:465–466. Guidetti G. Terwindt GM. Schmidt R. 118. 123. Bostantjopoulou S. 87:543–552. Rascol A. Mori Y. Headache 1992. A placebo-controlled. Influence of flunarizine on the altered electronystagmographic (ENG) recordings in migraine. Nuijten ST. Logothetis I. Spierings EL. 135. 4:169–172. eds. 1990:436–462. Nimodipine in migraine: clinical efficacy and endocrinological effects. 8th ed. Saper JR. Cerebrospinal fluid gamma aminobutyric acid levels in migraine. Mathew NT. Verapamil prophylactic therapy of migraine. et al. 8:269–272. 27:76–79. 145. placebo-controlled crossover study. 159. placebo-controlled study of headache frequency and side effects. 140. Festenstein R. Eur J Clin Pharmacol 1991. Headache Quart 1995. Nifedipine versus propranolol for the initial prophylaxis of migraine. 149. Neurology 1994.Preventive Treatment for Migraine 353 138. 154. Somerville B. Sjaastad O. Chabi E. Piepko RW. Nifedipine in the prophylaxis of classic migraine: a crossover. Brinck T. in the prophylactic treatment of migraine. An open label crossover comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. 6:1343–1346. S Afr Med J 1970. 7:477–478. Rall TW. Silberstein SD. Ansell E. 5:7–10. Cleronis JCD. et al. Sadjimin T. et al. Headache 1989. clonidine and carbamazepine in the interval therapy of migraine. 150. Dotarizine in the prophylaxis of migraine headaches. Klinger D. New York: Pergamon Press. Neurology 1984. et al. Baumgartner C. Cephalalgia 1988. Klapper JA. Preliminary results of a double-blind study with the new migraine prophylactic drug Gabapentin. Schwartz A. Annagers JR. Marek K. Mathew NT. Sodium valproate has a prophylactic effect in migraine without aura. European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). 19:333–334. Saper J. Ryan RE. Welch KMA. Sodium valproate has prophylactic effect in migraine without aura: a triple-blind. et al. 33:335–338. McCans JL. Clonazepam (rivotril) in migraine prophylaxis. Hanston PP. A pilot study of the calcium channel antagonist diltiazem in migraine syndrome prophylaxis. 3:516–517. 142. McArthur JC. A comparative trial of prindolol. Neurology 1994. Headache 1987. Can J Neurol Sci 1982. 148. Fazzone T. Brinck T. 161. Horn JR. Stensrud P. Mathew NT. Peroutka SJ. 44:75–80. Olesen J. Headache 2001. Coulam CB. Lance JW. Diltiazem prophylaxis in refractory migraine. Nimodipine in migraine prophylaxis. 16:367. Wessely P. D’Andrea G. Pestronk A. Newsletter 1985. 39:350. Rapoport A. Headache 1999. Nimodipine versus flunarizine in common migraine: a controlled pilot trial. Riopelle R. Drug interaction. 29:215–218. Taylor P. Hamik A. a new calcium antagonist. 147. Formisano R. Smith R. 158. 139. 153. Headache 1989. Gelmers HJ. 146. 20:519–525. 151. Epilepsia 1979. 52:281–286. 163. Bartosh K. McArthur J. 155. Albers GW. Neurology 1989. New anticonvulsants reduce the efficacy of oral contraception. Olesen J. 34:973–976. Meyer JS. 160. . Comparison of the efficacy between flunarizine and nifedipine in the prophylaxis of migraine. et al. Diamond S. Nimodipine. Migraine prophylaxis with divalproex. Rompel H. Bussone G. Arch Neurol 1995. 44:647–651. Markley HG. 157. Schleifer LS. 141. Achar VS. Headache 1993. Etiology of migraine and prevention with carbamazepine (Tegretol). double-masked. Br Med J 1975. Goodman and Gilman’s the pharmacologic basis of therapeutics. Lamsudin R. Migraine-Nimodipine European Study Group (MINES). 41:119–128. 156. Headache 1979. Headache 1983. Jensen R. et al. 143. 41:69–71. Anthony M. 310:1327–1328. 29:633–638. Simon LT. Efficacy of gabapentin in migraine prophylaxis. Bauermeister PW. Baldini S. Falaschi P. Klapper JA. 152. 9:269. Med J Aust 1972. Cephalalgia 1987. 5:50–53. Peroutka SJ. Drugs effective in the therapy of epilepsies. Nies AS. Cerbo R. 23:106–109. Rall TW. In: Gilman AG. 44:241–244. N Engl J Med 1984. Cephalalgia 1996. Jensen R. 162. Gabapentin in migraine prophylaxis. 39:284–286. 144. 181. 5:171–184. Valproic acid hepatic fatalities: a retrospective review. 167. Maryanoff BE. Urban G. Cephalalgia 1997. Trends Biochem Sci 1994. Neurosci Lett 1997. Easterling DE. Woodbury DM. Silberstein SD. Kuritzky A. Rattya J. Neurology 2003. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. 5:524–525. Zona C. Driefuss FE. 1986:713–736. 171. Moline KA. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Sweeney KP. An update on sodium valproate. long-term study (for the long-term safety of depakote in headache prophylaxis study group). 36:547–555. Pharmacol Rev 1990. Mechanisms of anticonvulsant action of valproate. Neurology 1991. Sombati S. 177. 172. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Collins SD. . 180. 58:1652–1659. Richens A. Moyer MD. 178. Neurology 1987. Epilepsia 1994. Rogawski MA. Willmore LJ. Shank RP. Gardocki JF. Knip M. 183. 41:271–278. 39:633–643. Chapman A. Safety of divalproex sodium in migraine prophylaxis: an open-label. 187. 179. Behan PO. MacDonald RL. Dodgson SJ. 174. 12:81–84. Cephalalgia 1985. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Headache 1999. Moskowitz MA. In: Escueta AD. 186. Meldrum BS. Langer DH. Porter RJ. Ciotti MT. Divalproex in the long-term treatment of chronic daily headache. Ward AA. Cephalalgia 1992. Silberstein SD. Epilepsia 2000. Rimmer EM. 175. 41:961–964. 13:307–311. Diamond S. DeLorenzo RJ. Hering R. Divalproex sodium in migraine prophylaxis: a dose-controlled study. New York: Raven Press. 166. Kaniecki RG. et al. Pellock JM. eds. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising development stage compounds. Trends Pharmacol Sci 1992. Freitag FG. 19:439. Shank RP. Gardocki JF. Santilli N. Divalproex sodium in headache—literature review and clinical guidelines. 173. Maryanoff B. 37:379–385. 19:315–359. Advances in Neurology. Coulter DA. Carlson HA. Epilepsia 1988. pharmacokinetics. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Plasma pharmacokinetics of topiramate. 170. 185. 29:662. Acta Neurol Scand 1988. 176. Ann Neurol 1999. 182. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. McLean MJ. 54:1141–1145. Avoli M. Epilepsia 2000. in humans. Prog Neurobiol 1982. 35:450–460. Topiramate: preclinical evaluation of structurally novel anticonvulsant. and mechanism of action. Vaught JL. 41:35–39. Collins SD. Headache 1996. Shank RP. Porter RJ. Freitag FG. Arch Neurol 1997. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. 41:S40–S44. Valproate: a new drug in migraine prophylaxis. Sorensen KV. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Diamond M. For the Depakote ER Migraine Study Group. Keane PE. Epilepsia 2000. The growth of research on protein phosphorylation. 78:346–348. Meander KB. 41:S3–S9. Klapper JA. Pharmacotherapy 1985. Headache 2001. et al. An overview of the preclinical aspects of topiramate: pharmacology. Krebs EG. 168. a new anticonvulsant. 165. Prophylactic treatment for migraine: a comparison of pizotifen and clonidine. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. 184. 42:223–286.354 Silberstein 164. Zakszewski T. 45:444–450. 17:103–108. et al. 231:123–126. Streeter AJ. 169. Vainionpaa LK. Anticonvulsant drugs: mechanisms of action. Topiramate. Huganir RL. A double-blind. Cephalalgia 1997. Greenwood RS. Effect of topiramate on attention. Epilepsia 2000. 21:374. Neto W. Steiner TJ. et al. Sachedo RC. Topiramate in the prevention of migraine headache: a randomized. For the MIGR-001 Study Group. Cephalalgia 2001. JAMA 2004. Persistent migrainous visual phenomena might be responsive to lamotrigine. 251:943–950. Topiramate inhibits trigeminovascular traffic in the cat: a possible locus of action in the prevention of migraine [abstr]. Sachedo RC. Clin Pharm 1998. Nutrition 2000. Topiramate in migraine prophylaxis: a pilot study [abstr]. Ahmed F. Topiramate. York DA. Bray GA. Postsynaptic injection of CA2þ/CaM induces synaptic potentiation requiring CaMKII and PKC activity. Pledger G. Wang JH. 16:967–975. 38:294–300. Glantz MJ. Jacobs D. Physicians’ Desk Reference. Mammen AL. 197. Zonisamide in the treatment of headache disorders [abstr]. placebo-controlled.Preventive Treatment for Migraine 355 188. . Neurology 2002. 189. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Control of topiramate-induced paresthesias with supplemental potassium [Letter]. randomized trial of topiramate versus placebo in the prophylactic treatment of migraine headache with and without aura [abstr]. Reife R. Storey JR. 57th ed. Thomson Healthcare. Storer RJ. Topiramate in migraine prophylaxis— results from a placebo-controlled trial with propranolol as an active control. Brandes JL. Kelly PT. Chen WT. 2003. Epilepsia 2000. 20:316. 17:109–112. Zonisamide in the prophylaxis of migraine headache [abstr]. 204. 4:S42–S51. Features of medication overuse headache following overuse of different acute headache drugs. Calder CS. J Receptor Signal Transduction Res 1995. multiple-dose study. Lu SR. Saper JR. 198. Cephalalgia 1999. 60:A238. Diener HC. 41:S66–S71. Effect of topiramate on body weight and body composition of Osborne-Mendel rats fed a high-fat diet: alterations in hormones. 194. 200. Epilepsy Res 1997. Epilepsia 1997. Drake ME. A double-blind. Functional modulation of ligand-gated GABAA and NMDA receptor channels by phosphorylation. et al. 209. Headache 2002. Shuaib A. 15:443–452. double-blind. 201. Neurology 2000. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. parallel study to determine the efficacy of topiramate in the prophylactic treatment of migraine [abstr]. Katsarava Z. Diamond M. Lim P. Neuron 1996. Diener HC. Cephalalgia 2000. Pledger G. Cephalalgia 2001. 15:325. Arch Neurol 2001. Roche KW. Hart DE. Harden C. Cephalalgia 2001. 210. Wu SC. Fritsche G. Dahlof C. Muratoglu M. O’Brien RJ. Edwards KR. 207. J Neurol 2004. Schmitt J. 16: 1179–1188. Sigel E. Silberstein SD. 196. Montvale: Thomson PDR. 195. Wang SJ. 208. Greathouse NI. 192. Shea P. Krusz JC. Norton JA. 59:1011–1014. Burton LA. 202. 21:374. randomized. Thomas S. Potter DL. Singer L. and uncoupling-protein mRNAs. Neuron 1995. 199. Goadsby PJ. 34:335–346. Topiramate monotherapy for partial onset seizures. Headache 2001. Fuh JL. Renner JB. 41:823–825. 193. 40:S71–S80. Silberstein SD. Topirimate for migraine prevention: a randomized controlled trial. Epilepsia 1999. 27: 29–32. 191. placebocontrolled. 21:374. 211. 54:A15. 61:490–495. Jones MW. 206. Wheeler SD. Limmroth V. Findley LJ. Neurology 2003. Lamotrigine efficacy in migraine prevention [abstr]. Reife RA. Przywara S. Tfelt-Hansen P. Yuen AW. Characterization of multiple phosphorylation sites on the AMP receptor GluR1 subunit. 19:379. 203. neuropeptide. 8:965–973. Adverse effects of antiepileptic drugs. 212. Kochanski P. 190. Cross N. 205. 42:85. Armenthright AD. 217. Headache 1973. 221. Nelson DL. 12:5–7. Saxena PR. Dihydroergokryptine (DEK) in migraine prophylaxis in a double-blind study vs methysergide. Humphrey PP. 214. Fox WR. Mueller EA. 227. Fibrotic disorders associated with methysergide therapy for headache. Heiligers JP. Fozard JR. Mailland F. 233. Brown SL. Forssman B. Blackburn T. Fozard JR. Blaney F. 43:605–609. 13:307–311. TiPS 1995. 224. 3H-lysergic acid diethylamide and 3H-spiroperidol. A comparison between BC105 and methysergide in the prophylaxis of migraine. Weatherall M. 228. eds. 216. Cephalalgia 1989. Suby HI. Kennett G. Boccuni M. Kalkman HO. Graham JR. Induction of migraine like headaches by the serotonin agonist m-chlorophenylpiperazine. 99:221. 222. Fozard JR. Mol Pharmacol 1979. Ergot alkaloids in migraine: is the effect via 5-HT receptors. Proceedings from the International Business Communications Conference on Serotonin Receptors in the Central Nervous System. Muller SE. In: Sandler M. Sicuteri F. 225. Cangi F. Henriksson KG. 102:323–330. Saito K. Martin GR. 215. Cephalalgia 1993. DenBoer MO. Heiligers JP. 16:105–110. Villalon CM. 24:732–737. Br J Pharmacol 1991. MacLennan SJ. 15:300–307. Ergot alkaloids specifically block the development of neurogenic inflammation within the dura mater induced by chemical or electrical stimulation. Sicuteri R. 5-HT in migraine: evidence from 5-Ht receptor antagonists for a neuronal etiology. Zanotti A. Prophylactic and therapeutic properties of 1-methylsergic acid butanolamide in migraine. 1992:297–304. Moskowitz MA. Brewerton TD. eds. Multiple serotonin receptors: differential binding of 3H-5-hydroxytryptamine. 104:183–189. et al. J Pain 2002. In: Olesen J. Saxena PR. Jan:25–26. Markowtiz S. 229. Headache and cortical responses to m-chlorophenylpiperazine are highly correlated. 1996. The role of 5-HT1like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan. New York: Raven Press. 223. Saxena PR. Int Arch Allerg 1959.356 Silberstein 213. 13:68–73. 5-Hydroxytryptamine mechanisms in primary headaches. Gordon ML. 48:204–212. Lipton RB. 5-HT2 receptor subtypes: a family reunited. 232. BC105 and deseril in migraine prophylaxis: a double-blind study. 329:111–119. 218. 274:360–368. 5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives. New York: Oxford University Press. Moskowitz MA. Migraine: A Spectrum of Ideas. Villain CM. 13:400–405. Acta Neurol Scand 1972. Br J Pharmacol 1991. Snyder SH. Sadowsky NL. 231. N Engl J Med 1966. Efficacy of zonisamide in prophylactic treatment of migraine headaches with or without aura: open-label experience in 7 patients [abstr]. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. 220. 230. Analysis of symptoms of patients with headaches and their response to treatment with ergot derivatives. 146:319–336. Interpreting vessel diameter changes in vascular headaches. 1990:128–146. DenBoer MO. 350:225–229. Andersson PG. The 5-hydroxytryptamine-nitric oxide connection: the key link in the initialization of migraine? Arch Int Pharmacodyn 1995. Wilkinson MIP. 9: 448–449. Jimerson DC. Arch Pharmacol 1994. Moskowitz MA. Comparison of the effects of methysergide and methylergometrine with GR 43175 on feline carotid blood flow distribution. Cephalalgia 1992. Philadelphia. 219. PA. 234. Collins GM. Clin Pharmacol Ther 1988. The role of 5-HT1-like receptors. Peroutka SJ. Humphrey PP. Barrie MA. Q J Med 1968. Murphy DL. TiPS 1992. 16:687–689. Baxter G. . Br J Pharmacol 1990. Ann Neurol 1988. Cochran JW. 3:39. Kihlstrand S. LeCompte PR. 226. Methysergide in migraine prophylaxis. Sacks OW. Lawrence ER. Foster JB. 14:302–308. N Z Med J 1971. Behan PO. Bellavance AJ.Preventive Treatment for Migraine 357 235. Headache 1968. Hockaday JM. Friedman AP. Carroll JD. Management of childhood migraine. 256. Curr Ther Res Clin Exp 1971. 1:54–55. Headache 1977. Elkind AH. Ostfeld AM. Newell DJ. Smyth GA. 88: 640–655. Sjaastad O. Headaches and Migraine in Children. 30:710–715. 245. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Headache 1971. Methysergide in the migraine syndrome. in the prevention of migraine. Hinterberger H. Acta Neurol Scand 1977. An evaluation of methysergide in the prevention of migraine and other vascular headaches. 13:63–68. Clin Pharmacol Ther 1964. Anthony M. Clinical trial of methysergide and other preparations in the management of migraine. 206:1041–1044. 260. 244. Curran DA. Am J Med Sci 1967. Sicuteri F.5. pizotifen. 17:109–112. Med J Aust 1968. Reid M. Lazarus L. Pedersen E. Siegelman SS. Fine RD. 45:594–600. . Curran DA. Hossain M. Graham J. 54:116–121. Med J Aust 1963. MacNeal PS. 238. 2:91–93. 250. Cardiac and pulmonary fibrosis during methysergide therapy for headache. J Neurol Neurosurg Psychiat 1964. Foster JB. 254. 236. LeCompte PM. 255. Bachman A. 224:201–204. BC105. Controlled trial of demigran in the prophylaxis of migraine. 237. Ryan RE. A comparative study of naproxen sodium. 1988:63–74. Engisch R. Res Clin Stud Headache 1967. Curran DA. 47:514–518. and 1-isopropyl-3-hydroxy5-semicarbazono-6-oxo-2. 247. 241. Lance JW. methysergide. Headache 1990. 251. Double-blind crossover comparison of BC105. 73:5–9. 243. Presthus J. Migraine in Childhood. 7:520–526. Arthur GP. Littlestone W. Stensrud P. Maclay WP. Acta Neurol Scand 1969. 242. 254:1–12. Pharmacol Ther 1966. Barlow CF. Br Med J 1967. and placebo in migraine prophylaxis. Ryan RE. In: Hockaday JM. 1:814–818. Meloche JP. A comparison between placebo. The ingestion of serotonin precursors (L-5-hydroxytryptophan and Ltryptophan) improves migraine headache. Hornabrook RW. 253. Clinical trial of a new serotonin antagonist. Silent retroperitoneal fibrosis associated with methysergide therapy. ed. 258.3. Forsythe I. Suppression of growth hormone secretion by melatonin and cyproheptadine. 56:17–28. 11:6–18. Pizotifen (BC105) in migraine prophylaxis. Philadelphia: 1984. Hudgson P. Krakowski AJ. Lance JW. J Clin Invest 1974. BC105. Moller CE. pizotyline. London: Butterworths. The treatment of migraine with BC105 (pizotifen): a double-blind trial. Bana DS. 249. Appraisal of BC105 in migraine prophylaxis. Practitioner 1980. a new preparation for the interval treatment of migraine: a double blind evaluation compared with placebo. Am Heart J 1974. 27:463–469. 1: 74–122. and placebo in the prophylaxis of migraine headache. Psychosomatics 1973. 239. 259. 8:118–126. Hughes RC. Shah Y. 13:19–22. Osterman PO. 252. Curr Med Res Opin 1975. 257. Headache 1973. Methysergide. 5:201–204. 3:68–71. Propranolol in the treatment of migraine. Lance JW. 246. BC105 and methysergide (Deseril) in migraine prophylaxis. Sanomigran for migraine prophylaxis: controlled multicenter trial in general practice. 248.6-tetrahydroindol (Divascan) in migraine prophylaxis. JAMA 1968. BC 105 in the prophylaxis of migraine. 240. A new agent for chemotherapy of migraine headaches: a controlled study. Lance JW. Shekelle RB. Acta Neurol Scan 1971. Graham JR. Jansen J. Hakkarainen H. 47:120–122. Drugs acting by modification of serotonin function. 276. Res Clin Stud Headache 1970. Kass B. 61: 351–356. Adv Neurol 1982. 7:7–13. 264. 17:169–172. Ahuja GK. et al. 58:288–295. Mancuso A. 56:405–412. 11:218–219. Acta Neurol Scand 1979. Cephalalgia 1987. 275. 1. Elkind AH. Shafar J. Cephalalgia 1989. J Fam Pract 1989. Drugs 1987. Comparative efficacy of cyclandelate versus flunarizine in the prophylactic treatment of migraine. Double-blind trial and followup. Rose FC. Trucco M. 277. Efficacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients. Bredfeldt RC. 263. 284. 15:199–212. Acta Neurol Scand 1978.5 mg nocte: a new approach in the prophylaxis of migraine. The prophylactic treatment of migraine with an antiserotonin pizotifen. Das SM. Moller CE. 5: 532–533. Narainaswamy AS. Herbertson RK. Price WH. 19:219–222. Lisuride and pizotifen in the treatment of migraine without aura. Serotonin precursors in migraine prophylaxis. Tallett ER. Havanka-Kanniainen H. Metoprolol vs clonidine in the prophylactic treatment of migraine. 280. Klee A. 265. Prophylactic treatment of migraine with clonidine: a controlled clinical trial. 262. Nestvold K. and pizotifen in migraine prophylaxis. 29:153–156. 22:272–275. 270. 60:214–217. Leunbach G. 1:403–407. Kallanranta T. Clonidine in migraine prophylaxis. Hokkanen E. Ryan JRRE. Hokkanen E. A randomized crossover trial.358 Silberstein 261. Biale L. . Savi L. Knowlson PA. Deth S. Sutherland JE. Martignoni E. Acta Neurol Scand 1977. Acta Neurol Scand 1971. 49:108–114. 283. Papalia F. 3:315–320. Schoenen J. Boisen E. 33:103–198. Adam EI. J R Coll Gen Pract 1978. Tuovinen T. Cephalalgia 1987. 53:233–236. Louis P. Kangasniemi P. 278. Myllyla VV. The effects of clonidine in the prophylactic treatment of migraine. cross over study of nimodipine versus pizotyline in common and classical migraine. 28:587–590. Headache 1975. 281. Headache 1979. Sjaastad O. Salmon S. Micieli G. 33:357–363. Double-blind trial of clonidien in the treatment of migraine in a general practice. 268. DeRysky C. 267. Bono G. Nappi G. Ryan SRRE. Cavallini A. Cephalalgia 1985. Hubbe P. 26:129–131. Agostinis C. Single-dose pizotifen. Sjaastad O. 2-(2. Headache 1982. 282. 1-Isopropylnoradrenochrome-5-monosemicarbazono. 279.6-Dichlorophenylamino)-2-imidazoline hydrochloride (ST 155 or Catapresan) as a prophylactic remedy against migraine. Headache 1986. Webster C. Cephalalgia 1985. Gore SM. Hubbe P. Lancet 1972. Headache 1977. 271. Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine: a comparative trial. Peatfield R. 274. Clonidine in prophylaxis of migraine. A double blind. Nattero G. 269. 266. Clonidine in the prophylaxis of migraine. Acta Neurol Scand 1980. Sandrini G. Stensrud P. Micieli G. Kruse JE. Mondrup K. Efficacy of nimodipine in comparison with pizotifen in the prophylaxis of migraine. Acta Neurol Scand 1973. Nimodipine vs pizotifen in common migraine: results of a double-blind crossover trial. 272. Capildeo R. Criscuoli M. Acta Neurol Scand 1976. Efficacy of guanfacine in a double-blind parallel study for migraine prophylaxis. Gawel M. Nappi G. Preliminary report on the use of clonidine (Boehringer Ingelheim) in the treatment of migraine. Stensrud P. Wilkinson M. Evaluation of clonidine in prophylaxis of migraine. Savoini G. 7:453–454. 5:159–165. Clonidine (Catapresan)-double-blind study after long-term treatment with the drug in migraine. 273. 9:369–370. Cephalalgia 1991. Hedman C. Trends in alternative medicine use in the United States. Cephalalgia 2001. Heptinstall S. Br Med J 1985. Hendriks H. Schrader H. Stovner LJ. 28:550–557. JAMA 1990. 290. Hylands PJ. 293. 305. 67:181–186. Alperin JB. 40:445–450. Wheatly K. Br Med J 1988. 289:65–69. 31:20–26. Treatment review: nonsteroid anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks. Lancet 1988. 280:1569–1575. 54:140–159. et al. Hylands DM. Headache 1988. Herbal medicines in migraine prevention: randomized double-blind placebo-controlled crossover trial of feverfew preparation. Pittler MH. Chesson AL. Peto R. Bovim G. Levin HS. Earon G. 288. an NK-1 antagonist. Buring JE. Peto R. 5:95–99. Offen WW. Davis RB. Schrader H. Acta Neurol Scand 1983. 299. et al. 20:13–18. Stovner LJ. Cephalalgia 2002. Tronvik E. 291:569–573. Cortelli P. 2:189–192. Stovner LJ. 44:581–586. Gray R. 296. Sjaastad O. Spierings EL. On behalf of the Protocol 125 study group. 2. Johnson ES. Murphy JJ. multicenter. in migraine prevention. Cochrane Database Sys Rev 2000. Proccaccianti G. Jenkin S. Ernst E. Dry J. 11:508–511.Preventive Treatment for Migraine 359 285. Hennekens CH. Friede M. et al. double-blind. Acta Neurol Scand 1976. Carusso R. Hemicrania continua: another headache absolutely responsive to indomethacin. 3. Headache 2004. Bovim G. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. The efficacy and safety of Tanacetum parthenium (Feverfew) in migraine prophylaxis: a double-blind. Headache 2000. Goldstein DJ. Ernst E. Feverfew for preventing migraine. Peters BH. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized. ‘‘Hemicrania Continua’’— a clinical review. 306. JAMA 2003. Mathew N. Klein EG. Hennekens C. Palevitch D. Dale I. Visser H. Solomon GD. 1990–1997: results of a follow-up national survey. Sand T. 21:102–106. Sjaastad O. Brandes JL. 295. Efficacy of feverfew as prophylactic treatment of migraine. Diener HC. dose-response study. 22:523–532. Cochrane Database of Systematic Rev 2004. Pradalier A. Phytomedicine 1996. 303. Bootsma HP. JAMA 1998. Phytother Res 1997. 4:65–70. A new (?) clinical headache entity: chronic paroxysmal hemicrania. 287. Mitchell JR. 286. Saper J. 296:313–316. Headache 1991. 297. placebo-controlled. Eisenberg DM. Platelet antagonists in migraine prophylaxis: a clinical trial using aspirin and dipyridamole. Gamberini GD. Ettner SL. 298. Henneicke HH. Headache 1980. Cephalalgia 1984. randomized. 302. Deweerdt CJ. Fischer M. 3:225–230. Montelukast for migraine prophylaxis: a randomized. Clin J Pain 1989. Bordini C. 294. 322:19–22. Clapin A. Helde G. Propranolol and acetylsalicylic acid in migraine prophylaxis. 3. Randomized trial of prophylactic daily aspirin in British male doctors. Sjaastad O. Jamrozik K. 301. 291. Vogler BK. crossover study. Sand T. 289. placebocontrolled. Lanepitant. Br Med J 2001. Botulinum toxin type A as a migraine preventive treatment: for the Botox1 Migraine Clinical Research Group. et al. Kadam NP. placebo-controlled study. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. 292. Pfaffenrath V. Farmer MV. 264:1711–1713. 300. Pittler MH. Collins R. Baldratti A. Randomized double-blind placebo controlled trial of feverfew in migraine prevention. Double-blind crossover study. Silberstein SD. Antonaci F. Feverfew for preventing migraine. Masel BE. 304. Helde G. Management of the headache patient with medical illness. Low-dose aspirin for migraine prophylaxis. . Coenzyme Q10 for migraine prophylaxis: a randomized controlled trial [abstr]. Wessely P. 22:137–141. Neurology 1996. Schultz L. 309. Chiarugi A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. diClemente L.. Sangiorgi S. Breslau N. Ohkubo M. Goadsby PJ. 323. Effectiveness of high-dose riboflavin in migraine prophylaxis. Cephalalgia 1998. Jacquy J. 310. Cephalalgia 1996. 311. Lipton RB. Yuasa T. 312. multicenter. Oshinsky ML. Feverfew as a preventive treatment for migraine: a systematic review. i: 1071–1074. Cephalalgia 1995. 2: 581–582. 315. 44:666–669. 47:1093–1095. Pittler MH. 16:436–440. Danesch U. Lenaerts M. Vogler BK. Reuter U. Elevation of cerebral lactate detected by localized 1H-magnetic resonance spectroscopy in migraine during the interictal period. Levine SRDG. Cephalalgia 1996. 51:507–516. Bolay H. Schoenen J. Neurology 2004. 318. Kohne-Volland R. Abnormal platelet mitochondrial function in patients affected by migraine with and without aura. and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Peikert A. Heptinstall S. Rozen TD. eds. Kerrebijn KF. et al. Tsuji S. Coppola G. Preventive treatment of migraine: an overview. Watanabe H. Ernst E. Lipton RB. 317. Wilimzig C. White A. nerve conduction. Boggard JM. Migraine: association with personality characteristics and psychopathology. Einhaupl KM. Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme. Migraine: diagnosis and treatment. 313. Lancet 1983. Scholte HR. 327. J Pharm Pharmacol 1987. 308. Silberstein SD. 44:2153–2158. 16:257–263. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. Mora M. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leukocytes. Ann Neurol 2002. 39:459–465. Penn AM. Sandor PS. In: Silberstein SD. 320. Eur Neurol 2004. Cephalalgia 2003. 314. Magnesium in the prophylaxis of migraine—a double-blind. Wilks K. Neurology 1998. Garavaglia B. 18:704–708. Goadsby PJ. 325. Silberstein SD. Luyt-Housen IE. Cephalalgia 1994. Pfaffenrath V. NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Neurology 1994. A dehydrogenase and respiratory chain deficiency. Heptinstall S. et al. Mauskop A. Monari L. 31P-magnetic resonance spectroscopy in migraine without aura. Extracts of feverfew may inhibit platelet behavior via neutralization of sulphydryl groups. Mochi M. MELAS syndrome with mitochondrial tRNALEU(UUR) mutation: correlation of clinical state. Prophylaxis of migraine with oral magnesium: results from a prospective. et al. 1998:61–90. Neurology 1992. et al. 316. 23:577. A randomized controlled trial. Mitchel JR. Open label trial of coenzyme Q10 as a migraine preventive. 324. Meyer C. Helpern JA. Neurology 1994. 42:2147–2152. placebo-controlled study. 326. Lancet 1985. Lee JW. Lipton RB. Gebeline CA. Nuclear factor-kB as a molecular target for migraine therapy. Rahlfs VW. Neurology 1989. et al. Arts WF. Groenewegen WA. 51:89–97. 14:21–23. Headache in Clinical Practice. et al. Riva R. Spangenberg P. . Williamson L. 39:538–541. placebo-controlled and double-blind randomized study. 322. 319. Antozzi C. Cephalalgia 2002. Oxford: Isis Medical Media Ltd. Preliminary observations on brain energy metabolism in migraine studied by in vivo 31phosphorus NMR spectroscopy. Welch KMA. Loesche W. 17: 67–72. Silberstein SD. Lipton RB. Thuillier P. 1st ed. 15:337–369. et al. Gobel H. 63: 2240–2244. 321. Kuwabara T. Montagna P. Moskowitz MA.360 Silberstein 307. Cortelli P. Diener HC. 50:466–470. Cephalalgia 1997. 52:281–286. Leira R. Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients. Arch Neurol 1995. Mathew NT. . Prophylaxis of migraine headaches with divalproex sodium. Brugger AM. et al. Saper JR. 271:918–924. Cephalalgia 2003. Swann AC. Silberstein SD. 329. Pascual J.Preventive Treatment for Migraine 361 328. JAMA 1994. 330. Bowden CL. 23:961–962. Lainez JM. Efficacy of divalproex vs lithium and placebo in the treatment of mania. . It is therefore of clinical interest that several treatments nearly devoid of adverse effects are available for migraine prophylaxis. in placebo-subtracted values. which are required for the activity of flavoenzymes involved in the electron transport chain (Fig. The first is that on average. and compare the data with those published in recent trials for slow release propranolol 160 mg (1) and for valproate (2). encephalopathy. lactacidosis. the energy reserve. Belgium University of Lie INTRODUCTION There are two major shortcomings with prophylactic therapies for migraine. In this chapter.4) that on 31P magnetic resonance spectroscopy. and its preventive action in migraine has been explored in several randomized controlled trials..23 Herbal Medicines and Vitamins Jean Schoenen and Delphine Magis Departments of Neuroanatomy and Neurology. Other ‘‘natural’’ elements like coenzyme Q10 and thioctic acid (a-lipoic acid) have also been studied.e. `ge. the mitochondrial phosphorylation potential. or plants like feverfew or butterbur. stroke. Riboflavin (vitamin B2) is the precursor of flavin mononucleotide and flavin adenine dinucleotide. RIBOFLAVIN Rationale The rationale for using high-dose riboflavin in migraine prophylaxis came from the observation made by two independent groups (3. if available. or mitochondrial myopathies on the assumption that at large doses (300 mg/day in children) it might augment 363 . we will review published data for these medications as well as for magnesium. 1). Magnesium is also considered a ‘‘soft’’ treatment. Lie `ge. i. Given to patients with mitochondrial myopathy. We will focus on efficacy data on 50% responder rates in absolute and. was reduced by 25% to 30% interictally in the brain (and muscle) of migraineurs with or without aura. Among them are vitamins like riboflavin and herbs. Headache Research Unit. two mainstays in preventive antimigraine treatment. The second is that most prophylactic drugs are endowed with a high prevalence of uncomfortable and sometimes intolerable adverse effects. efficacy rate of any prophylactic agent does not exceed 50% in most patients. an antinociceptive effect was recently found in several B vitamins.9). and for a migraine index (headache days þ mean severity) 41% . was found to be effective as a preventive treatment of migraine in an open pilot trial (7). It can stimulate the activity of methylene-tetrahydrofolate reductase. flavin mononucleotide.8]. for migraine days 59% (NNT: 2. randomized parallel group trial (12). FAD. administered as intranasal hydroxycobalamin. After a onemonth. in an animal model of chemonociception (10). Note that FAD is also a cofactor for methylene-tetrahydrofolate reductase. Another interaction between riboflavin and NO could be the flavin domain in the NOS gene. single-blind placebo run-in. Finally. Abbreviations: FMN. patients were randomized either to riboflavin or to placebo as long as they had at least one attack during the run-in period. After three months of treatment with riboflavin.364 Schoenen and Magis Figure 1 Outline of the mitochondrial electron transport chain illustrating the potential impact of riboflavin at the level of complex I (via FMN) and complex II (via FAD). the metabolizing enzyme of homocystein. Riboflavin can also be a precursor in the biosynthesis of vitamin B12. More recently. The Belgian riboflavin trial was investigator initiated. Clinical Evidence After a positive open pilot study (11). which. of which the genetic polymorphism C677T could predispose to migraine (8. the metabolizing enzyme of homocystein. Riboflavin may indeed counteract the inhibition of mitochondrial respiration by nitric oxide (NO) (6) and act as a reactive oxygen species scavenger. the 50% responder rate for reduction in attack frequency was 56% [numbers-needed-to-treat (NNT): 2. sponsored by the Belgian Headache Society and included a relatively small number of patients: 27 in the placebo group and 28 in the riboflavin (400 mg once per day) group. flavin adenin dinucleotide.3). including vitamin B2. (5)]. activity of mitochondrial complexes I and II. riboflavin was able to improve clinical and biochemical abnormalities [see Ref. the Headache Research Unit of the University ` of Liege steered a multicenter placebo-controlled. a number of alternative mechanisms of action for the effects of riboflavin in migraine have been discussed. 4. Finally. Abbreviation: NNT. headache days. and 8%. (14) studied the prophylactic antimigraine effect of a combination of three ‘‘natural supplements’’—riboflavin 400 mg. Since the riboflavin trial was published. One woman in the riboflavin group had diarrhea two weeks after starting the drug and withdrew from the study. both by adult and child migraineurs. the number of patients needed to harm was 33. 15%. Reports on favorable results were exchanged confidentially. upper abdominal pain. In the placebo group. her symptoms disappeared within 72 hours. one patient mentioned recurrent abdominal cramps of moderate intensity but did not interrupt the trial. NNTS are indicated.Herbal Medicines and Vitamins 365 Figure 2 Fifty percent responder rates for attack frequency. Another patient receiving riboflavin complained of polyuria but completed the trial. The placebo-subtracted 50% responder rate for riboflavin was 37%. Boehnke et al. and migraine index (mean severity þ headache days) as assessed in the third month of randomization period in riboflavin (400 mg/day) and placebo groups. In 23 patients. numbers-needed-to-treat. Three patients experienced mild adverse effects (diarrhea.5 tablets/mo after 3 months and to 4 tablets/mo after 6 months (p ¼ 0. Maizels et al. which again compares favorably with valproate for which this number is around 2. 2) (2).005). The use of abortive antimigraine drugs significantly decreased from 7 tablets/mo to 4. riboflavin has been used in several countries. On follow-up. but no formal studies were conducted.006). Only three adverse events were recorded during the trial. (NNT: 3. and facial erythema) during the study. Median attack frequency was reduced from four attacks/month (range 3–5) at baseline to two attacks/month (range 2–3) after three months of treatment (p < 0. the results were overall in line with the Belgian riboflavin trial. Comparing riboflavin with placebo.001) and remained at two attacks/month (range 2–4) after six months of treatment (p ¼ 0. placebo-controlled trial. in an interesting recent randomized double-blind. magnesium 300 mg. which compares favorably with the 23% reported in the valproate trial by Klapper (Fig. and feverfew 100 mg in 24 patients and compared them to 25 patients treated with a .3. (13) performed an open label study to determine the prophylactic antimigraine effect of riboflavin 400 mg in a specialized tertiary headache center.016 and p ¼ 0. Recently.1) compared with respective placebo responses of 19%. which tend to normalize the deficient habituation found interictally in migraineurs (15). We have shown that riboflavin does not influence habituation of cortical-evoked potentials. There was no significant difference in responder rate for reduction between the two groups. Adverse events are extremely rare with riboflavin at 400 mg per day. It can therefore be considered a first choice drug only in moderately disabled patients with a low attack frequency (below four to five attacks/month) and not in severe or chronic migraineurs. A greater than 50% reduction in number of days with migraine was found in 61. An important difference with most antimigraine prophylactic drugs is that riboflavin does not induce weight gain. the presence of magnesium (and/or feverfew) could interfere with the intestinal absorption of riboflavin. It may also act as an antioxidant. These results could have different explanations: the 25 mg riboflavin dose might not be inactive. Rozen et al. Association of riboflavin with other prophylactic agents. the placebo effect was particularly high in this study. it seems obvious that riboflavin has a slow onset of action. it can also be given during pregnancy. may allow for keeping the latter at a dose low enough to avoid side effects. Our clinical impression is that riboflavin may be more effective in migraine with aura. be considered as a first line preventative drug in children. which disappeared after withdrawal and recurred after rechallenging the patient with riboflavin. As no teratogenic effects are known for riboflavin. contrary to beta-blockers and sodium valproate. but this could be biased by the lower average attack frequency compared to migraine without aura. such as beta-blockers. and none of the products tested are superior to placebo. riboflavin can. there was a significant improvement in both groups of patients. The maximal effect on the attack frequency does not occur before the third month of treatment. One percent of patients have gastrointestinal intolerance.3% patients. however. 1). Clinical Experience From the randomized controlled trial and our clinical experience in over 1000 patients. It transfers electrons from mitochondrial complex I (nicotinamide adenine dinucleotide dehydrogenase) and complex II (succinate-Q-reductase) to cytochrome c (Fig. . The 50% responder rate for reduction in attack frequency was 44% (40% for migraine days) for the active cocktail and 42% for the placebo (33% for migraine days). COENZYME Q10 Rationale Coenzyme Q10 is an essential element of the mitochondrial electron transport chain. The beneficial results obtained with riboflavin have initiated trials with other drugs acting on energy metabolism like coenzyme Q10 and thioctic (a-lipoic) acid. Clinical Evidence After an open label trial in 31 patients.366 Schoenen and Magis ‘‘placebo’’ containing 25 mg riboflavin. but until now this has not been formally studied. Because of its excellent efficacy/adverse effect profile. if migraine prophylaxis is warranted. after three months of treatment. (16) suggested that coenzyme Q10 (150 mg/day) could be effective in migraine prophylaxis. Surprisingly. We have encountered an allergic cutaneous rash in one patient. prostaglandin.03).6% for coenzyme Q10 (p ¼ 0. It has various pharmacological actions that may be relevant to migraine pathophysiology. Larger studies are needed for this drug. Its main sesquiterpene lactone.4% for placebo and 47. One of the patients in the coenzyme Q10 group withdrew due to cutaneous allergy. Thioctic acid produces a clinical and biochemical improvement in various mitochondriopathies such as Leigh’s encephalomyelopathy. headache days (p ¼ 0.e. After three months of treatment. It remains however. placebo-controlled study (19). and pyruvate carboxylase deficiency (18). The formulation (MSE 2001. may be a nonspecific norepinephrine. and days with nausea (p ¼ 0. we included 44 patients who received either thioctic acid or placebo 600 mg/day. although there was an indication for a beneficial effect of thioctic acid on various secondary outcome measures. It did not demonstrate a clinically meaningful advantage of thioctic acid over placebo in migraine prophylaxis. Clinical Evidence In a multicenter double-blind. Unfortunately the trial had to be interrupted because of slow recruitment in several centers and time limitation in drug quality. thioctic acid (a-lipoic acid) is able to stimulate mitochondrial oxygen metabolism and adenosine triphosphate (ATP) production. It inhibits the interaction of platelets with collagen substrates and 5-HT release (21). MSE Pharmazeutika GmBH.i. Because of its excellent tolerability and proven efficacy. Regarding attack frequency. which has an excellent tolerance. ‘‘responders.. prostaglandin synthesis. parthenolide. placebo-controlled trial with a new formulation of coenzyme Q10 100 mg t. . in 42 patients. and acetylcholine antagonist.01). to be determined whether the conclusions of this trial can be extrapolated to all available coenzyme Q10 formulations. coenzyme Q10 is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug. and nuclear factor (NF)-kappa beta.02) and the NNT for effectiveness was 3. coenzyme Q10 was found to be superior to placebo in reducing attack frequency (p ¼ 0. pyruvate dehydrogenase deficiency.04). Germany) is a patented nanodispersion of well-characterized. THIOCTIC ACID (a-LIPOIC ACID) Rationale Like riboflavin and coenzyme Q10. FEVERFEW (TANACETUM PARTHENIUM) Rationale Feverfew (Tanacetum parthenium) has been known for its headache relief potential since medieval times (20).d. Sanomit Q10 . using an intention-to-treat analysis. i. using the same protocol as in our riboflavin study (17).’’ was 14. the proportion of patients who improved by at least 50%. No adverse effects were reported. very small nanoparticles containing Q10. bradykinin. serotonin.Herbal Medicines and Vitamins 367 We performed a randomized. a subanalysis of a subset of patients with at least four attacks per 28 days during the baseline period was also performed.9 Placebo (n ¼ 13) À0. 3) but. Abbreviations: FF. and VPA trials discussed in this chapter. 6. FF.9 0 36.i.1 FF 6. VPA. magnesium.5a FF 18.i. coenzyme Q10 (Q10).25 mg t. The 50% responder rate for attack frequency was 27. 18. Interestingly. (23) performed a large. phase II. BB. multicenter.25. feverfew.d. the placebo-subtracted 50% responder rate was negative (À3. Abbreviation: FF. MG. with ! 4 attacks during baseline FF 2. MG.08.5 Æ 1.d. butterbur. randomized. BB. In this ‘‘confirmatory’’ intention-to-treat sample of 49 Table 1 Subanalysis of 49 Patients Having at Least Four Migraine Attacks During the OneMonth Baseline Before Randomization Confirmatory ITT sample (23). n ¼ 49 pat. (n ¼ 19) À1. dose was found to have some efficacy.75 mg t. PRO.8% 37. feverfew.d. .).d.i. (22) concluded that the clinical efficacy of feverfew in the prevention of migraine had not been established beyond reasonable doubt (22). valproate. Only the 6.8% in a sample of 36 patients (Fig.d.2 Æ 1. More recently.25 mg feverfew t. because of a high placebo response.08 mg t.i.6%).25 mg t.d.368 Schoenen and Magis Figure 3 Fifty percent responder rates for attack frequency (absolute values) for the riboflavin (B2).8 Æ 1. PRO.i. Clinical Evidence A review of five randomized controlled trials of feverfew on small samples of patients by Vogler et al. propranolol. (n ¼ 8) À1.3 Æ 1. (n ¼ 9) Absolute change in attack frequency 50% responder rate À0. placebo-controlled study of three doses of a CO2 extract of tanacetum parthenium (Mig-99 ) (2.i.5% 15.75 mg t.4% a The amelioration with the 6. dose is significant. Pfaffenrath et al. The mechanism of action of Petasites extract in migraine is uncertain. group compared to 15.d.d. A recent update of the Cochrane Database Systematic Review (24) concluded that the overall results of five trials that met the methodological standards did not formally establish that feverfew is efficacious in preventing migraine. They suggested that butterbur might be effective in migraine prophylaxis. in migraine prophylaxis in 60 patients (26). placebo). Petasites extract 50 mg b. it has been found to have anti-inflammatory properties including antileukotriene activity. Over four months of treatment.29) and reported conclusions from animal toxicity studies. and back pain.i. 36% for Petasites extract 50 mg b. The trial was a three-arm. and three months based on this endpoint. and 26% for the placebo group. placebo-controlled parallel-group study of a special butterbur root extract 25 mg t.25 mg t. predominantly burping.d. in 245 patients with migraine..i. In laboratory studies.Herbal Medicines and Vitamins 369 patients..d. parallel-group.8% in the 6.5) compared to the placebo group (À0.05).d. (p 0. . No significant difference was found between placebo and butterbur regarding adverse events. BUTTERBUR (PETASITES HYBRIDUS) Rationale Butterbur (Petasites hybridus).3 Æ 1.d. a plant flourishing in the moist areas of Europe has been used for centuries in medical practice for its spasmolytic and analgesic effects in conditions such as migraine.i. asthma. placebo). which have occasional adverse effects. or placebo b. A larger trial has recently been published (27) and largely confirms the results from previous studies. Another possible mechanism of action involves an effect on the calcium channels. Clinical Evidence As far as clinical evidence is concerned. The active ingredient used for migraine prophylaxis is a special extract made from the underground parts (rhizome) of the plant (25). group (¼19) (À1.0012 vs. Safety and adverse effects of butterbur extract were examined by Danesch and Rittinghausen (25).d. who analyzed the results of two controlled clinical trials (28.i. randomized trial comparing Petasites extract 75 mg b. the decrease in attack frequency was significant in the 6. Results were also significant in favor of Petasites 75 mg at one.9). At three months the 50% responder rate for migraine frequency was 45% in the butterbur group and 15% in the placebo group. in the perprotocol analysis. (p 0. migraine attack frequency was reduced by 48% for Petasites extract 75 mg b. a total of 187 patients with migraine were exposed to doses of the special butterbur extract between 100 and 150 mg daily for at least three months. Diener et al. In the two controlled trials. urinary tract spasms.4% in the placebo group (Table 1). two.127 vs. reanalyzed the outcome of a randomized. Butterbur was well tolerated.i. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events.i.i.8 Æ 1.d. The 50% responder rate was 36.25 mg t. Different preparations of feverfew containing various concentrations of parthenolide are available in some countries. the most frequent being mouth ulcerations and oral inflammation with loss of taste. The proportion of patients with a !50% reduction in attack frequency after four months was 68% in the Petasites extract 75-mg arm and 49% in the placebo arm (p 0.i. placebo-controlled studies in parallel groups of patients have been performed in German-speaking countries. MAGNESIUM Rationale Low brain magnesium levels have been detected with 31P magnetic resonance spectroscopy during migraine attacks (30) and interictally in migraine with aura (31). Clinical Experience Our clinical experience with high-dose magnesium (450 mg Mg element bid) in migraine prophylaxis is limited.. 43 receiving the magnesium preparation. and activation of Naþ/KþATPase (37). Therefore the manufacturing process requires a complete removal of toxic PA below 0. the 50% responder rate for attack frequency was 52. such as beta-blockers or antiepileptics. substances with hepatotoxic properties that may cause liver cancer.’s study is a well-known transient adverse effect and occurred in 20% of patients.4%. One study using a drinkable aspartate salt of magnesium (20 mmol) was prematurely interrupted after inclusion of 69 patients because of lack of efficacy (38). Trial Evidence Two double-blind. i. but the placebo-subtracted 50% responder rates was only 18.08 ppm. In the other trial. but with less short-term adverse effects. saliva. which is below that estimated for the classical antimigraine prophylactics. CONCLUSIONS There is convincing evidence that certain natural substances or drugs quasidevoid of adverse effects are efficacious alternatives to classical antimigraine prophylactic medications with a high incidence of side effects. which as in Lipton et al. They reach a magnitude of effect that is close to that observed with classical preventive antimigraine drugs. and cerebrospinal fluid (32–36). To conclude. Between attacks. the limit of detection. In this study (39). in the finished extract (25). In the published trials.370 Schoenen and Magis except burping. Moreover. Moreover. high doses of Petasites hybridus extracts (150 mg/day) seem undoubtedly effective in migraine prophylaxis. magnesium dicitrate was used at a 24 mmol dose in 81 patients.e. decrease of intracellular calcium.8% (Fig. monocytes. diarrhea occurred in Æ20% of patients and gastric irritation in Æ12%. low magnesium levels were also found in various other biological tissues such as erythrocytes. several patients complained of gastrointestinal intolerance. 3) which is well in the range of responder rates reported for propranolol and valproate. for example. It remains to be shown which combinations of high-dose magnesium and other prophylactic agents may be beneficial. but we did not find it useful as a monotherapy. Magnesium is essential for energy metabolism and decreases neuronal excitability via blockade of N-methyl-D-aspartate receptors. serum. in constipated migraineurs. butterbur is known to contain pyrrolizidines alkaloids (PA). The latter were developed by large pharmaceutical companies and . 17(2):103–108. Another reason why substances with proven efficacy such as riboflavin. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. To conclude. The former were studied in less numerous and smaller trials by small companies or independent investigators. 2. and to a lesser degree feverfew. or feverfew are not considered as first line antimigraine treatments may be that they act slowly and are thus not ideal for patients with frequent attacks. As far as pharmacoeconomic factors are concerned. concentrations of the active substance. submitted to extensive trials providing type I evidence of efficacy. Divalproex sodium in migraine prophylaxis: a dose-controlled study. et al. It is unlikely that the established pharmaceutical companies will ever invest in such trials. the existing headache societies should feel ethically obliged to do so. which is one reason why they do not reach type I evidence in evidence-based guidelines (40). However. were found effective in randomized controlled trials. REFERENCES 1. 4). it is unfortunate that certain unconventional prophylactic antimigraine drugs are not evaluated in supplementary and larger controlled clinical trials. Matias-Guiu J. Cephalalgia 1997. There are indeed important differences in quality. Cephalalgia 2002. Klapper J. butterbur. Although high doses of riboflavin and coenzyme Q10. if sufficient funds are available. most of these substances compare favorably with classic antimigraine prophylactics.Herbal Medicines and Vitamins 371 Figure 4 Cost effectiveness of prophylactic antimigraine drugs as estimated by the ratio of cost in Belgium for a six-month treatment over the placebo-subtracted 50% responder rate for attack frequency. 22(3):209–221. Diener HC. . the results cannot be extrapolated to any commercial preparation of these substances. and/or pharmacokinetics between available preparations. but there are also cost efficiency differences between them (Fig. Direct comparative studies with conventional drugs are also eagerly awaited. Hartung E. butterbur. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. Ernst E. Boehnke C. multicenter. 17. Valle N. A randomized controlled trial. Neurology 1992. Yasui K. et al. Diener HC. Efficacy of Coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Cephalalgia 2004. a nitric oxide scavenger. magnesium. MTHFR T677 homozygosis influences the presence of aura in migraineurs. Groenewegen W. 12. pilot study. 421(3):157–164. Blumenfeld A. High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study. Bastings E. Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. et al. Reuter U. Almeida KR. Oterino A. Neurology 1994. Murdoch J. 44(9):885–890. 22(7):489–490. 7. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Neurology 2005. 11(7):475–477. Cephalalgia 2002. 21. 21(4):P2–I29. 14. 40(1):30–35. Feverfew as a preventive treatment for migraine: a systematic review. 42:209–210. Schoenen J. Cephalalgia 2001. Schuh-Hofer S. Coppola G. Burchette R. Schoenen J. Pittler MH. 11. 96(6):762–764. Cochrane Database Syst Rev 2004. Back to vitamins?. randomized placebo-controlled dose-response study. Cortelli P. Afra J. 22(2):137–141. Jill V. 18. Lohman JJ. Am J Med Genet 2000. Schoenen J. 22(7):523–532. Ambrosini A. 42(6):1209–1214. Fischer M. et al. Flach U. 31P-magnetic resonance spectroscopy in migraine without aura. Cephalalgia 2002. Sandor PS. 242(7):472–477. Franca DS. Deprez C. 4. Gebeline CA. Arnold G. 19. Cortelli P. Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. An extract of feverfew inhibits interactions of human platelets with collagen substrates. 44(4):666–669. Heptinstall S. Medori R. 10. A randomized. Einhaupl KM. Thromb Res 1987. 13. Merkus FW. Pfaffenrath V. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Schoenen J. Feverfew for migraine prophylaxis. van der Kuy PH. ter Berg JW. Maizels M. 22(7):513–519. Ambrosini A. 14(5):328–329. Di Clemente L. Repin V. 15. Takeshima T. et al. 50(2):466–470.372 Schoenen and Magis 3. . Coelho MM. Eur J Neurol 2004. Pittler MH. Bravo Y. Souza AL. 5. in the prophylaxis of migraine: an open. Funct Neurol 1998. Montagna P. Barbiroli B. Urakami K. Feverfew for preventing migraine. 64:713–715. Kowa H. Jacquy J. et al. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis—a double-blind. High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care center. Can J Hosp Pharm 1989. Lenaerts M. Hydroxocobalamin. A combination of riboflavin. Sandor PS. 9. 48:511–518. Dolabella SS. 24. and feverfew for migraine prophylaxis: a randomized trial. Effectiveness of high-dose riboflavin in migraine prophylaxis. 6. double-blind placebo-controlled parallel group study of thioctic (or a-lipoic) acid.o. Nakashima K. Cephalalgia 1994. Headache 2000. in migraine prophylaxis. Lenaerts M. Montagna P. Montagna P. 16. 8. Rozen TD. Losche W. 23. Magis D. 20. Jacquy J. Oshinsky ML. Mazurov A. Henneicke-von Zepelin HH. Vogler BK. Monari L. 18(10):704–708. Hooymans PM. 13(1):7–15. Tritschler HJ. J Neurol 1995. Barbiroli B. Eur J Pharmacol 2001. Open label trial of coenzyme Q10 as a migraine preventive. Ernst E. et al. Sakai F. The pathophysiology of migraine: a review based on the literature and on personal contributions. Cephalalgia 2002. (1):CD002286. 24(6):491–494. 22. Cephalalgia 1998. Neurology 1998. Friede M. Martinelli C. 600 mg p. Cephalalgia 2002. Headache 2004. Schoenen J. 348(15):1498–1501. 30. Morucci P. Jain AC. Blood magnesium levels in migraine. Nelson JA. Diener HC. Gobel H. Welch KMA. Boska MD. 36. phospholipid and energy metabolism between migraine syndromes. Halvorson H. Cephalalgia 1996. 63:2240–2244. Headache 1992. Goadsby PJ. 232(suppl):161. Spezialextrakt aus Petasitesrhizom ist wirksam in der Migraeneprophylaxe: Eine randomisierte. 34. Firenze C. Danesch U. Results in a group of juvenile patients. Contrasts in cortical magnesium. 29. 33. Sianard-Gainko J. Possible role of ICa2þ/IMg2þ ratio. multizentrische. 58:1227–1233. doppelblinde. 15(suppl 1). Peikert A. Neurol Sci 1995. et al. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. Herbal medicine. Mitochondria. . Abbritti G. 51(2):89–97. J Neurol 1985. placebokontrollierte Parallelgruppenstudie. Cracco RQ. Grossmann M. Lipton R. Schoenen J. Deficiency in serum ionized magnesium but not total magnesium in patients with migraines. 31. 38. Wilimzig C. Sarchielli P. author reply 1498–1501. and magnesium in serum and cerebrospinal fluid (CSF) in cases of migraine. Int J Clin Pharmacol Ther 2000. Low brain magnesium in migraine. Gobel H. Neurology 2004. Serum and salivary magnesium levels in migraine and tensio-type headache. A clinical electroencephalographic and trace element study with special reference to zinc. Altura BM. 32. Mauskop A. Rahlfs VW. Levine SR. Lipton R. 40. placebo-controlled and double-blind randomized study. 11:97–99. Morucci P. Cephalalgia 1992. 35. Cephalalgia 1996. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Wessely P. Gallai V. Headache 1989. Lenaerts M. N Engl J Med 2003.Herbal Medicines and Vitamins 373 25. Costa G. Firenze C. Danesch U. Altura BT. Serum and salivary magnesium levels in migraine. 134:9–14. Sethi NC. Schultz L. Ramadan NM. Gallai V. Welch KM. Barker PB. 33:135–138. Magnesium in the prophylaxis of migraine—a double-blind placebo-controlled study. 32:132–135. Vande-Linde A. Schmidramsl H. Costa G. Balbar PK. magnesium and migraine. Mauskop A. 16(6):436–440. 12:21–27. Offenhauser N. 38(9):430–435. 43(1):76–78. Wilks K. Cephalalgia 1991. Kohne-Volland R. 28. 29:416–419. Einhaupl KM. 39. Ramadan NM. Sarchielli P. Eur Neurol 2004. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Der Schmerz 2001. Abbritti G. copper. Einhaupl KM. 27. Rittinghausen R. multi-center. Results in a group of adult patients. 37. Helpern JA. Headache 2003. Pfaffenrath V. Welch KMA. Headache 1993. Meyer C. 16:257–263. Safety of a patented special butterbur root extract for migraine prevention. Prophylaxis of migraine with oral magnesium: results from a prospective. Neurology 2002. 26. . as well as provide a comprehensive treatment approach. which is a helpful base in the review of treatment options (8). preventive treatment strategies should be designed with a goal of substantially reducing headache frequency (at least 50%). the physician initially needs to identify potential triggers and outline an acute treatment strategy with a goal of eliminating headache in one to two hours. The majority of childhood headache patients who are brought to a physician for evaluation will prove to have a diagnosis of migraine (2. it is often possible to taper a preventive regimen within six months of its initiation (1). INTRODUCTION Advances in the management of headache for adults have translated into improved treatment for children and adolescents. the physician needs to consider either repeating the initial medication or starting a possible rescue medication with the goal of eliminating all pain symptoms by four hours. Studies conducted in children and adolescents are helping us to outline the appropriate management strategies for this population (1). Pharmacologic practice parameters related to the treatment of migraine in children and adolescents have been recently published. Because there is a relatively high remission rate of migraine in children. with a possible reduction of the headache severity. Moreover. with reevaluation. In this chapter.S.A. and Nova Southeastern University. headache may last only for one to two hours. 375 . To effectively treat headache (migraine). they should be used on an average for six-month periods. In this case.3). Florida. U. we review treatment issues related to the management of the pediatric headache patient. In this age group. If the initial medication is not fully effective. Fort Lauderdale. including both pharmacologic and nonpharmacologic methods.24 Treatment of Migraine in Children and Adolescents Paul Winner Palm Beach Headache Center. especially children under the age of 12. Practitioners should review the causative mechanisms of headache with the patient and the parents. When appropriate. a more moderate approach toward treatment and pain relief can be used (1–7). with special attention to pediatric migraine. Opioids such as meperidine hydrochloride and codeine can be used in children over the age of six with caution and physician supervision (13). it was noted that 47% of these children received medication for every headache (9). In a child reporting headache at school entry. Differences between ibuprofen compared to acetaminophen were not statistically significant at two hours. The first study compared ibuprofen (10 mg/kg) to acetaminophen (15 mg/ kg) and placebo. and naproxen (8%).376 Winner Box 1 Analgesic use limit suggested at the Palm Beach Headache Center    No more than 10 tablets of an analgesic per month for a young child No more than 20 tablets for an adolescent No more than 2 headaches treated with these parameters per week ACUTE TREATMENT Nonspecific Analgesics In children and adolescents with mild to moderate migraine. The 5-HT1 agonists are being studied in adolescents. Butalbitalcontaining compounds and mild analgesics can be used safely and effectively in young children and adolescents.5 mg/kg) was found to reduce headache severity in children aged 6 to 12. placebocontrolled trials to be safe and effective in the treatment of childhood migraine (10. These medications can be used effectively as a rescue treatment. these parameters can be followed rather easily.13). The Food and Drug Administration (FDA) approves the use of ibuprofen and naproxen in children over the age of two. mild analgesics. No statistically significant adverse effects of ibuprofen or acetaminophen were reported in these studies (11. In the second study. At our center. With the assistance of a parent and a diary. salicylic acid (27%). Both ibuprofen and acetaminophen were significantly more effective than placebo in providing pain relief at two hours (12). ibuprofen (7. It is important to discuss the issue of medication overuse headache in young children and adolescents in an effort to avoid its occurrence. and nonsteroidal anti-inflammatory drugs (NSAIDs) are often quite effective. Although Reye’s syndrome is rare. Ibuprofen (7. salicylates should be avoided in children who are febrile and/or in whom there is concern for an underlying metabolic disorder (1.5–10 mg/kg) has been shown in two double-blind. combination analgesics. acetaminophen (30%). We suggest they be limited to a maximum of two doses per week as a guide.11). we suggest the parameters explained in Box 1. but some limits need to be provided. Triptans The introduction of the 5-hydroxytryptamine (5-HT1) agonists has revolutionized the treatment of adults with moderate to severe migraine attacks. Acetaminophen was considered effective and well tolerated (12). The dose will vary depending on the age and weight. The medications that were taken were ibuprofen (36%). it has been noted that 24% of children had seen a doctor for their headache complaints.12). so that they too may benefit from this form of therapy when appropriate. but was significant at the two-hour primary end point only in boys. . for example. photophobia. and 100-mg tablets in 302 adolescents in 35 sites (15). The headache recurrence rates varied from 18% to 28% across all three doses and were lower than those seen in adults possibly because children tend to have a shorter duration of headache. the dose needs to be increased to 100 mg as the initial dose and repeated in two hours. placebo-controlled trial in which adolescents aged 12 to 17 were treated for a single attack with three NS doses: 5.or 20-mg dose of sumatriptan NS reported significant postdose headache relief compared with 41% in the placebo group (16). pressure. The side effects of the placebo and 25 mg of sumatriptan were almost identical. Cardiovascular palpitations. ‘‘Oral sumatriptan’’ has been studied in a double-blind. tachyarrhythmias. double-blind. but often with triptans it is not necessary.06 mg/kg and showed an overall efficacy of 72% at 30 minutes and 78% at two hours. 50-. Although the associated symptoms of migraine such as nausea. documented the effectiveness of ‘‘subcutaneous sumatriptan’’ 0. burning. there was a slight increase in side effects reported. and hypotension were reported to be 0% to 1% for the 25. and 20 mg (16).and 240-minute mark showing 74% pain relief at the four-hour mark. and statistical significance was not met due to a high placebo rate. ‘‘Sumatriptan nasal spray’’ was studied in a randomized. the 50-mg dose side effects of a feeling of warmth. stinging. the same triptan medication needs to be repeated so that the patient is pain-free by four hours. and 100-mg oral tablets of sumatriptan were effective in treating acute migraine. in an open-label study (8). 10. and 100 mg at the 180. Young adolescents should begin with 50-mg sumatriptan tablets for the treatment of migraine. tightness. which in this adolescent study may be due in part to study design. the dose should be repeated. Rescue medication can be used at anytime for the relief of associated symptoms. No such side effects were reported in the placebo group. For example.Treatment of Migraine in Children and Adolescents 377 Linder. the fact that children have a shorter duration of headache. 56% of patients using the 10. strangeness. The side effects of chest discomfort. 50-. If adult placebo rates are substituted at the two-hour mark. tightness. placebo-controlled trial of 25-. If they do not have complete relief within two hours. Children who prefer to avoid the parenteral route of administration now have the option of using the oral and nasal spray (NS) forms of 5-HT1 agonists (7). When reviewing the pain-free . All three doses were superior to the placebo with respect to the cumulative percentage of patients who obtained headache relief within two hours of administration. and then a further increase was reported at 100 mg. if needed. much like in adults. or phonophobia often respond to triptan. and pressure ranged from 1% to 4%. 50. No significant adverse events were documented in this study of 302 patients (9). This was compared with the side effects range of 0% to 1% at the 25-mg tablet dose. Sumatriptan was statistically significant over the placebo at 25. As the dose was increased to 50 mg. with a recurrence rate of 6%. At one hour. Because children tend to have a shorter duration of headache. is to obtain a pain-free status for the child or adolescent at two hours. The study demonstrated that 25-. Should 50 mg not be effective. The goal. if this has not occurred. numbness. statistical significance could be obtained. with similar efficacy profiles across all three dosages.and 50-mg tablets and slightly higher for the 100-mg tablets. they may not be completely relieved. and heaviness ranged from 0% to 1% for the 25-mg tablets as compared with side effects from 0% to 3% for the placebo and side effects from 3% to 4% for the 50-mg tablets. New study designs are being implemented to address the special issues of the pediatric population. The primary end point of the study was at two hours. a recurrence rate of 6% would seem appropriate for this study population (14). and two hours (67% vs. p ¼ 0.05) (16). as compared with the placebo group at 6. respectively. respectively. placebocontrolled. which ranged from 16% to 20%. 57%. The most frequent treatmentrelated adverse events for placebo. p ¼ 0. For the pain-free end point. respectively.007).and 20-mg sumatriptan NS patient groups at 8 and 8. 30%.7 hours (Table 1) (16). 48%. 10 mg Orally disintegrating tablet 5.037).06 mg/kg up to 6 mg NS 5. the pooled results show a greater efficacy with sumatriptan NS 20 mg compared to placebo at one hour (20% vs. parallel-group studies in adolescents.046). 14%.087). possibly due to the shorter duration of headaches in the adolescent population. A recent sumatriptan NS study compared the efficacy and tolerability of 5 and 20 mg versus placebo in the acute treatment of migraine in adolescent subjects (10). the overall incidence of adverse events for the nasal treatment group is similar to the placebo group. 100 mg Subcutaneous 0. The total pooled population was 1105 (placebo N ¼ 374. p ¼ 0.003). Headache recurrence was lower in the 10. The recurrence rates tend to be lower in adolescent groups than in adult groups. sumatriptan NS 20 mg) (10). and 25%. A recent study assessed the pooled efficacy and tolerability results of 5 mg and 20 mg sumatriptran NS versus placebo from two large U. If this is removed from the calculations. one hour (59% vs.S. No AEs were serious or led to study withdrawal. Sustained relief from 1 to 24 hours was greater for sumatriptan NS 5 mg (37%. the 20-mg sumatriptan NS provided a statistically significant greater response of 36% at two hours postdose compared with the placebo at 25% (p < 0. 33%. In general. 19%. 1 hour (61% vs.016). p ¼ 0. p ¼ 0. 5 mg N ¼ 377. Table 1 Selected Triptans for the Acute Treatment of Migraine in Adolescents Triptan dose and formulation Sumatriptan (Imitrex) Tablet 25.001). sumatriptan NS 5 mg. 58%. p ¼ 0. . double-blind. 28%. The results for sumatriptan NS 20 mg demonstrate significantly greater headache relief compared to placebo at 30 minutes (39% vs. Source: From Refs. 10 mg Tablet 2. for sumatriptan NS 5 mg. No serious adverse event was reported in the sumatriptan treatment population in this study. and 2 hours (68% vs.025) postdose. 57. nasal spray.005). 20 mg Tablet 5.2 hours. 50. the study showed significantly greater headache relief compared to placebo at two hours (64% vs. 5 mg NS 5 mg Rizatriptan (Maxalt) Zolmitriptan (Zomig) Note: The most common adverse event reported by this patient group was taste disturbance. p ¼ 0. sumatriptan NS 5 mg was more effective than placebo but the differences did not reach statistical significance.5. 17–19. Sumatriptan NS 20 mg provided greater headache relief than placebo at 30 minutes (42% vs. 52%.041) and for sumatriptan NS 20 mg (41%. It should be noted that each dose of sumatriptan was superior to the placebo with respect to the cumulative percentage of patients reporting pain-free response two hours postdose.034) and two hours (42% vs. 5 mg and 20 mg sumatriptan NS.378 Winner data. p ¼ 0. and 20 mg N ¼ 354). The most common event was taste disturbance (2%. placebo. There was no difference in headache recurrence among the treatment groups. and the placebo group at 20%. randomized. p ¼ 0. p ¼ 0. Both doses of sumatriptan NS were well tolerated. p ¼ 0. Abbreviation: NS. 2. Overall. and the results are similar to those reported in the adult sumatriptan NS clinical trials (10.5 mg and subsequent attacks with 2. The majority of patients used one dose of study medication. Sumatriptan NS is effective and generally well tolerated in the treatment of acute migraine in adolescents (20). respectively). The taste disturbance also may be lessened by reinstructing adolescents of the correct administration of the NS medication (16). significantly more adolescent patients (44%) on rizatriptan 5 mg had no functional disability at two hours as compared with the placebo group (36%). There were no serious adverse events in the adolescent patient rizatriptan population. 2%. Infrequent treatment-related adverse events (1%) were pressure/tightness and chest symptoms reported in each of the treatment groups (20). and 26%). their variable receptor affinity and intrinsic activity. ‘‘Rizatriptan (Maxalt) 5-mg tablets’’ have been evaluated in patients aged 12 to 17 in a double-blind.Treatment of Migraine in Children and Adolescents 379 were: taste disturbance (2%.5 and 5 mg. The most common adverse events reported were fatigue. and their variable organ-specific–receptor . The overall headache response at two hours was 80% (88% and 70% with zolmitriptan. The headache-free status at two hours was 32% for the rizatriptan 5-mg group and 28% for the placebo. ‘‘Zolmitriptan (Zomig) ’’ has been studied in a subgroup of adolescents (12–17 years).21). 19%. parallel-group. Treatment was well tolerated (23). single-attack study. It also proved to be well tolerated. Future pediatric studies should prove helpful. double–blind. Despite the reported taste disturbance by some patients. The first two migraine subgroups were treated with 2. Adult patients use Rizatriptan 10 mg tablet or MLT. sumatriptan NS 20-mg provided the most rapid treatment across this adolescent population group. dizziness. With regard to functional disability. and nausea. At the Palm Beach Headache Center. 4%. somnolence. vomiting (1%. this is similar to that seen in the adult population receiving a 5-mg dose. and burning/stinging sensation (1%. Significantly more sumatriptan NS 20 mg subjects were pain-free beginning at one-hour postdose. We have found Rizatriptan 10 mg to be well tolerated in the adolescent patient. placebo-controlled. but is not statistically significant because the response of the placebo group was 57%. The results also demonstrate significant sustained headache relief from 1 to 24 hours for sumatriptan NS 5 and 20 mg. The disturbance in taste may be reduced in some patients by the use of flavored lozenges or hard candy after administration of the NS. A total of 149 adolescents were treated with rizatriptan 5 mg. nausea (3%. and 4%).17–20). Presently there is limited data available regarding the use of other triptans in the pediatric population. and 7%). we will often use Rizatriptan 10 mg in adolescents when Rizatriptan 5 mg is not fully effective. and 147 were treated with a placebo. These studies provide evidence of significant headache relief compared to placebo by 30 minutes for sumatriptan NS 20 mg and two hours for sumatriptan NS 5 and 20 mg. and 3%). 1%. Their diversity results from their interaction with multiple receptors. Rizatriptan 5 mg is well tolerated in this adolescent population study (22). dry mouth. but presently there are no randomized. The percentage of adolescents receiving pain relief at two hours for the rizatriptan 5-mg group was 66%. placebo–controlled studies in the pediatric population.5 or 5 mg at each patient’s discretion. this did not discourage some adolescents from the continued use of the NS medication (1. Ergot Alkaloids The ergot alkaloids are a family of chemicals that have many pharmacologic effects. In adults. It may be helpful to give adolescents or children a test dose of DHE on a day when they do not have a migraine to determine if the treatment causes any significant nausea. 12 to 16 years. side effects can be avoided by lowering the dose or by diluting the DHE with 30 to 60 cc of saline and administering it over a period of 30 minutes to 1 hour intravenously (27). 0. metoclopramide should be given to prevent nausea or vomiting (27). nausea. DHE is a medication that often requires dosage titration (27).H. nasal. 0. Females must be evaluated appropriately for concerns of pregnancy when necessary. actually may indicate that the dose is slightly high. 0. Dihydroergotamine (DHE) (tradename D. Articles have been published outlining the use of DHE in adolescents and children in both inpatient and outpatient settings (27. for example. 45) is a synthetic ergot with a modified pharmacologic profile. which often needs dose adjustment depending on the patient’s age. . one of the more common side effects. In general. or oral forms of DHE in children or adolescents have been done. Both ET and DHE have 5-HT1A–. as well as a lower headache recurrence and lack of rebound headache. In children and adolescents.1 mg/dose. Linder has studied the use of DHE in children and adolescents. in 1945 (24). 5-HT1B–. DHE. and if there is incomplete relief of the headache symptoms within one hour.27). Rapid administration of intravenous DHE in children can be associated with adverse effects and a more constant rate of infusion is recommended with a coadministered antiemetic. no studies involving intramuscular. can be used in an intravenous form concomitantly with an antiemetic (27):    6 to 9 years. the dosing of DHE is extremely important for both efficacy and the prevention of adverse events.380 Winner access. the oral form of DHE is poorly absorbed and ineffective for acute migraine. Prior to initiating an outpatient or an inpatient protocol. promethazine hydrochloride or metoclopramide hydrochloride. a detailed history and physical and neurologic examinations are necessary to clinically define the situation. The intramuscular and subcutaneous forms can be used without a concomitant antiemetic. DHE offers numerous benefits compared with ET because of a lower reported incidence of nausea and vomiting. For example. Ergotamine tartrate (ET) was one of the first ergot alkaloids to be isolated.E. and 5-HT1F–receptor agonist affinity. In addition. Limited work using intravenous forms has been performed (26. 5-HT1D–.5 mg/dose. Intranasal delivery vehicles also have been shown to be effective in adults. 9 to 12 years.28). Although reports of serious adverse events on recommended doses of DHE are rare. side effects can be seen with either the antiemetic metoclopramide or DHE.2 mg/dose. a second dose may be given. DHE was first reported to be effective in migraine by Horton et al. Intramuscular or subcutaneous administration can be effective for moderate to severe migraine (26). Intravenous administration in adults provides an effective form of rapid headache relief for migraine and often is used for refractory severe migraine headache patients. 20 to 30 minutes prior to the administration of DHE. However. The initial dose of DHE is recommended to be given in the emergency department or office at the onset of a migraine headache. the medication fell into disuse until Raskin reintroduced it in 1986 (25). DHE exhibits a greater adrenergic antagonist activity and has less potent arterial vasoconstriction and emetic potential than ET. Unfortunately.3 to 0. or 50-mg suppository form.or 50-mg tablet form can be used. or other significant underlying cardiovascular disease Uncontrolled hypertension Hemiplegic or basilar migraine Use of another 5-HT agonist or ergot-type medication (dihydroergotamine) within 24 hr of treatment Administration of monoamine oxidase inhibitors within previous 2 wk (1) Abbreviation: 5-HT.Treatment of Migraine in Children and Adolescents Table 2 Contraindications for the Use of Triptans. Caution is advised for patients with a history of congenital heart disease or other medical problems (Table 2). Promethazine hydrochloride. is readily reversible with diphenhydramine. both the suppository and the oral forms. The use of DHE. as well as triptans. Both inpatient and outpatient DHE protocols may be used to break intractable migraine headaches. Antiemetics Antiemetics. These extrapyramidal side effects are readily reversed using ‘‘diphenhydramine’’ at a dose of 1 mg/kg up to 50 mg. Because triptan medications have been approved for the treatment of adult migraine. and may develop extrapyramidal side effects. Ergot Alkaloids 381 Symptoms or findings consistent with ischemic heart disease. in children who have nausea symptoms without vomiting either the 25. and if this is the case. and. promethazine hydrochloride may be substituted. DHE is used less frequently. PREVENTIVE THERAPY Children or adolescents who do not respond adequately to the acute treatment of migraine and/or who are missing excessive periods of school days or have significant disability in their life due to frequent and incapacitating migraines. can prove to be quite efficacious in the younger child who has significant vomiting associated with migraine. Prochlorperazine maleate and metoclopramide can also be quite effective. although they should be used with caution because of potential extrapyramidal side effects. DHE has been used in pediatric patients since the early 1990s as an effective treatment of moderate to severe migraine headaches. The pediatric patient population tends to be sensitive to some antiemetics. can be used in children and adolescents with acute migraine accompanied by nausea or vomiting. should consider . coronary artery vasospasm. The extrapyramidal side effects can also be seen using the oral form of metoclopramide. again. but it still is a reliable alternative should triptans prove to be ineffective or their side effects prove intolerable. If the patient has difficulty with metoclopramide. and thyrotoxicosis. This is especially true when the medication is given in an intravenous form. Antiemetics can be used effectively in conjunction with other acute therapies for treating moderate to severe migraine in children and adolescents (1). including metoclopramide. it is normally seen between the fifth and eighth dose. 5-hydroxytryptamine. either the 25. is contraindicated in patients with certain high-risk factors such as uncontrolled hypertension. DHE also has proven to be useful for migraine headaches that last for more than two to four days (status migrainosus) (29). carotid or peripheral artery disease. Stress may play a significant role in precipitating migraine events. Biofeedback has been demonstrated to be effective in children as young as nine years (Table 3) (31). a regular balanced diet is beneficial. and most importantly. and exercise. Nonpharmacologic Measures in Children and Adolescents Nonpharmacologic preventive measures that may reduce headache frequency include sleep hygiene. Lack of sleep can be a significant trigger for many children. It is quite helpful if the patient arises every morning at the same time. the degree of disability caused by the headache (1). Frequently. then a decision to initiate Table 3 Nonpharmacologic Treatment of Migraine Education Biofeedback Stress management and relaxation exercises Elimination of triggers Sleep regulation (1) . Several issues must be addressed prior to considering the use of a pharmacologic agent. such as going to bed late or sleeping late. as well as dosing guidelines based on the limited data available and the clinical experience. Pertinent literature on the preventive treatment of migraine in children and adolescents.382 Winner preventive therapy. except flunarizine. The preventive therapy of migraine includes not only the pharmacologic treatment but also nonpharmacologic approaches such as the identification of migraine triggers. establishing a lifestyle that includes adequate exercise. and physical activity certainly cannot be harmful to the child’s overall well-being. in the preventive treatment of migraine headaches in children or adolescents (8). There are limited well-controlled clinical trials with sufficient patient numbers to support the use of any particular agent. This results in a relatively severe headache later in the day. An alteration of sleep behavior. diet. the identification of possible triggers. identification of such triggers in a particular patient can be quite beneficial (30). both sleep hygiene and diet can be significant triggers that can be somewhat difficult to control (1). Riback identified stress as a provoking factor in 23% of 226 children (30). and often doses need to be tailored to the individual child adolescent. and yet the child continues to have disabling headaches at a significant frequency. which may involve adjusting lifestyle. adolescents concerned about weight gain may choose not to eat breakfast or lunch. In the adolescent. In addition to sleep hygiene. Although food triggers for migraine headache are relatively infrequent. Regular physical exercise appears to reduce headache frequency. the effectiveness of current episodic medications. Although the value of this has never been demonstrated in children. Age can play a role in the selection of appropriate therapy. probably occurring in less than 20% of the patients. When all of the above issues have been addressed. Stress management using relaxation techniques and/or biofeedback can be helpful in children who are motivated to use them. will be reviewed (1). These include an accurate assessment of headache frequency and severity. sleep. may precipitate headaches. up to 10 mg bid 0. The divalproex sodium migraine prevention study group has shown that 500 to 1500 mg/day of divalproex sodium is effective in reducing headache frequency in adults (33). Headache disability.5 mg/kg. up to 10 mg hs 10 mg/kg. twice daily. there are several medications from which to choose. which can be assessed by a variety of headache disability scales but. treated 31 children in the age range of 7 to 16 with divalproex sodium as a preventive agent (35). divalproex sodium.25–0. The appropriate dose for any of these agents has not yet been determined. Extended-release divalproex sodium (Depakote ER) has been demonstrated to be effective and well tolerated at doses of 500 and 1000 mg once daily in adults (34).25–0. carbamazepine. Caruso et al. (DepakoteER) 2000 Timolol (Blocadren) 1990 Propranolol (Inderal) 1979 Methysergide (Sansert) 1962 Abbreviation: FDA. and topiramate. including phenobarbital. even the child who experiences only one severe headache a month that results in a significant disability may also be considered for preventive medication (1). Certainly. hs. up to 125 mg daily 15 or 25 mg preventive medication needs to be considered. should be used to determine who should be placed on preventive medication. Anticonvulsants Several anticonvulsants have been used for migraine prevention in the pediatric population. up to 10 mg hs 0. The information provided herein is a summary of the literature. more importantly.5 mg/kg. a child experiencing three to four significant migraine headaches a month resulting in disability for several hours each time should be considered for preventive medication. Food and Drug Administration. Intravenous infusion of valproate sodium (Depacon) has been reported to abort acute migraine headache (32). phenytoin. However. Pharmacologic Preventive Treatment Once the decision to add a pharmacologic agent is made. with dosage recommendations based on the few clinical reports as well as clinical experience (Tables 4 and 5). Dosages Table 5 Drugs with FDA Approval for Migraine Prevention Drug year of approval Divalproex sodium (Depakote) 1996. . by the impact on the individual patient’s life. 383 Initial dosage 2 mg bid or 4 mg hs 1 mg/kg. at bedtime.Treatment of Migraine in Children and Adolescents Table 4 Preventive Therapy Agent Cyproheptadine (Periactin) Propranolol (Inderal) Amitriptyline (Elavil) Nortriptyline (Pamelor) Divalproex sodium (Depakote) (sprinkle) Topiramate (Topamax) Abbreviations: bid. The mean severity using a visual analog scale was reduced from 6. 2 to 4 mg daily.3 topiramate vs.1 placebo). whichever was less.5% for topiramate and 4.1% placebo). The sprinkle formula. 76% of the patients had a greater than 50% reduction in headache frequency.0% topiramate vs. or their maximum-tolerated dose. More recent anticonvulsant data regarding the prevention of migraine in children and adolescence is from a randomized.3 topiramate vs. and increased appetite. can be added to the treatment for adolescent girls. The most common adverse events in the topiramate group were upper respiratory tract infection (19. and temporary hair loss. 6. After four months of treatment. but no serious side effects were reported (38). Due to the potential teratogenic effects.37). 52% male.2 placebo). Limited data is available for the efficacy and safety of topiramate in the pediatric population. Another open labeled study using divalproex sodium included children 9 to 17 years who were treated with doses between 500 and 1000 mg reported reduction in both headache frequency and severity. These studies suggest that divalproex sodium may be effective as a migrainepreventive agent in children and adolescents. The dose can then be increased in the second week of treatment to 15–20 mg/kg/day divided either twice or three times a day.3% topiramate vs. 125-mg divalproex capsules. Divalproex sodium (Depakote) and (Depakote ER) have been approved by the FDA as a treatment for the prevention of adult migraine (Table 5). weight decrease (9. There are no data on serum drug levels to suggest a therapeutic range for migraine prevention.1% for placebo.5 days. Mean headache attacks were reduced from 6 per month to 0. and the mean duration from 5. p ¼ 0. especially when higher doses are given.0 mg/kg/day. paresthesia (8. Topiramate has been demonstrated to be effective for migraine prevention in adults. Divalproex sodium can also reduce platelet counts in a dose-dependent manner.1 placebo). 6. monitoring of platelet counts should be considered. increased appetite. therefore. placebo-controlled trial evaluating topiramate (Topamax) (39). Topiramate reduced mean monthly migraine days by 2. Topiramate was initiated at 15 mg/day and titrated over eight weeks to a dose approximating 2. Other reported potential side effects of divalproex sodium include sedation. double-blind.5 to 1. this titration phase was followed by a 12-week maintenance phase (39). However. the percentage of topiramate-treated patients exhibiting a ‘‘greater than 50%’’ reduction in mean of monthly migraine days (55%) was not satisfactory different from that of placebo-treated patients (47%).9 days for placebo from a baseline of 5. Hyperammonemia can also occur from divalproex sodium without elevated transaminases. which approached statistical significance (p ¼ 0. folic acid. age range 6–15 years.0 to 3. 0. drowsiness.6 from a baseline of 5.020). and 6% were essentially headache-free (36.8 to 0. and somnolence (8.7 (38). . Clinical experience with divalproex sodium for seizures suggests that 10 mg/kg/day divided twice daily is a safe starting dose (Table 4). The maximum dose allowed was 200 mg/day. 18% had a greater than 75% reduction. A significantly greater percentage of patients receiving topiramate (32%) showed greater reduction in mean monthly migraine days than patients receiving placebo (14%.384 Winner ranged from 15 to 45 mg/kg/day. Adverse events included dizziness. 48% female) was randomized 2:1 to topiramate (n ¼ 112) or placebo (n ¼ 50). Discontinuation rates due to adverse events were 6. 6. anorexia (13.4 days compared to a reduction of 1.7 per month.065).4% topiramate vs.0% placebo).1 hours (38). is well tolerated and may help to decrease any potential gastrointestinal side effects. Topiramate has been studied in children with migraine with or without aura (n ¼ 162. 8. therefore serum ammonia levels should be obtained from patients who report being excessively tired. 10 mg is a reasonable starting dose. For an adolescent.Treatment of Migraine in Children and Adolescents 385 This preliminary study notes the potential utility if topiramate for the prevention of pediatric migraines. The side effects of nortriptyline are identical to those of amitriptyline (1). the medication should be titrated upward to either efficacy or intolerable side effects. In our center.to three-week period. suggested a standardized dosage of 1 mg/kg/day (40). Further studies are warranted to establish the efficacy of topiramate for the treatment of pediatric migraine (39). A dosage ranging from 10 to 75 mg/day is usually effective in reducing headache frequency. the SSRIs are used when there is clinical suspicion of depression. the antiepileptic doses are usually prescribed. This is the first report of standardized dosing of amitriptyline based on body weight. were more precise in reporting a reduction in headache frequency in their open-label study. there are limited studies to support their use. followed by increased appetite and weight gain. Although the other anticonvulsants have been used by clinicians. Fluoxetine has been shown to be effective in treating mild headaches in the adult population in a limited study (42). Worsening of headache may occur in some patients. The dosage is usually administered in the morning to avoid difficulties with insomnia. Levinstein used a dosage of 15 mg/day (41). a 10-mg single daily dosage is usually maintained. In that study. the efficacy of amitriptyline has not been studied in a placebo-controlled trial. there is appetite suppression with concomitant weight loss.5 mg/kg up to 10 mg/day administered at bedtime (Table 4). but had included a mixture of headache types including headaches occurring at a frequency of greater than three per week (41). There are no data to support their use in migraine prevention in children (1). Nortriptyline also has been widely used as an alternative to amitriptyline with the belief that there are fewer side effects.to 10-year-old child is 0. A dosage exceeding 75 mg/day is rarely needed to control headache (1).41).25 to 0. Antidepressants The tricyclic antidepressant amitriptyline has been reported to reduce headache frequency in children (40. Hershey et al. Children may experience drowsiness with the medication in the early phases of treatment. Hershey et al.to four-week trial. with the target dose being 100 mg daily divided bid. The appropriate dosage of amitriptyline has not yet been determined. Because of the potential cardiac side effects. Clinical experience suggests that a reasonable starting dosage of amitriptyline for a 5. It is not noted how many children were treated with amitriptyline. Levinstein compared amitriptyline with propranolol and cyproheptadine in an open-label study (41). However. electrocardiography should be performed if dosage escalation is required. 30 children were randomized to receive one of the three treatments. The serotonin syndrome may occur in patients on SSRIs who are treated with 5-HT1 agonists for an acute headache. At the end of a two. He reports a moderate 50% to 60% improvement to an excellent 80% improvement at three months of treatment with amitriptyline. This usually resolves over a two. . Serotonin selective reuptake inhibitors (SSRIs) have been studied in adults but not in children. The usual starting dosage is 10 mg/day administered at bedtime (Table 4). Initially. Topiramate was well tolerated in this pediatric population. When used in migraine prevention. In the first two to four weeks. One of the most significant side effects. nausea. was one of the earliest medications reported useful in migraine prevention in children (43). Forsythe et al. The dosage can be titrated slowly. its antimigraine effects may be the result of calcium channel blockade (44). The recommended starting dosage of propranolol for the treatment of hypertension in children is 1 mg/kg/day up to 10 mg twice daily. and memory disturbance. Adolescents may experience significant drops in blood pressure. an antihistamine with antiserotoninergic properties. Although it has antiserotoninergic properties. is the onset of depression. dizziness. The antihistaminic effects of cyproheptadine may cause weight gain. the signs may be subtle. If a child experiences nightmares or vivid dreams while taking propranolol. several side effects can occur including fatigue. treated 19 children with cyproheptadine for three to six months in an uncontrolled trial (43). The evidence that propranolol is effective in migraine prophylaxis is very weak. increasing over two to four weeks to a maximum of 3 to 4 mg/kg/ day divided twice daily. changing the dosing . insomnia. Ludvigsson studied 28 children with dosages ranging from 60 mg/day. Beta-Blockers The beta-blockers may exert their effect through antagonism of the 5-HT2 receptors or through modulation of adrenoreceptors. yet propranolol remains a mainstay in the preventive treatment of migraine headaches in children. Patients should be monitored for signs of mild depression within the first four to eight weeks of therapy initiation. Olness et al. if tolerated (Table 4) (13). which can easily be missed in an adolescent. drowsiness.4 mg/kg/day. Cyproheptadine can be used as a single daily dosage administered at bedtime. in a study comparing self-hypnosis to propranolol for the treatment of classic migraine headache. suggested that propranolol had no impact on frequency of migraine headache and may have increased the duration of headache in some children (47). and 4 of 17 had resolution of their headaches. used a dosage of 3 mg/kg/day (46). Dosing of propranolol (Inderal) has not been systemically studied. Dosages used ranged from 0. They found that self-hypnosis was more efficacious than propranolol in reducing headache frequency.386 Winner Antihistamines Cyproheptadine. Neither self-hypnosis nor propranolol affected subjective or objective measures of headache severity.2 to 0. this dosage of cyproheptadine has been quoted in several medical texts and review articles as appropriate for migraine prevention. and irritability (13). starting at 2 to 4 mg/day (Table 4). Although this was an uncontrolled study in a small number of children. vivid dreams. dry mouth. Seventeen of the 19 children had improvement in their headache frequency. the dose may need to be decreased or discontinued. The beta-blockers can also reduce stamina and should be used with caution in athletes. for children weighing less than 35 kg to 120 mg/day. Although the majority of children have no significant side effects from propranolol. He concluded that a dose of 1 mg/kg/day is effective. The vast majority of patients respond to a dosage between 4 and 12 mg/day. If depression symptoms are observed. Bille et al. depression. Propranolol is contraindicated in children with a prior history of reactive airway disease or diabetes and in some children with cardiac arrhythmia. The final dosage per kilogram used in that study was not reported. for children weighing greater than 35 kg (45). nightmares. this was a very small study involving only 17 children.57). Only nimodipine. it is unknown if treatment beyond that point would have demonstrated a continued clinical efficacy. However. a calcium channel blocker. In spite of the potential for side effects. Although other beta-blockers have been used clinically for several years. In the flunarizine-treated group. The efficacy of flunarizine should not be generalized to suggest that all calcium channel blockers would be effective. However. The authors conclude that nimodipine is efficacious as a migraine preventive agent. depression. After crossover. Nadolol has been reported to be as equally efficacious as propranolol in adult studies (49). has been reported to reduce the frequency of migraine headache in children (57). there was an identical reduction in headache frequency in both the placebo and the active drug group. the data do not appear to support their conclusions (8. Calcium Channel Blockers Calcium channel blockers have been used quite extensively in the adult population (51). there are no studies to demonstrate their usefulness in children. However. in the first phase of this double-blind. patients were crossed over from active drug to placebo following a four-month active treatment phase (52). However. Calcium channel blocker side effects include constipation. placebo-controlled crossover trial.3 per month. The side effects of the calcium channel blockers may prove limiting in some patients (1). nausea. weight gain.52–56). a class-2 (nifedipine-like) calcium entry blocker for slow calcium channels. AV block. is available in Europe but not in the United States. and occasionally. It has been shown to be effective as a preventive medication in children (8. the data must be interpreted with respect to the assessment of Ramadan et al. concerning the scientific merit of many of these studies (50). the actual change in the number of headache attacks was small but statistically significant. Thus. Noronha reported that the beta-blocker timolol is not effective as a preventive medication in children (48).Treatment of Migraine in Children and Adolescents 387 schedule so that the child receives the medication several hours before retiring usually eliminates that side effect (13). Clinical experience suggests that calcium channel blockers are not more efficacious than other classes of agents. the initial placebo group responded to nimodipine with a reduction in headache frequency greater than the second placebo group. Patients should be evaluated at approximately 4 and 12 weeks into the treatment phase to determine if the medication has been effective and well tolerated. Nonsteroidal Anti-inflammatory Drugs The NSAIDs such as naproxen sodium are known to be efficacious in the treatment of acute migraine headache and have been reported to be effective as a migraine . most children tolerate propranolol well. A minimum of 12 weeks of treatment at appropriate doses is needed to determine if the medication has been efficacious. Propranolol (Inderal) and timolol maleate (Blocadren) have been approved by the FDA for the treatment of migraine prevention (Table 5). All studies of flunarizine report similar outcomes (53–56). thus. The baseline mean number of headache attacks per month was 3 for both groups. No data are presented beyond four months. It is important to remember that beta-blockers may take several weeks for full effect. hypotension. the mean number of attacks per month decreased progressively to as low as 1. In the double-blind. Flunarizine.. placebo-controlled crossover study performed by Sorge et al. Other Agents Reports on the use of trazodone and pizotifen in a small number of children suggest that these agents may be effective in preventing migraine (59. However. CONCLUSIONS Treatment options are improving for both children and adolescents with regard to the acute and preventive management of migraine and headache in general. Clonidine has been studied in a single double-blind. The combined use of nonpharmacologic and pharmacologic modalities can prove to be quite efficacious in the complete relief of migraine headaches in this patient . There was no significant difference in headache frequency between treatment and placebo groups. is somewhat limited (1). If significant headache control has been achieved. Ergotamine compounds such as methylergonovine maleate (Methergine) and methysergide have not been studied in the adolescent or pediatric population. in a double-blind. Treatment Period—When to Discontinue Preventive Treatment A difficult and unanswered question is how long should a patient be treated with preventive medication? Treatment periods with preventive medication typically range from as short as 3 months to as long as 18 months. Ten of the 19 patients completed the study. Lewis et al. no confirmatory data are available. it may be discontinued either through a prolonged break or through the following year and withdrawn the following summer depending on the clinical situation (1).60). Treatment periods of 6 to 12 months generally result in a significant reduction in frequency and a persistent effect after withdrawal of preventive medication. A starting dosage of 10 mg/kg twice daily reduces migraine headache frequency and lessens the severity of breakthrough headaches. their use. As these compounds have a long-term potential to cause retroperitoneal fibrosis. Clonidine was most helpful in a subset of patients with visual aura and a positive family history of migraine. However. Our clinical experience indicates that naproxen sodium is an effective preventive medication. six reported a significant reduction in the frequency and severity of their headaches. treated 19 children with naproxen sodium. and 1 a greater than 90% reduction. this may be a reasonable short-term alternative for up to four to eight weeks (1). Children started on preventive medications in the beginning of the school year should continue the medications throughout the school year.388 Winner preventive medication. placebo-controlled trial involving 57 children. the medication may be withdrawn preferably the following summer. 50% reduction in headache frequency. 250 mg twice daily. If. Of the 50% reported. with 6 months being the mean (1). Long-term use of NSAIDs may not be advisable because of their effects on the gut and on renal function. 2 a greater than 70% reduction. on the other hand. this relatively small study suggests that naproxen sodium may be effective. the children’s medication is begun late in the school year. and of these. placebo-controlled crossover trial (58). for some patients who have difficulty tolerating the other treatments. Thus. even in the adult population. Headache 2002. 23:15–19. Sillanpaa M. double-blind. Diamond S. 1996. May. Headache 1993. 33:497–500. May. 6. 7:234–240. Adams C. Neurology 1997. 106(5P):989–997. Sanner G. 17:61–63. Hoppu K. Classification of pediatric migraine: proposed revision of the IHS criteria. Practice parameter: pharmacological treatment of migraine headache in children and adolescents. American Association for the Study of Headache Scientific Meeting. The first 50 consecutive patients with acute migraine in a pediatric neurology office practice. et al. Lewis D. placebo-controlled study. crossover study. Sumatriptan nasal spray for the acute treatment of migraine. 3. Multicenter prospective evaluation of proposed pediatric migraine revisions to the IHS criteria. Winner P. 48:102–107. 36:419–428. Valkeila E. Hamalainen M.Treatment of Migraine in Children and Adolescents 389 population (1). Treatment of juvenile migraine with subcutaneous sumatriptan. Results of two clinical studies. 17. Winner P. Santavuori P. Sumatriptan nasal spray in the treatment of acute migraine in adolescent. Headache 2004. Peralta L. et al. Gladstein J. et al. Efficacy and safety of oral Sumatriptan in adolescent migraines. Headaches in children. International Headache Society criteria and childhood headache. 19. 48:1100–1103. Raven M. 7. Diagnoses and symptom patterns in children presenting to a pediatric headache clinic. American Association for the Study of Headache Scientific Meeting. Lines CR. 15. Rothner AD. Elkind A. 13.C. placebo-controlled study of sumatriptan nasal spray in adolescent migraineurs. Ryan R. 101(5): 81–90. Bille B. Rothner A. 1996. Linder SL. Winner P. 2. Winner P. Changes in the prevalence of migraine and other headaches during the first seven school years. Headache 1983. 8. Overall efficacy of Sumatriptan Nasal Spray in Adolescent Migraineurs: Pooled Results from US Placebo-Controlled Trials. Wolstein JR. Rothner D. 10. 14. 18. Gladstein S. San Diego. Postgrad Med 1995. Visser WH. . CA. Ames M. Holden EW. Headache 1996. 2001:87–125. et al. 12. Webster C. Headache 1995. 44(5):465. Headache 1977. 20. Neurology 2004. Headache 1994. Wooen J. Multiple-attack efficacy and tolerability of sumatriptan nasal spray in the treatment of migraine. et al. Arch Fam Med 1998. Dev Med Child Neurol 1994. 9. for this patient population. Ames M. Jackson R. Headache in Children and Adolescents. placebo-controlled. Winner P. Decker. Prophylaxis of migraine in children. 4. 63:2215–2224. 34:581–582. A significant need exists for well-designed studies evaluating the efficacy and safety. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind. Mate L. 49:1225–1230. Hamel R. Chicago. MacDonald J. Winner P. Burke B. REFERENCES 1. Do children with migraine respond to oral sumatriptan differently from adults? Neurology 1997. Pediatrics 2000. Neurology 2004. Baker C. Martinez W. 36:419–422. 42:780–786. Hamalainen M. IL. Subcutaneous sumatriptan in the clinical setting. Children’s ibuprofen suspension for the acute treatment of migraine headache. Winner P. Bello L. Winner P. Sumatriptan for migraine attacks in children: a randomized. 11. Ashwal S. 5. Hoppu K. Elkind A. Linder S. Webster B. Saper J. randomized. 16. Randomized. Seshia SS. Rothner AD. et al. as well as tolerability. Kellstein D. Lewis D. 62(suppl 5):A148. et al. Hamilton: B. 35:407–410. et al. Hershey A. Pensky A. Ludvigsson J. Neurology 1997. 39:353. Schoenen J. Saper J. and propranolol in the treatment of adolescent migraine. 44:567. 41. 25. Horton BT. Winner P. Migraine prophylaxis with divalproex. 14:55–63. Levinstein B. Saper J. 17:61–63. Jordon D. et al. 52nd Annual Meeting of the American Academy of Neurology. Report of the Quality Standards Subcommittee of the American Academy of Neurology. 24. Blumenthal LS. . Brenntti AL. et al. Linder SL. 26. Headache 1977. Santarcangelo V. 42:819–822. 38. 23. 34:578–580. 9:547–555. 52:281–286. Standard dosing of amitriptyline is highly effective in a pediatric headache center population. CA. Silberstein S. Dowson AJ. placebo-controlled trial. et al. Adly C. Ann Neurol 1999. Exil G. 34:304–309. Winner P. Ferri R. Headache 1992. 45:585–587. 54:466–469. 34. Linder SL. Serdaroglu G. 11(suppl 11):122–123. 22. 32. Zolmitriptan provides effective migraine relief in adolescents. Int J Clin Prac 2000. Tekgul. Cephalalgia 1991. Arch Neurol 1996. Linder S. Edwards KR. April. Linder SL. et al. Factors precipitating migraine headache in children. double-blind. Collins D. 42. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. 43. Topiramate for the prevention of migraines in children and adolescence: a randomized. Canada. longitudinal study. 36:995–997. Riback PS. Hulihan J. Ann Neurol 1998. Peroutka SJ. Klapper J. 12:269–272. Peters GA. The efficacy of divalproex sodium in the prophylactic treatment of migraine. Neurology 1986. Headache 1994. Treatment of childhood headache with dihydroergotamine mesylate. Soduim valproate prophylaxis in childhood migraine. Caruso JM. Sanner G. Headache 1999. Neurology 1995. Winner P. American Academy of Neurology Annual Meeting. Fisher A. Practice parameter: appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus (summary statement). Raskin NH. Winner P. 33. 39. Clinical profile of Rizatriptan 5 mg in adolescent migraineurs. Freitag F. 20:241–248. Ludvigsson J. Hershey AD. Bulcke J. Montreal. Pearlman E. Ricalde O. 46:541. 28. 30. Depakote ER in migraine prophylaxis. et al. 27. Cephalalgia 1997. Prophylaxis of migraine in children. Repetitive intravenous dihydroergotamine as therapy for intra migraine. Chesson A. Headache 1999. Fluoxetine prophylaxis of migraine. 11(suppl 2):120–121. 44. Headache 2002. A comparative study of cyproheptadine. 29. Le Force B. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Winner P. 17:103–108. 53:180–184. The calcium antagonist properties of cypropheptadine: implications for anti-migraine action. Treatment of acute childhood migraine headaches. Silberstein S. a preliminary report. 40. Headache 1996. Allen GS. Matthew N. Mayo Clin Proc 1945. A new product in the treatment of migraine. Straumanis J. 31. 44(5):481. Arch Neurol 1995. 35. 2000. Caebeke J. Rhan E. Neurology 1984. 37. San Diego. amitriptyline. Self-treatment of acute migraine with subcutaneous sumatriptan using an auto-injector device: comparison with customary treatment in an open. Pediatric headaches: what’s a new? Curr Opin Neurol 1999. May 1. Powers SW. Cephalalgia 1991. Intravenous valpropate for acute treatment of migraine headache. Cephalalgia 1994. Headache 2004. 32:101–104.390 Winner 21. 36. 2000. 39:357–358. Divalproex sodium in headache: literature review and clinical guidelines. Bille B. Comparison of self-hypnosis and propranolol in treatment of juvenile class migraine. 79:593–597. Headache 1986. 5(suppl 3):174–175. 7(suppl 6):385–386. 8(suppl 8):15–20. Furberg B. Flunarizine in prophylaxis of childhood migraine. et al.C. Olerud B. Acta Neurol Scand 1974. Sills MA. . 26:490–493. Ann Neurol 1994. Cephalalgia 1988. Forsythe JI. Nadolol and propranolol in migraine management. low-dose acetylsalicylic acid in children migraine—a double-blind study. Cernetti R. Gustausson CL. 52. Flunarizine and migraine in childhood. et al. long-term multicenter trial. Middlebrook M. 46. A placebo-controlled crossover trial of nimodipine in pediatric migraine. (B. Gilkey SJ. Welch KMA. Moscato D. 49. Flunarizine (Sibelium) in the prophylaxis of migraine. 51. Calcium antagonists. A double-blind study. Cephalalgia 1987. 53. 55. 36:542. Cephalalgia 1988. 50. Pothman R. Tfelt-Hansen P. Headache 1995. Double-blind randomized cross-over trial of timolol in migraine prophylaxis in children. Headache 1990. Tfelt-Hansen P. 5(suppl 2):145–148. An open. Cephalalgia 1997. Lewis DW. et al. NY: Raven Press. Pizotifen. A placebo-controlled crossover trial using trazodone in pediatric migraine. et al. 60. Ulden DL. Battistella PA. Gillies D. DeSimone R. Marano E. Calcium-antagonist flunarizine vs. Ruffilli R. 105 Sandomigran) in prophylaxis of childhood migraine. 58. Martinez-Lage JM. Olness K. 8:1–6. MacDonald JT. 17:73–78. Noronha MJ. Battistella PA. 30:264–268. 35:174. 59. Dev Med Child Neurol 1984. Salmon M. 7:263–266. Mehallick M. Ottauiano S. Ramadan NM. 33:36–39. Migraine prophylactic drugs: proof of efficacy. et al. 1993:383–390. 54. Guidetti V. Flunarizine V. Sorge F. New York. Marano E. 57. Propanolol (‘Inderal’) in treatment of childhood migraine.Treatment of Migraine in Children and Adolescents 391 45. Ludvigsson J. placebo in childhood migraine. The Headaches. Toda N. Moro R. Propranolol used in prophylaxis of migraine in children. Naproxen for migraine propphylaxis. Shultz LL. 47. Cephalalgia 1985. Sorge F. Cephalalgia 1985. Cephalalgia 1987. 48. Headache 1993. In: Oleson J. Pediatrics 1987. utilization and cost. Ruffilli R. 50:109–115. 26:737–741. eds. 56. . superior outcomes compared with alternative treatment programs as demonstrated in a recent controlled clinical trial (4). Some of these therapies are described in this chapter. Chicago College of Osteopathic Medicine. This study found that patients who received the initial treatment on an inpatient basis had greater improvement in their pain. and utilized overall health-care services less than those 393 . and often are. Downers Grove and Department of Family Medicine. Most of the strategies described can also be used. Chicago and Department of Family Medicine. The concept of inpatient treatment for headache may have been fostered by Fordyce (2. North Chicago.A. Illinois. there are patients who are refractive to standard pharmacological and nonpharmacological treatment.25 Inpatient Management and Invasive Treatment Strategies for Migraine and Chronic Daily Headaches Frederick G. while others can be used in the outpatient setting). which is divided into two subsections.S. First we describe the inpatient management of migraine. INTRODUCTION While the treatment of migraine is commonly delivered in an outpatient environment. were able to maintain control of the pain more effectively over one year. INPATIENT TREATMENT Historical Background and Economic Considerations The evolution of specialized treatment of headache has progressed from the first headache clinic in the United States established in 1945 at Montefiore Medical Center in New York (1) to the use of dedicated inpatient treatment units for those whose headaches require intensive multidisciplinary therapy. Inpatient pain specialty assessment and treatment units have. Many of them can be treated with more aggressive modalities of treatment. We then describe some invasive treatment strategies for migraine and the chronic daily headaches (some of which require hospitalization. Freitag Diamond Headache Clinic. for severely disabled headache sufferers.3) in the treatment of other chronic pain conditions. U. for the treatment of chronic daily headaches. Rosalind Franklin University of Medicine and Science/Chicago Medical School. Further study of this situation is necessary. The frequency of headache that still permitted employees to work was similar in the two groups. Furthermore. all patients who are treated in the hospital environment have daily or near daily headache. even with the progress in migraine-specific pharmacologic treatments and the increased use of nonpharmacologic approaches. The prevalence of headache in this survey. evidence demonstrates that comorbid disorders increase the burden on individuals with headache and on society (22) by compounding the effect on the impact of headache and increase loss of productivity in the workplace (23. All of the patients in this study have been referred for closure because of apparent paradoxical cerebral embolism. Beyond the headache itself. the treatments necessary for headache may have an impact on the optimal management of the comorbid medical condition (9. was 64% of the private sector employees and 78% of those in the public sector.5% of the 800 distributed. Closure of the patent foramen ovale produced a 54% reduction in migraine attacks in this population. there are additional factors that may contribute to the severity of the illness in the form of coexisting medical and psychiatric disease. Reports from other countries that do not have dedicated inpatient treatment lend support to other options for the treatment of headache. migraine patients generated nearly twice as many medical claims in comparison to other group patients.24). In another study.10). conversely.26) found roughly twice the prevalence of migraine among these patients as would have been expected based on population prevalence studies. and is responsible for a major impact on businesses and the economy. medication overuse (11–15). These reports have suggested that aggressive outpatient treatment is an option in headache management. treatment of headache patients in primary care costs 87% more than those without headache (6). there are patients who fail at outpatient treatment (27).1 days and at a cost of almost $7000 (7). psychiatric issues such as depression. The first inpatient headache clinic was established in the late 1970s in Michigan. and their pharmacy claims were almost 2. severity. insomnia. Essentially. A review of hospitalization costs in the year of 2000 showed that for migraine there was a mean length of stay of 5. with approximately two days per month of headache. These comorbid medical issues may impact the treatments available for headache. employees had a mean of 25% reduction in their effectiveness at work. In many cases. and several others existing as part of other chronic pain programs. However. Von Korff et al.394 Freitag patients matched for type. These migraine-specific costs are only a portion of the overall medical costs of caring for patients with migraine. During the headache attacks. found that 60% of the patients . Currently. Among the comorbid medical issues present in the migraine population may be a congenital anomaly that has been recently linked to migraine. A Swedish study (8) examined headache in the private and public sector. and head injury (16–21). A study of patients being assessed for closure of patent foramen ovale (25. and duration of pain treated as outpatients. and.5 times greater. and stressful or traumatic life events. In a study (5) conducted at a managed care organization. The role of this embolism on the migraine situation is unclear. This severity of illness produces significant health-care costs. used more emergency services. returned by 71. there are three dedicated inpatient headache treatment programs in the United States. factors that influence the severity of the treatment situation include. The migraineurs. often associated with significant disability. In a longitudinal study of patients with headache in a primary care setting. when compared to other patients. Previously. with a disproportional contribution from those with high-frequency refractive headaches (29). Inpatient treatment will differ based on the facility and type of headache. but achieving this goal is often complicated by patients who come in with medication overuse headache. These factors. which influence both the need for hospitalization and the type of care rendered. significant differences may exist in the sophistication of other aspects of medical management. One of the primary goals of an inpatient headache treatment program is pain control. These patients require addressing the medication . or prescription analgesics (30). In the evaluation of the patient clinically. One survey was conducted in 174 physicians with an interest in headache selected from the membership of the American Headache Society (known as American Association for the Study of Headache at the time of the study).  the medical stability of the patient. the multidisciplinary services offered. Inpatient treatment was viewed as necessary for at least a portion of all patients requiring detoxification from opioids. Additionally.  the occurrence of medication overuse headache and associated drug dependency issues. criteria from inpatient programs substantially overlapped in their guidelines. barbiturates. Community/regional inpatient treatment and dedicated headache inpatient treatment units may all share the common elements of treatment protocols. The choice of the setting for this inpatient care may also to a degree depend upon these same considerations and aid in determining the need for referral to a center with a dedicated inpatient headache unit. Dedicated inpatient treatment units are characterized by the broad availability of a multidisciplinary team (Table 4).  presence of coexisting medical illness. there are a number of considerations that need to be entertained in determining the appropriate treatment setting. These patients cause an important economic burden to society. Currently. as did those of community/regional physicians treating in the community setting.Inpatient Management and Invasive Treatment Strategies 395 had continued disability at one year. A second survey (Table 1) involved both clinicians and the insurance industry and surprisingly had a number of areas of similar views and criteria for inpatient treatment (31).  psychological and psychiatric comorbidities. Several convenience surveys have been conducted to assess criteria for hospitalization. and the recidivism of the patients in treatment. include  intractability of the patient’s pain. Seven major factors have been identified for this consideration of care (Table 5) (34).  the refractoriness of the patient and the headache to established preventative treatment regimens. these criteria are being excerpted by a section of the Department of Health and Human Services as recognized evidence-based criteria for inpatient treatment of headache. there had been two sets of published criteria for admission to headache treatment centers (Tables 2 and 3) (32. with 20% continuing with significant pain and disability at two years (28). Inpatient Treatment—General Considerations Inpatient headache treatment occurs in two different hospital environments: community/regional hospitals and specialty headache treatment units.  need for patient monitoring during administration of medical therapies.33). 7 4. 42. 14. 4. This would not normally require close monitoring.7 5.0 3. 0.1 1. 0.0 1.9 0. This is especially the case in the patient who needs to undergo a rapid transition between SSRI antidepressants and monoamine oxidase inhibitors (MAOI).2 5. 9. 0. 23.5 0. 0.0 3. 57.0 0.8 6. 4. 0.0 4. 4.0 0. This is not a practical solution for patients with disabling headaches. 0. % 3.0 0. 38.0 4.7 12. 4. Medication overuse includes not only analgesics but also migraine-specific therapy such as the triptans. 23.9 1. 4.3 0. 0.5 2.7 8.7 1. 18. 33.3 3.0 1 (with loss of consciousness). Other Reasons for Inpatient Treatment Risk of Serotoninergic Syndrome Rapid transitions in medical therapies control the patient’s headaches in a timely fashion. 4.0 0. etc. 0.7 1. 0.3 0.5 8.0 0. However.4 1. 9.0 0. 14. 0. may increase the potential for the development of serotonin syndrome. 0.7 1. from different families [triptans.8 5. 28. 85. 14. % 1.] in high doses. 71. 14.8 1.396 Freitag Table 1 Results of Survey of Physicians Interested in Inpatient Treatment of Headache and Available Admission Criteria from Insurance Companies Number of physicians (total N ¼ 21). selective serotonin reuptake inhibitors (SSRIs).3 5.0 Reason for admission Change in headache pattern Organic disease Clinically significant nausea and vomiting Frequent parenteral medications Complicated migraine Status migraine Patients at risk from triptan use or other observation needed Failed acute therapy Failed outpatient dihydroergotamine-45 Severe drug allergies Medication overuse headache/drug dependency Failed prophylaxis Failed outpatient treatment Copharmacy management issues Prolonged pain state Chronic daily headache Comorbid medical and/or psychiatric disease Disability Intractable cluster headaches Trauma related acute or chronic Distance Comprehensive treatment program Refer for admit elsewhere No interest or no guidelines overuse component as a first step in bringing pain control to the patient.0 7. 14.3 0.0 0.4 2. Differing therapeutic approaches may be needed to address the control of patient’s pain based on the withdrawal of the offending acute agent.5 5. 19. 14.7 1.0 2. 71. 38. the use of a combination of different serotonergic agents. 4. .0 1.8 0. 23. 4. 42. a drug-free interval of 10 to 14 days is required before starting the new agent.4 Number of insurance companies (total N ¼ 7). 57. 9.2 0. 0. 0. 0. Product labeling specifies that in almost all of these cases.0 6.0 0. 0. opiates. but appropriate treatment of headache symptoms aggravates or induces further illness Failed outpatient detoxification for which inpatient pain and psychiatric management may be necessary Intractable and chronic cluster headache for which inpatient administration of histamine or dihydroergotamine may be necessary Treatment requiring copharmacy with drugs that may cause a drug interaction.. in cases in which this cannot be achieved effectively or safely on an outpatient basis Presence of dehydration. requiring careful monitoring and drug level evaluation) Need to urgently address other comorbid conditions contributing to or accompanying the headache. barbiturates. structural disorder with accompanying symptoms (e.g. Untreated. acute vascular compromise (e. vomiting. or tranquilizers Pain that is accompanied by serious adverse reactions or complications from therapy— continued use of such therapy aggravates or induces further illness Pain that occurs in the presence of significant medical disease.g. agitation. or diarrhea Need to detoxify and treat toxicity. meningitis). severe hypertension) Need to rapidly develop both immediate pain reduction and an effective pharmacologic prophylaxis in order to sustain improvement achieved by parenteral therapy (aggressive daily drug manipulation.g. dependency. a potentially morbid situation could occur. 32. or rebound phenomena and/or monitor protectively against withdrawal symptoms. subarachnoid hemorrhage. monoamine oxidase inhibitors and beta-blockers) Source: From Ref.Inpatient Management and Invasive Treatment Strategies Table 2 Admission Criteria of Michigan Headache and Neurological Institute for Inpatient Headache Treatment Program at Chelsea Hospital 397 Presence of moderate-to-severe intractable headache that fails to respond to appropriate and aggressive outpatient or emergency department measures and requires repetitive sustained parenteral treatment (e. including seizures. Close observation of the patient for warning signs of a serotonin syndrome with elevated temperature. . if allowed to continue. Table 3 Admission Criteria of the National Headache Foundation for Treatment of Headache Severe dehydration for which inpatient parenteral therapy may be necessary Diagnostic suspicion (confirmed by appropriate diagnostic testing) of organic etiology such as an infectious disorder involving the central nervous system (e. and other serotonergic indications is required..g. 33. and prostration that requires monitoring and intravenous fluids Presence of unstable vital signs Presence of repeated previous emergency department treatments Likely presence of serious disease (e. dihydroergotamine) Presence of continuing nausea. brain tumor) Prolonged unrelenting headache with associated symptoms such as nausea and vomiting which. and a more rapid transition with a shorter transition period may be used.. intracranial infection. thus necessitating careful observation (e..g. brain abscess. electrolyte imbalance. cerebral ischemia. would pose a further threat to the patient’s welfare Status migraine or dependence on analgesics.. ergots.g. aneurysm. subarachnoid hemorrhage). including medical and/or psychological illness Presence of concurrent medical and/or psychological illnesses requiring careful monitoring in high-risk situations Source: From Ref.. and their current antidepressant treatment is discontinued. Cyproheptadine is given as a preventative for serotonin syndrome during rapid transitions between SSRI and other novel newer antidepressants and MAOI. but the first several days of the initiation of the new antidepressant medication class agent. Patients are started on 4 mg of cyproheptadine four times a day. the patient will be under close observation as an inpatient.398 Table 4 Typical Treatment Modalities in a Multidisciplinary Inpatient Headache Treatment Program Detoxification Pharmacologic therapy Nursing intervention Physical therapy Dietary management and education Stress management Exercise programs Biofeedback and relaxation therapy Cognitive-behavioral treatment Group psychotherapy Individual and family psychotherapy Family groups Interactions between patients Lifestyle management Discharge planning Freitag Cyproheptadine may be given preventatively to reduce the risk and is one of the treatments of choice should a serotonergic syndrome manifest. Inpatient Treatment Factors Degree and intractability of pain Refractoriness to established regimens Need for supportive medical measures Degree of toxicity and drug dependence Psychological health considerations Comorbid medical disease considerations Need for close patient monitoring . monotherapy may not have provided adequate preventative effects in the past. Five days after the patient has been off the MAOI or SSRI and while still taking the cyproheptadine. These more complex regimens may also be necessitated by the coexisting and comorbid medical and psychiatric illnesses of Table 5 Outpatient vs. if the patient is tolerating it well. Complicated regimens may be needed to produce an effective therapeutic response. The patient is maintained on the cyproheptadine while other appropriate treatments for the headache disorder are initiated other than the new antidepressant class. Need of Politherapy In patients with difficult-to-treat headache. After three to five days on the new agent. The patient undergoes the latter stage almost invariably as an outpatient. the patient will be started on the new agent in the alternative class. cyproheptadine is discontinued over the course of the next 4 to 10 days while monitoring the patient for symptoms of a serotonin syndrome. The use of clonidine for opiate withdrawal (39) may be of benefit in the outpatient arena especially. Failure to achieve successful detoxification of the patient with medication overuse as an outpatient occurs due to the increased pain during the initial period of withdrawal. however. Our protocol is based on the amount of butalbital-containing medication the patient is taking. concomitant use of tricyclic antidepressants is withheld to avoid blocking of the alpha-adrenergic effects of the clonidine to suppress the withdrawal symptoms. The patient who has been using only several tablets per day of these agents is most unlikely to require a phenobarbital taper in my experience.3 mg/day in divided doses. Long-term followup research has found that patients with multiple psychiatric diagnoses have a poorer long-term prognosis than patients with little or no psychiatric disturbance (35–37). can increase the likelihood of adverse effects and drug interactions. Phenobarbital can be used for the withdrawal of short-acting barbiturates (40). While there are no defined criteria for establishing when a patient will have toxicity from opioids. Presence of Symptomatic Comorbid Diseases Chronic headache may be exacerbated by psychological problems. but may be needed in those with significant toxicity from these agents in the inpatient setting as well. The dose is based on the weight and sex of the patient. Biofeedback has demonstrated efficacy in the treatment of migraine in combination with these other psychological therapies. Initial observation and management within the hospital environment facilitate prompt treatment of complications that may result from copharmacy.Inpatient Management and Invasive Treatment Strategies 399 many of these patients. Close monitoring of the clinical response and tolerability of the treatment are necessary to optimize the outcome without substantially compromising the patient’s functional abilities during the initiation of therapy. Group therapy sessions and individual counseling is initiated during the hospitalization. with doses from 0. then the likelihood of withdrawal phenomenon begins to increase substantially. and acute withdrawal symptoms typically associated with butalbital and opioid use. During this initial phase of treatment. long-term treatment is imperative to establish a pain management program to help these patients deal with the psychological aspects of their condition. Treatment of medication overuse headache is crucial. Accurate diagnosis by qualified psychologists and psychiatrists and appropriate treatment are essential if development of a long-term treatment program is indicated. it has been my personal experience that it would be unusual at dose equivalents to 200 mg of meperidine parenteral per day. As the amounts the patient uses increase or if the patient has used small amounts of this type of medication but for periods in excess of a year. After an initial assessment and basic psychological intervention. Psychological intervention may be undertaken in the hospital. This. unmasking of the underlying headaches. The Inpatient Treatment of Medication Overuse The outpatient treatment of medication overuse headache is beyond the scope of this chapter. Continuation of this treatment after hospitalization is often necessary.1 to 0. because preventive therapy often does not work to control the underlying chronic headaches that contributed to the development of the overuse situation. Clonidine is given either orally once or twice a day or as a long-acting patch that may be used in place of the tablets. This may be verified in . It may take as long as 12 weeks to reverse the effects of medication overuse (38). often may produce substantial resolution of the daily headache to allow the patient to regain functional ability related to their headaches in the matter of days versus weeks or months. propofol (41. are continued with a gradual taper over up to three months. coupled with appropriate preventative medications. in general. Withdrawal of triptans and ergotamine compounds necessitates the use of analgesics to control the headache pain during this phase. Dosing adjustments may be made for excessive sedation. where nausea and vomiting constitute significant components of the migraine attack or in those with adverse effects to the treatment. the patient is lethargic or asleep. Diluting the DHE in normal saline and giving it over 15 to 30 minutes also improves the adverse events associated with the treatment. Its use. abrupt withdrawal or rapid tapering of the offending analgesic is used in most patients. Another scenario in which parenteral administration of DHE over several days is useful may be as an adjunctive in terminating the chronic phase of migraine.400 Freitag many episodes of case-history taking with the patient. There are several situations in which intravenous administration of dihydroergotamine (DHE) may be appropriate in patients with severe headache in a headache unit. We will administer a dose of 100 mg of phenobarbital when it has been at least six hours but not more than 24 hours from their last dose of butalbital-containing medication. The basic protocol first proposed by Raskin (44) has undergone modification to suit specific treatment needs of patients and improve the tolerability of the treatment. the administration of a course of IV DHE over two or three days may provide adequate control of the underlying migraine. nonopioid analgesics. because prolonging the withdrawal period only delays the time until the effectiveness of the preventative therapies can be achieved. but. Corticosteroids in the Inpatient Treatment of Migraine and Chronic Daily Headaches There are several reports that have suggested the usefulness of corticosteroids in the treatment of refractive migraine.42). minimizing the need for additional adjunctive approaches to pain management. and if the patient is awake and alert then they will be started on phenobarbital 60 mg three times a day. The intravenous use of diverse agents including antidopaminergic. In the inpatient unit. and valproic acid may be required to provide interim control of headaches while initiating treatment with preventive medications. Lobo et al. The patient is reevaluated in one hour. If. where they relate withdrawal symptoms occurring when they missed doses of their pain medication for more than a day or two. then an initial phenobarbital treatment would not be started. In patients with medication overuse headache. however. Among the variations on this basic protocol (Table 6) are dose reductions in patients with response to the initial test dose as well in those with adverse events. Repetitive intravenous DHE used for more than two days has been recognized by the American Academy of Neurology in their practice parameter as an indication for inpatient headache monitoring (43). noticed that corticosteroids can . muscle relaxants. Patients who subsequently show signs of agitation or tremor while on phenobarbital or those who have not been treated will have 30 mg/day of phenobarbital added to their regimen. A variety of antinauseant agents have also been adapted for this treatment in those. The primary benefit of this adjunct beyond minimizing the acute withdrawal symptoms is the prevention of butalbital withdrawal seizures. ondansetron 4 mg IV or PO) 30 min after premedicating: administer 0.. Numerous outcome studies have been published in article and abstract form (48–67). My personal preferences include the use of oral dexamethasone or methylprednisolone in migraine and prednisone in patients with cluster headache. Rozen (46) suggests the same approach but also points out that it can be used as a treatment for status migraine. metoclopramide 10 mg IM or PO.g.5 mg DHE by slow IV push Vital signs should be monitored and adverse effects assessed prior to dose and for 30 min postdose Subsequent doses should be given every eight hours for a total of nine doses If headache responds to 0. seven papers (totaling 561 patients) gave sufficient information to be included in the analysis of short-term outcomes. Here. These seven papers were .5 mg DHE then increase doses 2–9 to DHE 1 mg If patient has adverse events with IV slow push administration of DHE then dilute additional doses in 50 mL normal saline and administer over 30 min If patient has nausea with administration of DHE after dilution then change to alternative antinauseant or reduce dose of DHE for subsequent doses by 50% Adverse effects may be reduced by dilution of DHE in 50 cc normal saline and administering as IV drip over 30 min Abbreviation: DHE. much like in the situation that occurs with the use of DHE for patients with medication overuse headache. Another potential use of corticosteroids is for the patient with medication overuse headache.Inpatient Management and Invasive Treatment Strategies Table 6 Inpatient Treatment Unit Protocol for IV DHE 401 Establish IV access Premedicate with antinausent (e. the choice of agents is of personal preference and familiarity than scientific foundation. migraine that has persisted for more than 72 hours. Outcome Measures—Assessing the Benefits of Inpatient Treatment There is no class I evidence for inpatient treatment outcomes (31). which is what set the stage for the patient to enter into the scenario of overusing acute medication in the first place. upon withdrawal of the overused medication not only do subjects have the headache occurring from the overused drug but they also have the underlying chronic migraine headache present. trimethobenzamide 200 mg IM or trimethobenzamide 250 mg PO. Because there are no defined trials of these agents. promethazine 50 mg IM or PO. Of the 14 published peer-reviewed papers describing the outcome of inpatient treatment for chronic daily headache. Therefore a course of corticosteroids as part of a comprehensive treatment program should be considered (47). that is. If a parenteral formulation is needed then either a depot form of intramuscular or the intravenous formulation of methylprednisolone is used.5 mg DHE continue this dose If headache continues with 0. be used as rescue therapy in patients who have failed to achieve adequate relief of their acute migraine attacks with specific agents such as triptans and DHE (45). dihydroergotamine. This is one of the first steps in the treatment of difficult migraine headache before a patient is considered for an inpatient hospital treatment in the absence of other treatment issues. Assessing outcomes across these various studies is further complicated by the changing health-care environment for inpatient treatment and even for patient referral to headache centers. a reduction in hospital admissions (from 39 to 10 per year). The number of patients engaged in full. the inpatient and outpatient groups were not comparable with twice as many inpatients as outpatients having analgesic abuse and a substantial difference in the occurrence of daily versus episodic headache. Weeks noted increasing comorbid psychiatric conditions.91 per week in the patients prior to treatment. At eight months. comparing outcome data from the early to the late 1990s. compared drug withdrawal for analgesic and abortive medications for inpatient and outpatient headache (69).402 Freitag used to construct a meta-analysis by Lake and coworkers (31). there was a marked reduction in emergency room visits (from 0. and reduced use of analgesic and other abortive medications. Mean number of dysfunctional days in a twoweek period (where the patient was disabled from normal function due to head-pain) declined from 6. comparing patients from the early and late 1990s (31).13 per week to 4. but found that frequency of severe headaches had increased from a mean of 3. both treatments show significant headache improvement but there was a higher rate of relapse in those treated on an outpatient basis. Lake et al. A shorter study with differing results was done by Pini et al. For both groups. found similar efficacy outcome and hospital lengths of stay. The number of patients with reduced work status resulting from headache dropped from 51% at admission to 22% at follow-up. and greater detoxification challenges along with more complex treatment strategies. An abstract by Diamond et al. (61) assessed health-care utilization in 66 patients and found that. only 4% remained on medical leave. Saper and Lake (65.30 prior to hospitalization to 2.68). and 1. (70) in Italy. Both groups had similar improvement in their headaches. They also found a 50% increase in the number of patients coming from outside their immediate geographic region. The remaining reports cited involved peer-reviewed abstracts only and while presenting similar findings did not provide sufficient information to include in a meta-analysis. though 25% of the inpatients and 15% of the outpatients contacted had relapsed to daily acute medications. Clinically significant depression on the Beck Depression Inventory dropped from 46% at admission to 6% at two-week follow-up and remained low (14%) at eight months. Here.or part-time employment rose from 31% on admission to 53% after eight months (65) (Table 7).94 at eight months. by comparing the one-year period following the discharge with the year prior to admission. this was approximately one-third of the original group. The proportion of patients with 50% improvement was 81% with short-term follow-up and 62. Thirty-one percent of these patients were on medical leave due to headache at the time of admission. However.38 at the two-week follow-up. Similarly. . Suhr et al. Casaly and coworkers in an abstract (66) reported similar reduction in outcomes in patients.3 to 0. Long-term follow-up (average of six years following treatment) was conducted only in the subset of patients who had resolution of their daily headache following withdrawal. Several reports have provided additional outcome information reflecting on treatment issues in this patient population. There have only been three papers that have attempted to assess outcomes for patients in a comparative fashion between outpatient treatment and inpatient treatment. assessed changes in headache activity as well other relevant measures (68). complicated medical histories. using a headache disability questionnaire.1 per month).5% with long-term follow-up. (50) Multidisciplinary Diener et al.Table 7 Outcomes of Inpatient Headache Treatment Lost days 39 20 19 Retrospective Retrospective Prospective 12 mo 3–6 mo 16 mo N Method Follow-up interval Pct.8 mo 57 66 38 Baumgartner et al.8 mo 35 mo Discharge Pharmacological only 9 Pharmacological only 4. (49) Raskin (45) Diamond et al.5 Prospective Retrospective Retrospective Prospective 16.3 mo 3 mo 6 mo 12 mo 24 mo 48 Prospective Discharge 3 wk Schnider et al. (59) 14 14 7.3 50 Retrospective 2 wk 8. with headache improvement >50% 50% 81% improved 71% with ‘‘sustained benefits’’ Outcome study Treatment program Tfelt-Hansen and Krabbe (48) Ala-Hurula et al. (52) Pharmacological only Multidisciplinary Inpatient Management and Invasive Treatment Strategies Lake et al. (51) Silberstein et al. (68) Multidisciplinary 103 42 214 100 Silberstein and Silberstein (53) Multidisciplinary 7. (54) Pharmacological only 10–11 50% (freq) 60% (freq  duration) 61% (defined as ‘‘significant relief’’) 67% 86% 92% 67% 68% 87% 72% follow-up 72% limited to pts 83% who were 87% HA-free at discharge 51% 62% (Continued) 403 .4 8.4 Pharmacological only (repetitive DHEþmetoclopramide vs.3 mo 8. diazepam) Multidisciplinary Retrospective 6. (55) Multidisciplinary Ford and Ford (56) Comparison of two forms of 4 DHE-45: repetitive vs. dihydroergotamine. Source: From Ref.404 Table 7 Lost days 14 75 Retrospective Discharge 38 Retrospective 5 yr N Method Follow-up interval Outcomes of Inpatient Headache Treatment (Continued ) Pct. Freitag . 31. with headache improvement >50% 50% (<8 days/mo) 47% (only mild HA) Outcome study Treatment program Schnider et al. continuous 2 6 96 32 32 Prospective Prospective 3 mo 3 mo 12 mo Pringsheim and Howse (57) Monzon and Lainez (59) Pharmacological only Pharmacological only 82% 57% Abbreviation: DHE. The 25-unit but not the 75-unit treatment group had statistically significant improvement compared to the placebo. has suggested that patients diagnosed with migraine and responding to occipital nerve block and or division of the greater occipital nerve instead had greater occipital neuralgia. the use of botulinum toxin type A injections may not only produce effects on the muscular components contributing to chronic headache but also alter underlying trigeminal nerve contributions to the chronic migraine state. A study of eight patients with chronic migraine who had a positive response to implanted suboccipital stimulators was recently conducted (71). Patients received repetitive blocks. 25 units of botulinum toxin type A. Subsequently there have been a number of studies conducted with this agent. Two recent studies have added (77. Anthony (73). Outcome was determined by a pain index. however.Inpatient Management and Invasive Treatment Strategies 405 INVASIVE TREATMENT OF MIGRAINE AND CHRONIC DAILY HEADACHES Therapeutic Blocks and Radiofrequency Stimulation In a recidivist population of patients. The therapeutic value of greater occipital and supraorbital nerve blockade was studied in 27 patients with migraine. Assessment of this contribution can include the use of diagnostic/therapeutic blocks of the greater occipital nerve (72) as well as the facet joints of the upper cervical spine or epidural steroid injections. The localization and persistence of activity during stimulation were consistent with that seen in episodic migraine. The largest of the placebo-controlled trials in migraine was a study on 122 patients (75). the number of migraine attacks. Input from upper cervical segments may act directly on trigeminal centers impacting the migraine headache situation as well as serving as a focal source of pain. or 75 units of the toxin. the difference was not statistically significant. Botulinum Toxin Although its mechanism of action is still to be determined. Successful outcomes with these procedures may lead to the use of radiofrequency procedures to produce longer treatment effects. Binder (74) first reported his results with botulinum toxin type A in an uncontrolled study. other adjunctive approaches to pain management may be needed. The activation pattern was highly suggestive of a role for this structure in chronic migraine. There were significant changes in rCBF in the dorsal rostral pons. The authors attribute the relative lack of response by the 75-unit treatment group to the reduced baseline numbers of headaches in this group. and with a similar treatment response as seen in migraine. Twenty-three patients (85%) responded and maintained a favorable response for as long as six months. Positron emission tomography scans were performed using regional cerebral blood flow (rCBF) as a marker of neuronal activity. Long-standing effects of trauma to the cervical spine can produce changes in mechanical contributions to headache. Patients were randomized to receive placebo injection. Local trigger point injections in painful cervical and scalp muscles can help to address these mechanisms in headache.78) support to the potential applicability of botulinum toxin type A in the population of patients with migraine headache and . Although baseline headache frequency was unequally distributed between the three groups. The efficacy of botulinum toxin type A in the treatment of chronic daily headache was first studied in a double-blind trial of 56 patients (76). The results of this trial suggested possible efficacy with improvements in headache duration and frequency. and analgesic consumption. even if the pain is not appreciated in the cervical region. There are several approaches to administering botulinum toxin type A. Joseph Tsui.406 Freitag daily or near daily headache. Figure 1 Possible posterior locations for injection of botulinum toxin type A.’’ With a fixed site approach.’’ The other is termed a ‘‘follow the pain approach. Sylvain Chouinard. The use of 100 to 200 units of botulinum toxin type A. A number of sites have been chosen as demonstrated in Figures 1–3. with repetitive injections every three months appeared to produce the greatest efficacy. Ian Finkelstein. . covering the region above and between the eyebrows and extending to the hairline and also including the temporalis muscles. One has been termed a ‘‘fixed site approach. the amount used. regardless of the location of their pain or its relative intensity. which are designed to target the muscles in the distribution of the first branch of the trigeminal nerve. Source: Courtesy of Drs. so this commonly includes the occipitalis. Despite these uncertainties that still exist. the administration. and Anna McCormick. so neuronal distribution may be of importance as well. Masseter injections are occasionally included for those patients who have significant bruxism. portions of the trapezius muscle may be injected as may the sternocleidomastoid muscle unilaterally. While relief of muscle spasticity may be important in the mechanism of botulinum toxin type A. In the follow the pain approach. the number of injections. in some patients. semispinalis. again the muscle innervated primarily by branches of the first three cervical rami is injected. In the posterior regions of the scalp and neck. the progress that has occurred and the clinical experience that has been gained allow us to utilize this agent with safety and efficacy in many of our most challenging patients with highly favorable results. head. and splenius capitus muscles. The potential overlap between the upper cervical segments and the trigeminal nucleus caudalis may explain the need to treat this region in patients with chronic daily headache. These studies have verified much of what has been the clinical impression with the use of botulinum toxin type A. and their locations is based on the location of the patient’s pain and even its relative intensity in one location versus another. given as multiple injections in the face. and neck. Many variables may play a role in determining outcome including the concomitant use of preventive medications and acute medication overuse. regarding the selection of injection sites. if the patient has spasticity. all patients receive botulinum toxin in the same locations in the head and neck region. there may also be effects modulated directly via the afferent nerves. Injections in the face should be kept within the midpupillary lines and directed superiorly. Larger quantities may also be used in patients based on their response to treatment at 100 units. These techniques will reduce the likelihood of eyelid ptosis. The application of ice packs and the use of a nonsteroidal anti-inflammatory agent for a day may reduce the discomfort associated with the injections. Whereas some patients demonstrate an improving duration of response with repeated injections of botulinum toxin type A.Inpatient Management and Invasive Treatment Strategies 407 Figure 2 Possible anterior cervical and facial location for injection of botulinum toxin type A. Dilutions of 2 cc to 4 cc in normal saline and injection with a fine scale subcutaneous needle is my preference. and Anna McCormick. but may occasionally use lesser amounts in patients with an extremely tight scalp aponeurosis. the use of preservative-containing normal saline solution also reduces discomfort. Ian Finkelstein. Sylvain Chouinard. Electromyogram needle placement is not needed in this type of treatment for chronic headache. Source: Courtesy of Drs. Ian Finkelstein. Joseph Tsui. While not recommended on the package label. most patients require reinjection on a schedule on average Figure 3 Lateral cervical and lower facial areas for possible injection of botulinum toxin type A. Joseph Tsui. . Sylvain Chouinard. Typically I will use 100 units of botulinum toxin type A. Source: Courtesy of Drs. acting as a mild local anesthetic agent. Multiple injections of small quantities should be used preferentially to a single injection of a large quantity in areas of the face. and Anna McCormick. CONCLUSION Inpatient hospital treatment of headache continues to be an important component of the practice of specialty headache management. These treatment characteristics make establishment of scheduled treatments important in minimizing loss of effect. This parasympathetic nerve inputs via the solitary tract nucleus and hence to other brain stem nuclei that act upon trigeminal vascular responses. Appropriateness for inpatient treatment is dictated by the intensity of the treatments being rendered. While controlled trials do not exist. coexisting disease processes. safety issues related to drug therapies. Another approach that has been suggested as being efficacious in treatment resistant migraine involves those with small nasal passages may benefiting from reconstructive surgery according to Novak (81). The loss of effect as the toxin’s action is physiologically reversed. These groups of patients whose headache histories. Substantial improvement occurred on a wide variety of parameters in follow-up over a year. Implanted Devices Recently. before progressing to a temporary occipital stimulator implant. the evidence strongly suggests and the clinical experience of specialty headache management continues to demonstrate specific rationales for this approach. The 25 patients were followed for an average of approximately 18 months. and may dissipate from maximal effect to loss of effect in less than a week in some patients. however. and disease impact on quality of life and work productivity have been shown to achieve the greatest levels of improvement in disability and expensive health-care utilization. Another study used corrugator muscle resection (80). We have patients with repeated successful blocks and or radiofrequency rhizotomy. A study by Popeney and Alo (82) examined the effect of occipital stimulation in a population of patients diagnosed with transformed migraine. treatment histories. Adverse events while not uncommon were not severe. and coexisting illness. Those responding to the injections underwent surgical procedures involving the nasal septum and turbinate or forehead surgery. have applicability in the treatment of less-challenging patients in the community level amongst physicians familiar with headache management. . there has been limited use of implanted devices for pain management. Recurrence of headache in the first month occurred in one of six patients. There are challenging patients who have refractive headache problems in the traditional outpatient milieu who are candidates for comprehensive inpatient headache treatment programs. Many of the individual components of inpatient treatment utilized in these specialty centers. Vagal nerve stimulation (83. The onset of activity takes several days to occur and develops progressively. The use of botulinum toxin type A to identify trigger sites for migraine has been suggested (79). the routes of administration complexity of regimens. These authors found that those with less-frequent migraine were more likely to have a favorable outcome. The use of occipital stimulators may be appropriate in those who respond to local block procedures of the greater occipital nerve or trigger point injections in this region.408 Freitag of every 12 weeks. Those who find this device producing acceptable results and comfort have a permanent stimulator implanted. with the vast majority having at least a 50% reduction in their pain. based on the previous study.84) has been used in a limited fashion for intractable headache following its successful use in refractive epilepsy. may be abrupt. Raak R. et al. The impact of migraine on health status. Headache and Depression: Serotonin Pathways as a Common Clue. 14:443–446. Lipton RB. Rothrock J. 19:231–244. 1987:340–384. Manzoni GC. Trigger point injections. 13(suppl 12):72–77. Sandrini G. In: Adler C. Mathew NT. Moon C. Work attendance despite headache and its economic impact: a comparison between two workplaces. Bonsel GJ. Richardson PH. 35:200–206. Patel M. . 10. Headache 2003. Rutten FFH. Wasiewski W. Inpatient versus outpatient pain management: results of a randomized controlled trial. Silberstein SD. An epidemiological approach to the nosology of chronic daily headache. 2. Fordyce WE. Transformed migraine. 16. Lehmann JF. Adler SM. 7. Healthcare resource use and costs associated with migraine in a managed healthcare setting. Pain 1996. 6. Arch Phys Med Rehabil 1973. 13. Poisson L. 10:1005–1012. Elston Lafata J. Neurology 1996. 43:1097–1101. Lozano P. Pharmacoeconomics 1994. Demographic and clinical characteristics of patients with episodic migraine versus chronic daily headache. Mathew NT. In: Nappi G. 9. St Louis: CV Mosby. These approaches involve the use of injections of a variety of agents from corticosteroids to botulinum toxin type A as alternative approaches for the management of challenging headaches. Headache 1995. Hershey AD. Chronic daily headache: clinical features and natural history. The medical care utilization and costs associated with migraine headache. eds. Koenig MA. facet blocks. Pharmacoeconomics 2001. Chronic care costs in managed care. Pharmacoeconomics implication of migraine and migraine therapies. REFERENCES 1. Kolodner K. Operant conditioning in the treatment of chronic pain. Williams ACdeC. Fishman P. Surgical approaches have again come to the fore as possible therapeutic approach in migraine. Behavior Methods for Chronic Pain and Illness. Headache 2002. Cephalalgia 1996. 42:491–500. 5. and other invasive procedure may even lead to the use of implantation of device to block pain or alter its regulation centrally. 14. 28:659–664. Chronic daily headache in children and adolescents presenting to tertiary headache clinics. 8. 1991. The International Headache Society (IHS) headache classification as applied to a headache clinic population. Perspectives from a headache center with an inpatient unit. Von Korff M. 3. The long-term success and implications of surgical approaches and these other interventions have yet to stand the tests of time of many of the traditional medical approaches. Saper JR. Packard RC. Zanferrari C.Inpatient Management and Invasive Treatment Strategies 409 Comprehensive multidisciplinary management is also needed by patients with longterm refractive disorders for headache. Baltimore: Williams and Wilkins. 11. Lyden P. Psychiatric Aspects of Headache. Cephalalgia 1994. Krabbe P. Gladstein J. Sanin LC. et al. Schreiber C. 47:871–875. 66:13–22. 54:399. Nicholas MK. Leotta C. Ali S. 12. Fordyce WE. Van Roen L. Osterhaus JT. 13(suppl 12):78–83. J Gen Intern Med 2004. and selected centers exist for these situations. New York: Raven Press. Cephalalgia 1993. 1976. Jackson C. 16:44–49. Essink-bot ML. Alternative approaches to management of refractive headache continue to be explored. et al. Fowler RS Jr. Lipton RB. Health Affairs 1997:239–247. Raak A. 17. Classification of daily and near daily headaches: field trial of revised IHS criteria. Mathew NT. Sliwinski M. Cephalalgia 1993. McCarter RJ. Bellmeyer LR. Cady R. 4. Clouse JC. 15. Nappi G. ed. Lipton RB. Von Korff M. 1:7–23. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. 3rd. MD. Gordon CD. 40:224–230. Wiher S. Headache Clinics and Inpatient Treatment Units for Headache. Neurology 1998. 6th ed. 50:133–149. 31. 28. Nedeltchev K. Freitag FG. Perez F. et al. Howard L. Migraine and reduced work performance: a population based diary study. Swidan S. Williams & Wilkins. Neurology 1993. Stubits E. 10(2):147–152. Scott V. 41:953–967. et al. Paolone MF. Stovner LJ. Eur J Neurol 2003. Hagen K. Villareal SS. Stephen Silberstein. Limbically augmented pain syndrome (LAPS): kindling. J Psychosom Res 2004. Mendes PM. 30. 2:133–134. Pain 1992. et al. 34:319–328. 42. Krusz JC. Psychiatric morbidity and cognitive representations of illness in chronic daily headache. Transformed or evolutive migraine. A Practical Guide to Diagnosis of Head. and the convergence of affective and sensory symptoms in chronic pain disorders. 41. 27: 102–106. Bovim G. 37. Simon DJ. Silberstein SD. Rozen TD. 30:634–638. Stang P.29. Ormel J. 19. Silberstein SD. Perez F. Lipton R. 33. Dahl AA. 43:1644–1649. In: Diamond S. Zwart JA. Lipton RB. Chicago. Hamel RL. Freitag F. The Nord Trondelag Health Study. Williams and Wilkins. 38. Rome HP. 22. Gutterman DL. Yankovsky AE. Kurman R. Dalessio DJ. Tension type and chronic daily headache. Page L. Headache 2002. Drug induced refractory headache—clinical features and management. Lake A. Transformation of episodic migraine into daily headache: analysis of factors. Cady R. Kuritzky A. 38:423–426. Headache Q 1991. Nigam MP. 27. 42:638–641. Headache 2003. Handbook of Headache Management. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. A comparative study of selected patient variable risk factors in hospitalization for chronic headache. 27:861–873. Headache 1995. Odegard KJ. Headache 2004. Grading the severity of chronic pain. Butalbital in the treatment of headache: history. Stewart WF. Headache 1998. 23. 1999. 35:349–354. Headache 1990. 62(8):1399–1401. Frank RG. Transformation into daily migraine with aura following transcutaneous atrial septal defect closure. MD. 32. Belanger J. Headache 1982. Intravenous propofol: unique effectiveness in treating intractable migraine. Saper JR. Headache 2001. Young WB. Headache 2000. 24. Mathew NT. et al. The Practicing Physicians Approach to the Treatment of Headache. pharmacology and efficacy. eds. Inpatient treatment of headache: an evidence-based assessment. 44:1–19. Reuveni U. Intravenous propofol in the treatment of refractory headache. 2004. 39. Smith R. Galli F. 18:455–462. 57:549–555. Mathew NT. Analgesic rebound headache in clinical practice: data from a physician survey. Dworkin SF. Silberstein SD. Dalessio DJ. Silberstein SD. 36. Silberstein S. 25. 22:66–68. Pain Med 2000. Illinois: National Headache Foundation. Headache 1996. 20. 34. 26. Neck and Facial Pain. The National Headache Foundation Standards of Care. The clonidine protocol. McCrory DC. G Solomon. Rome JD. 36:14–19. Headache 1987. Dyb G. The impact of psychiatric disorders on work loss days. 29. Fabrizi P. 2nd ed. Von Korff M. Schwerzmann M. on behalf of the US Headache Guidelines Consortium. An update on the epidemiology of migraine. Stewart WF. Section on Inpatient Treatment Chairpersons: Seymour Diamond. Cephalalgia 1998. Neurology 2004. Philadelphia: Lippincott.410 Freitag 18. Cady R. Psychol Med 1997. Husain K. 21. Rapoport A. 40. Guidetti V. Impact of migraine on the family. corticolimbic sensitization. 50:1741–1745. . Mathew NT. Depression and anxiety disorders associated with headache frequency. Baltimore: ML Diamond. Freitag FG. Kessler RC. 43(5):496–498. Headache 1994. 35. Keefe FJ. 49. 53. Headache 1994. Cephalalgia 1996. Symptomatic pharmacotherapy of migraine. Landy SH. Baskin SM. Do patients benefit from withdrawal? Cephalalgia 1981. Treatment of headache in an inpatient headache unit: long-term results [abstract]. 50. Tfelt-Hansen P. 64. Headache 1995. 51. Am Acad Family Physicians Monogr 1985. Practice parameter: appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainous [summary statement]. Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up. Cephalalgia 1982. Clin Ther 1999. Comprehensive inpatient treatment for intractable head pain: patient factors associated with outcome [abstract]. 25:146–150. Wessely P. 63. 30:334–339. Ergotamine abuse: results of ergotamine discontinuation. Gerber WD. 16: 481–485. 57. Haugh MJ. with special reference to the plasma concentrations. 28:317. 5(suppl 3): 440–441. Saper JR. 60. 32:439–445. Madden S. 37:129–136. 61. Aull S. Improvement of decreased critical flicker frequency (CFF) in headache patients with drug abuse after successful withdrawal. Cooke SC. 4(5):395–401. Lobo BL. Can J Neurol Sci 1998. Wessely. 47. Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Weeks RE. 27:306. . Ford RG. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Prager J. Bingol C. 1:29–32. Auall S. outcome. Rapoport AM. 46. 48. Raskin NH. Silberstein JR. 33:285. 28:315. Ford KT. Long-term prognosis of analgesic withdrawal in-patients with drug induced headache. Lainez JM. 45:585–587. Ergotamine abuse. Headache 1993. Prospective outcome evaluation of an accredited inpatient headache program [abstract]. Hokkanen E. Migraine headache: immunosuppressant therapy. and recidivism [abstract]. Maliszewski M. Baumgartner C. 56. 52. Howse D. Headache 1989. Headache 1990. Wall DJ. Baumgartner C. Headache Q 1998. A prospective analysis of repetitive intravenous DHE in the treatment of refractory headache [abstract]. 44. 45. 62. Headache 1993. Silberstein SD. Freitag FG. Saper JR. Freitag FG. Impact of in-patient headache treatment on subsequent medical care [abstract]. Headache 1993. 54. Chronic daily headache: long-term prognosis following inpatient treatment. Headache 1988. Krabbe AA. Lake AE III. Schnider P. Continuous intravenous dihydroergotamine in the treatment of intractable headache. 36:995–997. In-patient treatment of chronic daily headache using dihydroergotamine: a long-term follow-up study. Treatment of ergotamine dependency: techniques. Lake AE III. J Neurol 1989. Headache 1997. Diamond S. Cephalalgia 1985. Diamond S. Scholz E. 9:326–330. 2:189–195. Repetitive intravenous DHE in the treatment of refractory headaches. Silberstein SD. Myllyla V. Freitag FG. 59. 29:510–514. Schnider P. Zeiler K. Maly J. Sheftell FD. Analgesic-induced chronic headache: long-term results of withdrawal therapy. Headache. Solomon GD. 69:1–54. Saper JR. Report of the Quality Standard Subcommittee of the American Academy of Neurology. 58. Biofeedback as an adjunct to repetitive intravenous dihydroergotamine in the treatment of refractory headache [abstract]. Ala-Hurula V. 55. Curr Treat Options Neurol 2002. Bille A. 34:514. 21(7):1118–1130. Gandhi S. Holzner F. Hopkins MF. Pringsheim T. Headache 1987. Neurology 1986.Inpatient Management and Invasive Treatment Strategies 411 43. 33:286. Maly J. 65. Monzon MJ. Diamond S. Grunberger J. 35:269–272. Rozen TD. American Academy of Neurology. Diener HC. 236:9–14. Kreeger C. Geiselhart S. et al. Neurology 1995. Headache 1988. Schulman EA. Dichgans J. Therapeutic blockade of greater occipital and supraorbital nerves in migraine patients. Casaly JS. Pathogenesis and surgical treatment of neurovascular primary headaches. Sternieri E. placebocontrolled study. Weiner R. Bauer B. 83. Brin MF. Anthony M. Silberstein SD. Suhr B. Binder WJ. Ital J Neurol Sci 1995. Botulinum toxin type A (BOTOX ) for the prophylactic treatment of chronic daily headache a randomized double-blind placebo-controlled trial. 19:44–49. 115:1–9. Silberstein SD. 45:293–307. Firetto V. Vagal nerve stimulation aborts migraine in patients with intractable epilepsy. Gibson J. 72. 35:306. Saper J. Rapoport AM. 67. Comprehensive inpatient treatment for intractable migraine: a prospective long-term outcome study. Comprehensive surgical treatment of migraine headaches. Vitale G. 75. 56(suppl 3):65. Bartsch T. Madden SF. Gawel M. 45(suppl 4):A379 [abstract]. Frishberg BM. Elkind AH. Sadler RM. 94:297–301. 74. Frackowiak RS. Inpatient treatment of chronic daily headache: outcome measures [abstract]. Dodick DW. Sheftell FD. 76. Mathew NT. 33:55–62. Kailasam J. Dawson GA. 69. Plast Reconstr Surg 2004. Headache and the greater occipital nerve. Grotemeyer KH. Saper JR. Rahey S. Goadsby PJ. Mauskop A. 79. 40:445–450. DeGryse R. Cephalalgia 2000. Vagal nerve stimulation for refractory migraine. Botulinum toxin type A as a migraine preventive treatment. 81. Headache 2000. 77. Botulinum toxin type A (BOTOX ) for the treatment of migraine headaches: an open label study. Botulinum toxin type A (BTX-A) for the prophylaxis of chronic daily headache. Davis J. Blitzer A. Headache 2003. Klapper A. Baskin SM. Headache 2005. Headache 1997. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind. Headache 1993. Surgical treatment of migraine headaches by corrugator muscle resection. Headache associated with chronic use of analgesics: a therapeutic approach. Cephalalgia 1999. Peripheral neurostimulation for the treatment of chronic disabling transformed migraine. Klapper JA. Turkel C. 43:369–375. Hussted TIW. Drug-induced headache: long-term results of stationary versus ambulatory withdrawal therapy. Mauskop A. Dirnberger F. Loughner BA. 70. Jenkins S. Mathew N. Headache 1996. Lake AE III. Neurology 2001. Brin MF. Caputi CA. 123:669–676. 20:291–292. 71. 78. Evers S. Headache 2005. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Clin Neurol Neurosurg 1992. 114:652–657. Weeks RE. 45:315–324. Schoenrock LD. 22:482–484. 84. Kreeger C. Matharu MS. Dimitrova R.412 Freitag 66. Guyuron B. 80. Plast Reconstr Surg 2005. Novak VJ. Neurology 1995. Gralow I. Kriegler JS. Amini SB. 68. Becker K. 73. Bigarelli M. 37:174–179. Headache 1995. . Mathew NT. 82. Alo KM. Purdy RA. Pini LA. Brain 2004. Ward N. Popeney CA. Otolaryngol Head Neck Surg 2000. 36:433–439. 16(8 suppl):49–55. Cephalalgia 2002. 127(Pt 1):220–230. Albert Einstein College of Medicine.S. the majority would not need to come to the ED. It is often true that an ED migraine visit represents a failure of the health care system. There have been few in-depth scientific assessments of the clinical features of migraine in the ED. New York. a disease-specific education sheet. migraineurs do not use EDs for emergency care—in an insured and 413 .6). In urban EDs. and reasonable expectations. a significant percentage of migraineurs are probably uninsured or underinsured (3). with tension-type headaches comprising a small. It is not uncommon for migraineurs to come to an urban ED without having taken any medication at all for their headache (3.S. and provide the patient with an appropriate discharge plan that includes a diagnosis. so a thorough description of these patients is not possible.A. Benjamin W. If patients were adequately diagnosed and treated. U.26 Migraine in the Emergency Department Merle Diamond Diamond Headache Clinic and Rosalyn Finch School of Medicine. prescriptions. INTRODUCTION Headache is a common emergency department (ED) complaint. representing around 2% of visits to American EDs (1–3).6). The Montefiore Headache Center. New York. Illinois. U.A. Chicago. Friedman Department of Emergency Medicine. More than five million ED patients report headache as one of three chief reasons for the ED visit (4). initiate migraine-abortive therapy when appropriate while controlling pain in the ED. The goals for emergency physicians and neurologists consulting in EDs on headache patients are to facilitate the correct diagnosis. in contrast to health maintenance organizations and rural community hospitals where patients are very likely to have insurance (8). ED migraine patients probably represent a heterogeneous population including some patients with very significant headache-related disability scores and some with minimal or no disease-related disability. In general. who visited an ED at least once for migraines report that they have not used a prescription medication (9). The vast majority of these headaches are primary headaches or headaches due to benign systemic illness such as upper respiratory infections and other febrile illnesses (5. Two-thirds of female migraineurs and one-half of male migraineurs. referrals. but significant minority (5. The vast majority of primary headaches in the ED are migraines.7). especially in immunocompromised or thrombophilic patients. which usually indicate the need for a diagnostic work-up. only 20% of female migraineurs and 13% of male migraineurs reported a lifetime ED visit for headache (9).414 Diamond and Friedman healthy population. worst. Typical ‘‘red flag’’ features. unbearable exacerbation of a chronic intermittent headache. migraineurs used the ED only slightly more often than nonmigraineurs (10). or changed headache (14). One of the most important questions is why headache patients come to the ED. One model describes two distinct groups: a ‘‘first or worst’’ syndrome and a ‘‘last straw’’ syndrome (11). HOW TO APPROACH A PATIENT WITH ACUTE HEADACHE IN THE ED Of late. This creates frustration and ineffective disease management. the emergency physician’s frustration with the repeater is transferred to other migraineurs. repeaters tend to rely on opiates for migraine relief and often request a particular medication and a particular dosage. The patient’s history should guide the clinician. these patients accounted for 43% to 50% of all ED visits or urgent clinic headache visits (3. Experts recommend performing a lumbar puncture in all patients with a first. A Canadian categorization reported that the ‘‘repeaters’’ were predominantly female and tended not to use multiple EDs (13). become less and less compelling. These patients require effective treatment and appropriate discharge planning. The questions below can help the emergency physician screen for secondary causes of headache:      Do you have recurrent headaches like this? Is this your first headache? Is this your worst headache? What evaluation have you had done in the past for these headaches? How often do you take medicine for your headaches? It tends to be more apparent when an evaluation for secondary headache is needed than when it is not. As the availability. speed. Although comprising less than 15% of the headache population. there is no way to exclude a subarachnoid bleed completely short of performing a lumbar puncture to evaluate for xanthrochromia. As yet. Patients at extremes of age are at risk for specific organic causes of headache as well. Certainly. the need to exclude potentially lethal causes of headaches has been discussed (14). The ‘‘last straw’’ syndrome presents with an acute. thunderclap . Patients with the ‘‘first or worst’’ syndrome present with their first severe headache or the worst headache of their lives. particularly in ED headache patients who have never had one. In a sample of the general population. ED health care providers often view the repeater with irritation and suspicion because of concern about their motivation for being there. The repeaters represent a problematic population because multiple ED visits represent an expensive and ineffective route for the delivery of health care. An important subpopulation of the ‘‘last straw’’ patients is the ‘‘repeaters’’— patients who make multiple ED visits within a short time period (12).8. and sensitivity of modern computed tomography (CT) scanners for space-occupying lesions continues to increase. and testing to exclude other lethal causes of headache should be performed as needed. At times. These patients require a diagnostic work-up in the ED. In general. Further. are listed in Table 1. or in those patients with fever and meningismus.12). the reasons not to perform a CT. This also allows the patient to undergo follow-up for a specific condition and form realistic expectations about the disease itself. and others with a history of hypercoaguable state. this should be a diagnosis of exclusion in an ED Classically. worst. An accurate diagnosis will allow the initiation of migraine-specific medication. After secondary causes of headache have been excluded.’’ the goal of therapy is to avoid nonspecific analgesia. . visual complaints in the elderly. emergency department. persistent focal neurologic deficits. The actual test characteristics of these descriptions of headache are unknown Intracranial hemorrhage and concussion should be considered if clinically relevant These patients are at increased risk of temporal arteritis and cerebrovascular accidents Consider carbon monoxide poisoning during winter months First.. an accurate diagnosis of migraine will allow the initiation of migraine-specific treatment in the ED and the creation of an appropriate discharge plan. venous sinus thrombosis should be considered Intracranial bleeds should be considered Although migraine with aura causes focal neurologic signs. meningitis should be considered as an etiology of the fever Cryptococcal meningitis or sinusitis are not uncommon in patients with AIDS and can present subtly In gravid patients.Migraine in the Emergency Department Table 1 Red Flags for Secondary Headaches in the ED Red flag Thunderclap headache Acute signs of increased intracranial pressure Fever Comment 415 Immunocompromised patient Thrombophilic patient Thrombocytopenic or anticoagulated patient Acute focal neurologic signs Incidence of subarachnoid hemorrhage in this population 10–20% (15–17) Papilledema or loss of venous pulsations mandates a work-up Although intercurrent upper respiratory infections and other viral illnesses can exacerbate migraines. i. suggest worrisome causes. the indication to evaluate for subarachnoid hemorrhage. headaches that reach a severe peak in intensity in less than one minute. Although a complete headache history may be difficult to obtain in a bright and busy ED. As we will discuss in the section on ‘‘Treatment. Similarly. the recently postpartum. or changed headache Blunt trauma Elderly patient Others in household with similar symptoms Abbreviation: ED.e. and stigmata of elevated intracranial pressure should generate an ED work-up. headaches. the diagnosis of migraine should be considered in any patient with painful or debilitating recurrent headaches. A correct initial diagnosis will allow appropriate initial treatment. Metoclopramide has a favorable pregnancy rating and is commonly used in pregnant patients for hyperemesis gravidarum. We believe that known migraineurs who present with an acute migraine attack and associated moderate hypertension should be treated with a migraine-appropriate analgesic medication prior to an antihypertensive agent if there is no evidence of end-organ damage.6). The prevalence of pure tension-type headaches in North American EDs has not been well documented.’’ it does behoove the emergency physician to determine which medications the patient has already used unsuccessfully during the acute attack and which medications have been used previously with success. the pain associated with a migraine headache could cause an elevation in blood pressure. The original diagnosis becomes the default diagnosis (i. Physicians should not exclude migraines as the diagnosis because of the presence of sinusitis or viremia. though this has not been well studied in the ED setting. A patient’s migraine should not be called a ‘‘hypertensive’’ headache. Chronic migraines and status migrainosus need to be diagnosed because they could dictate a different disposition for the patient. Routine neuroimaging and blood work are likely to be of no benefit in a patient with a typical migraine attack—dehydration and evidence of infection can usually be diagnosed based on history and physical exam. or a parenteral nonsteroidal.e. Acetaminophen is safe for use in pregnancy and can be administered to a pregnant patient. until the head pain and blood pressure have been controlled and a more complete history taken. because either of these conditions could coexist with. the emergency or consulting physician should consider tension-type headaches. The epidemiology of ‘‘hypertensive’’ headaches in the ED has not yet been established. When determining ‘‘appropriate and aggressive ED treatment. . especially if the patient has taken nothing for her headache. a patient with persistent pain after several hours of appropriate and aggressive ED treatment. The patient in status migrainous needs admission and the patient with chronic migraines needs an expedited referral to a neurologist or headache specialist. Whether and how often hypertension causes headache is uncertain—even more so at levels of hypertension that are considered moderate. Although 72 hours is used as the formal cut-off for status migrainosus. chronic sinusitis) and the patient never receives migraine-appropriate medication (18). which typically are not as severe or disabling as migraines. Physicians should be careful not to cause an unnecessary precipitous drop in blood pressure. Similarly. Once a patient has already been diagnosed with an alternative type of headache. or exacerbate an acute migraine. when a patient comes in with a severe migraine headache and an associated rise in blood pressure. Medication-rebound headaches. both contraindicated in hypertensive patients. A reasonable approach would be the use of a dopamine receptor antagonist. they are less likely to receive the diagnosis of migraine.. possibly represent a significant percentage of emergency headaches. be confused by. Pregnancy should be actively determined in migraine patients because teratogenicity and abortificant properties are a concern with certain migraine-abortive medications. The dilemma for the emergency physician is whether or not to use a triptan medication or ergotamine. but European and South American EDs report that tension-type headaches represent 18% to 44% of all their primary headaches (5. has status migrainosus and needs admission for further aggressive parenteral therapy.416 Diamond and Friedman When diagnosing migraines. for all intents and purposes. merely because the blood pressure is elevated. A stepwise treatment approach in these patients. As many as 55% of migraine patients do not take any medication prior to presentation to an urban ED (3. General Interventions The role of routine intravenous (IV) fluids in ED migraineurs is unknown. Specific Classes of Medications Triptans Although well established in outpatient headache medicine. many migraineurs are nauseated or vomiting and unable to tolerate oral medication. Initial emergency treatment should be based on medications that have worked well for the patient previously. these medications are not commonly used in North American EDs (4. previous headache-related disability dictates the most appropriate class of medication for a patient. Third. the goals of therapy should be rapid alleviation of pain with a minimum of side effects and an eye toward preventing recurrence of headache. using cheap oral nonsteroidals. First. the bioavailability of oral medications is often limited.20). That they are of benefit in ED migraineurs is not in doubt—a well-done multicenter ED trial has clearly shown the benefit of subcutaneous sumatriptan versus placebo (Table 2) (21). The exception to this statement is patients who request their usual dose of opiate medication—methods to address the concerns of these patients are discussed in the section on ‘‘Opiates. pain intensity and a patient’s ability to tolerate oral medication should dictate management. Thus. The optimal treatment paradigm has not yet been reported for the ED— however. These patients likely need the best medication up front. For now. Most patients in an ED should receive parenteral medications. it is not always needed. General Approach In outpatient headache medicine.’’ Redosing the same class of medication already used by a patient at home is unlikely to provide relief to a patient. For these reasons.7). a stepwise approach in which stronger medications are used successively will likely not be tolerated by a very uncomfortable ED patient. More research is needed. Second. Although likely to be of benefit. A clinical assessment of fluid status should be performed in all migraineurs. migraineurs in an ED are often suffering severe attacks—parenteral medications will usually relieve the migraine pain more rapidly. especially in patients with pronounced nausea and vomiting. might sometimes be acceptable in patients who have not yet taken any medication at all. migraineurs in the middle of an acute attack suffer from gastroparesis. we will limit the discussion in the following section to parenteral medications.Migraine in the Emergency Department 417 TREATMENT Goals of Treatment As with outpatient headache medicine. . using the stratified care plan (19). This is important for several reasons. tension-type drowsiness. and headaches and hypotension migraine Commonly used as Monitor for first line in EDs akathisias. and use of triptan Phenothiazines/dopamine receptor antagonists Metoclopramide 10–80 mg IV/IM Monitor for Commonly used akathisias. renal or hepatic disease. atherosclerotic vascular disease. electrocardiogram. . and hypotension Useful adjuvant therapy Caution in patients with peptic ulcer disease or renal insufficiency and the elderly Must be given rapidly (under 10 min) Chlorpromazine 25–50 mg IV/IM Prochlorperazine 5–10 mg IV/IM Droperidol 2. dihydroergotamine. as first line in drowsiness.418 Table 2 Commonly Used Medications Medication Triptans Sumatriptan Dose 6 mg subcutaneous Diamond and Friedman Main utility in the ED Early arrivers. considered first line prior to onset of allodynia Considered first line Cautions/ contraindications Hypertension and atherosclerotic vascular disease Ergotamines DHE 0. and hypotension Check EKG prior to Black box warning administration. EKG. headaches drowsiness. should not preclude Monitor for use in intractable akathisias. drowsiness. emergency department. and EDs.5 mg IV/IM Nonsteroidals Ketorolac 30 mg IV/60 mg IM Other Valproic acid 500 mg IV Magnesium 1–2 g IV Failure to respond to first-line medications Failure to respond to first-line medications Abbreviations: DHE. sepsis.0 mg IV/IM (with metoclopramide 10 mg) Hypertension. pregnancy. usually in hypotension combination with other products Effective for episodic Monitor for akathisias. ED.5–1. likely give many emergency physicians pause. If fear of administering a triptan to a patient with an elevated blood pressure prevents the emergency physicians from using this medication. The former include failure to respond or a history of nonresponse or allergy/ intolerance to nonopioid medications.Migraine in the Emergency Department 419 It is unclear why emergency physicians in North American EDs favor opiates over triptans and other migraine-specific medications. Dopamine Receptor Antagonists/Phenothiazines Although not widely used as a primary migraine-abortive therapy in the outpatient population.30). central sensitization most likely has already set in—duration of headache prior to ED presentation is rarely less than eight hours (see Chapter X) (3. and a more complete history has been obtained. then a triptan can be added to another analgesic once the patient’s pain has slightly abated. Physician-centered factors include a lack of knowledge. the blood pressure has gone down. This drug also should not be used in patients on retroviral agents or with significant intercurrent infection. Ergotamines Ergotamines have a long history of successful use in select migraine patients (26). Dihydroergotamine is often combined with a dopamine receptor antagonist. However. The form of triptan that is to be used is not clear. unlike the triptans. the only injectable form is the first-generation sumatriptan. the efficacy of parenteral ergotamines has not been clearly demonstrated in clinical trials (26. Their . should not be used in patients with coronary artery disease.23–25). though not quite as efficacious in the short term as subcutaneous sumatriptan has better pain-relief results at 24 hours (28). or. In triptan-naive patients and over-the-counter (OTC) users. However. their contraindication in patients with atherosclerotic vascular disease and their relative contraindication in patients with poorly managed hypertension. or. and this combination has efficacy (29. a preference for opioids. injectable sumatriptan is likely to produce more success than in patients with frequent migraine attacks on multiple analgesics. by the time patients present to an ED. Other parenteral triptan choices are the nasal spray formulations of zolmitriptan and sumatriptan. like the triptans. A useful paradigm to understand this issue divides reasons into patient-centered factors and physician-centered factors (4). Most ED patients have ‘‘missed the boat’’ for early intervention. the dilemma of the emergency physician is compounded by the fact that patients in pain often have an elevated blood pressure at triage. so it is likely that a parenteral form will be most useful. Dihydroergotamine is often a useful tool for patients with a prolonged migraine attack because of its sustained action. these medications have taken hold in North American EDs. Added to the difficulty of treating a patient in pain about whom not much is known. To date. Although triptans do not seem to cause cardiovascular morbidity in healthy young patients (22).27). lack of willingness to change practice. fear of side effects or contraindications. or poorly managed hypertension. either because of a history of relief with this class of medication or a desire for the associated euphoria. or a disagreement with recommendations based on personal experience. whose brains are more sensitized to frequent migraine attacks. Subcutaneous dihydroergotamine. peripheral vascular disease. Dihydroergotamine. a desire to appease or please the patient because of a desire to avoid confrontation or prevent complaints to administration. The optimal dose of this medication for migraines has not yet been established and might be considerably higher than commonly used (7. their efficacy and tolerability has been at least as good as the more expensive medications (7. this medication should be considered first line. Some authors report rate of akathisias as high as 44% with IV administration of a dopamine antagonist (37. It is difficult to summarize conclusions about this class of medications because there are multiple small trials. though this has not yet been consistently demonstrated in large-scale studies.44). each with different enrollment criteria. Chlorpromazine.420 Diamond and Friedman mechanism of action in migraine patients is unknown but is possibly related to the inhibition of dopamine hypersensitivity (31. However. the ability to perform activities of daily living after receiving the combination of IV metoclopramide and diphenhydramine is probably no worse than migraineurs administered subcutaneous sumatriptan (7). Metoclopramide. It has been shown to be better than placebo (45). Dopamine receptor antagonists have efficacy in tension-type headaches as well (36). though concerns still linger about their ability to allow the return of patients to normal daily activities as rapidly as the triptans. diphenhydramine can be coadministered with the dopamine antagonists (39). In individual double-blind clinical trials. However. In the gravid. and at least as efficacious as prochlorperazine (49. this class of medication is old.34. It has been shown to be better than placebo (48). Because of safety concerns expressed by the Food and Drug Administration. the data consistently demonstrates that this class of medications is effective and safe for migraine headaches. chlorpromazine has been shown to have two-hour pain-free rates significantly better than placebo (40. or potentially gravid patient. Some data suggest that chlorpromazine might be a better monotherapy than dihydroergotamine (42). Further. To prevent akathisias. Despite the sedative effect of each of these two centrally acting classes of medication. the burden of differentiating severe tensiontype headaches from migraines is removed from the emergency physician. Nonsteroidals Ketorolac has enjoyed some efficacy as a parenteral treatment for migraines.5 mg (48).41) and as good as sumatriptan (34). cheap. perhaps in combination with another category B–drug diphenhydramine. this medication should be used with caution. This drug is now available again after a recent short-term absence.50). and metoclopramide (45. Droperidol. Metoclopramide has been shown to be better than placebo and nonsteroidals (43) and at least as good as sumatriptan (7. Common adverse effects of these medications include akathisias and other extrapyramidal side effects.32). There have been no large-scale studies demonstrating the efficacy of the parenteral version of these medications. and known to be safe in considerably higher doses than used in emergency medicine or neurology practice (33). although it tends not to be as efficacious as the other medications discussed above .47). Dose-finding studies have not occurred and the class of medication received adverse publicity when a black box warning was added to droperidol for causing QTc prolongation. By using this class of medication. There is no apparent benefit from dosing more than 2. ketorolac (46). widely used for a variety of indications. Metoclopramide is pregnancy category B and is commonly used during pregnancy. outcomes.38). and comparative agents.35).35). when the parenteral versions of these medications have been compared to the triptans. Prochlorperazine. There might be a role for this medication as part of a multidrug cocktail for migraines (53). nonrandomized trials demonstrated benefit of IV valproate for the treatment of acute migraines.52). Some evidence suggest that one gram of IV magnesium sulfate reduces the duration of migrainerelated photophobia and phonophobia (59). . it serves to enhance the efficacy of other analgesics by increasing absorption or gastric motility. When first-line therapy fails. although considerable practice variation exists among different EDs (8). Corticosteroids are commonly used in intractable migraines. the emergency physician can use ketorolac when uncertain whether the diagnosis is migraine or tension-type headache. but until then.56).51. The role of corticosteroids for the acute attack is unknown. In general. and should be considered in all discharged migraineurs.Migraine in the Emergency Department 421 (29. but trended toward less efficacy when coadministered with metoclopramide (44). Further study is warranted. Magnesium IV magnesium has demonstrated benefit when used alone against placebo (59). this treatment might be tried as rescue therapy. but an oral form of caffeine combined with a nonsteroidal was comparable to a nonsteroidal without caffeine (61). This medication might also have a role for the treatment of admitted patients with chronic headaches (58). Caffeine Although some data suggest that caffeine has efficacy for the treatment of postlumbar puncture headache (60). with headache response of about 60% with 300 to 500 mg of IV valproate (55. Because of the efficacy of this medication in tension-type headache (54). caffeine should not be used as a first-line migraine therapy. Valproate Multiple open-label. randomized controlled trial that we could find reported that IV valproate has no benefit for acute migraines (pain intensity scale did not change before and after treatment) and demonstrated that parenteral prochlorperazine is significantly better for acute migraines (57). It is possible that it has primary efficacy.62). or it merely treats a caffeine-withdrawal headache in certain patients. Corticosteroids Dexamethasone is likely to have benefit in decreasing the incidence of recurrence (24. More research should be done before this medication is used clinically as first-line ED migraine therapy.20). It is also a benign and perhaps useful treatment in the pregnant migraineur. we could find no literature discussing the utility of IV caffeine for migraines. Opiates This class of medication is commonly used in North American EDs (4. However the only blinded.46. The role of this medication in the ED treatment of migraine is unclear. Caffeine is commonly used in OTC migraine preparations. opiates should not be used as first-line migraine therapy because they do not modify the underlying disease mechanism. If a patient has not taken acetaminophen.64). Patients. Consider coadministration of a triptan or a dopamine antagonist along with the opiate. but it seems likely that the migraineur will merely switch their first choice of therapy to a different opiate. With this in mind. Be particularly careful in populations at risk of habituation. the emergency physician avoids a confrontation and eventually discharges a satisfied patient. for example teenagers and patients with substance-abuse histories. Despite guideline recommendations not to use opiates as first-line therapy. this too can be used.422 Diamond and Friedman Patients who receive opiates as first-line therapy tend to have a shorter duration of headache prior to ED presentation and are more likely to have taken a prescription headache medication prior to ED presentation (20). SPECIFIC SITUATIONS Pregnancy The latter half of pregnancy and the immediate postpartum period is known to be a thrombophilic period. By administering the opiate. If the emergency physician is fortunate enough to practice in a health care system with extensive resources. emergency physicians are often placed in a difficult situation when a patient presents with a headache and demands an opiate medication by name. refuses to accept any other treatment. Care of all opiate-seeking migraineurs should be coordinated with the neurologist or headache specialist. IV fluids will not cause harm and might be of benefit. However. then a comprehensive disease management program might be of benefit (65). Whether this maneuver is effective is unknown. . Patients who present with headache during this time period should arouse concerns in their physicians. we present strategies to deal with migraineurs with regard to opiates:  Newly diagnosed migraineurs. Of the medications discussed earlier in this chapter metoclopramide and magnesium are safe and commonly used during pregnancy. should not be allowed to self-prescribe. patients who receive opiates as first-line therapy do not have higher pain scores than patients who do not receive opiates (20). Do not use opiates as first or second line of therapy in this population. Judicious and infrequent use of opiates is appropriate for pregnant patients when absolutely necessary (Table 3). in general. suggesting that these patients are more familiar with their headaches. Opiates should be used as a therapy of last resort. Use of controlled substances is a common feature of ED ‘‘repeaters’’ (12). Some evidence suggests that patients who use opiates for their migraines might be at increased risk of developing chronic headaches (63. Some hospitals and regions have attempted to deal with this patient group by removing meperidine from the hospital’s formulary.  Migraineurs usually treated with opiates and unwilling to try another medication. and there are numerous alternatives that can be given. and often improves after one or two doses of the opiate medication.  Migraineurs usually treated with opiates but amenable to migraine-specific therapy. Find an alternate therapy that allows the gradual removal of opiates from the migraineur’s regimen. This population represents the most difficult of the three groups. . renal insufficiency. magnesium Phenothiazines þ diphenhydramine. DISPOSITION Migraineurs should be discharged once their pain has been adequately controlled and any necessary work-up completed. Patient preference and tolerability should dictate management Need to weigh side effects profile against potential benefit. Similarly. Nauseated Unable to tolerate oral medication Phenothiazines/ dopamine antagonists Elderly As in late pregnancy. the concern for secondary headaches rises substantially in the elderly patient. though they represent a smaller percentage of all ED headaches (67). probably because of the increased frequency of presentation of headaches associated with viral syndromes. In the absence of more data. elderly patients are at risk of oligoanalgesia (66) and their migraine pain should not be ignored.Migraine in the Emergency Department Table 3 Specific Situations Category Pregnancy Reason for concern Teratogenic or laborinducing effects of medication Tolerability Recommended medication Metoclopramide. This is a population in which dopamine receptor antagonists might have a more important role. In the only pediatric clinical trial we could locate. Nasal spray forms of medication might be better tolerated by the youngest migraineurs. Ideal medication in the elderly has not yet been established Superiority of this class of mediation in these patients has not been established Pediatric Elderly Increased incidence of atherosclerotic vascular disease. Pediatrics Scant data are available to guide the pediatric emergency physician. Nonetheless. triptans. We know of no data that specifically reports the efficacy and adverse-effect profile of antimigraine agents in the elderly. Migraines are a common chief complaint in the pediatric ED. ergotamines Comments 423 Nonsteroidals okay in early pregnancy Medical comorbidities less of an issue in this group. pediatric emergency physicians are encouraged to use the medications discussed above. the prevalence of hypertension and coronary artery disease increases with age. parenteral prochlorperazine proved superior to ketorolac (51). 68). The patients who have never received a diagnosis of migraine should be given standard educational material. Recurrent or persistent 24-hour headaches rated as moderate or severe in intensity occurred in 14% to 43% of subjects.424 Diamond and Friedman Data from several clinical trials suggest that ED migraine patients often suffer from headaches after discharge (24. Abbreviation: DHE. Migraineurs who are going home should be warned about recurrence or persistence of headache and given appropriate medication to deal with it when it occurs. . One observational cohort study reported a rate of headache-related functional impairment of 45% in subjects within 24 hours of ED discharge (69). dihydroergotamine. Figure 1 Status migrainosus/intractable migraines.44. available on the American Headache Society website.25. however. especially in a patient with a migraine severe enough for Figure 2 Raskin protocol for status migrainosus/intractable migraines. Source: Refs. 1). PRN. 70. Migraineurs need to be admitted to the hospital in the following situation: Status Migrainosus Intractable Pain. adequately dosed medications that have not proved effective should not be continued. regardless of how long their headache has lasted (Fig. 71. STATUS MIGRAINOSUS/INTRACTABLE PAIN Patients with intractable migraine headaches unresponsive to appropriate ED treatment and rehydration should be admitted to a neurology service for aggressive management of their headache. Abbreviations: DHE.Migraine in the Emergency Department 425 Some data exist to suggest that parenteral corticosteroids substantially decrease the recurrence of migraines after ED discharge. dihydroergotamine. Medicationrebound headache should be considered and excluded as the diagnosis in these patients. . Opiates should not be withheld on principle. It is unclear which inpatient regimen should be used. EKG. This intervention should be considered in all discharged migraineurs (24). electrocardiogram. Lipton RB. Vinson DR. N Engl J Med 2000. Cephalalgia 2002. Vandenberg JT. Some data and clinical experience support the use of corticosteroids (24. et al. Lipton RB. Am J Emerg Med 1994. Treatment patterns of isolated benign headache in US emergency departments. REFERENCES 1. 41:90–97.62) and dopamine antagonists (72. Martinez-Menendez B. Metoclopramide versus sumatriptan for the ED treatment of migraines. Dhopesh V. Use of narcotic analgesics in the emergency department treatment of migraine headache. 9. Headache in an emergency room in Brazil. The medical care utilization and costs associated with migraine headache. Moon C. Use of any of the medications discussed in this chapter the primary treatment section is possibly beneficial. Caplan LR. 19:37–42. 4. Friedman B. 17. Stewart WF. The role of concomitant headache types and non-headache co-morbidities in the underdiagnosis of migraine. Speciali JG. Hurtado TR. Vinson DR. Medication use and disability among migraineurs: a national probability sample survey. 34:172–174. Fridriksson S. Poisson L. Luna-Gonzales H. Herring C. Anwar R. 12:134–137. Lipton RB. 10. Corbo J. Ann Emerg Med 1980.73) in these patients. Lipton R. Lledo A. Ann Emerg Med 2004. Worst headache and subarachnoid hemorrhage: prospective. Edlow JA. et al. Sicuro L. Luda E. Kolodner K. 32:223–228. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: a randomized trial. Comitangelo R. 3. 42:747–753. Celentano DD. though rigorous clinical trials are lacking. Watson WA. Bordini CA. Huber JC Jr. Lainez MJ. Hillman J. 14. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. 13. 16. Ann Emerg Med 1998. 19. The Raskin IV dihydroergotamine/metoclopramide protocol (Fig. 39:215–222. 284:2599–2605. Leotta C. Banwart L. Portera-Sanchez A. Althoff JR. Zilkalns B. Chan BT. Variations among emergency departments in the treatment of benign headache. modern computed tomography and spinal fluid analysis. Neurology 2005. 43:238–242. Diamond ML. 19:1005–1012. Non-traumatic headache in the emergency department. 11. Stewart WF. 28:675–679. Johansson G. Sudden onset headache: a prospective study of features. 32:297–304. Neurology 2002. 12. Morgenstern LB. A retrospective assessment of emergency department patients with complaint of headache. Chronic migraineurs: an important subgroup of patients who visit emergency departments frequently. 5. The symptom of headache in emergency departments. Landtblom AM.426 Diamond and Friedman admission. Johansson I. Headache 1994. Perez-Sempere A. Thomas RW. Ann Emerg Med 2002. Sao Paulo Med J 2000. Edmeads J. Bigal M. Headache 1992. Elston Lafata J. Headache 1988. An evaluation of the role of the ED in the management of migraine headaches. 7. 342:29–36. Health resource utilization of the emergency department headache ‘‘repeater. 8. Maizels M. Colman I. 16:295–301. 22:354–360. Wright SC. 9:404–409. Reed ML. Ovens HJ. 58:S3–S9. Calandre L. Emergency management of headache. 118:58–62. Stone AM. Neurology 2004. Boivie J. incidence and causes. Acute headache of recent onset and subarachnoid hemorrhage: a prospective study. 2) has long been used with success in these patients (70). Rowe BH. . J Gen Intern Med 2004. 20. Sawyer JP. Salomone JA III. Rothney A.’’ Headache 2002. 18. 2. Leicht MJ. The experience of a neurology emergency department. Ital J Neurol Sci 1995. 15. 62: 1695–1700. 6. Headache 1979. Ann Emerg Med 2003. JAMA 2000. Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine. Speechley M. Montoya D. Tek DS. 41. Ann Emerg Med 1995. et al. Drotts DL. 42. Athanasiou E. 24. Dopamine and migraine: a review of pharmacological. 62:563–568. neurophysiological. 25:464–469. 26:265–270. Cephalalgia 1998. 15(suppl 3):171–181. Winner P. Ricalde O. Speciali JG. Ann Emerg Med 1990. Can J Emerg Med 1999:1. 34:469–475. Alessandri M. MacRae KD. Ardagh M. Olsen JC. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. Martinez CGR. Intravenous chlorpromazine in the acute treatment of episodic tension-type headache: a randomized. placebo controlled. Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department: a multicenter study. Vinson DR. 19:1079–1082. Olshaker JS. Silberstein SD. A comparative trial of three agents in the treatment of acute migraine headache. Akpunonu BE. 64:463–468. Bigal ME. Ann Emerg Med 1990. Revista de la Sanidad Militar Mexico 1999. 31:523–524. Klapper JA. Dahlof C. 26. A prospective. Current emergency treatment of severe migraine headaches. Dinsdale HB. 16:758–763. J Emerg Med 2004. Esteban-Morales A. 18:609–611. Neurology 2004. Del Rosso A. and therapeutic data. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. 43:144–166. J Pain Symptom Manage 1999. Respuesta clinica de metoclopramida en comparacion con sumatriptan en el tratamiento de ataques agudos de migrana. 23:141–148. 31. Dimitrakopoulos A. 43. Katsikas M. 29. Ann Emerg Med 1987. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. Linardaki G. double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. 60:537–541. 33. Tsavaris NB. Acad Emerg Med 1995. Headache 1993. pharmacology. Federman DJ. Prochlorperazine induces akathisia in emergency patients. 36.Migraine in the Emergency Department 427 21. Tfelt-Hansen P. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Shuaib A. Neurology 2005. Antiemetic prophylaxis with ondansetron and methylprednisolone vs metoclopramide and methylprednisolone in mild and moderately emetogenic chemotherapy. 123(Pt 1):9–18. J Emerg Med 2002. Triptans in migraine: the risks of stroke. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. Clark JA. Hall GC. Mutgi AB. McCrory DC. and efficacy. Mascia A. Allen CL. Keng JA. Frequency of adverse reactions to prochlorperazine in the ED. Fanciullacci M. Ergotamine in the acute treatment of migraine: a review and European consensus. Funct Neurol 2000. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. biochemical. Headache 2003. Cameron JD. Dillon E. Afra J. Bordini CA. double-blind study. Lee MA. Chavez PT. Bordini CA. 32. 19:1083–1087. Saper J. Dopamine involvement in the migraine attack. et al. Brain 2000. Lane PL. 22. Le Force B. Bell R. McClellan DS. 38. 35. Arq Neuropsiquiatr 2002. and death in practice. 27. 14:209–211. 18:174–182. 23. Macphail I. Kelly AM. Koufos C. Vinson DR. 39. Klapper JA. Schoenen J. Stanton J. 53:180–184. Corbo J. J Accid Emerg Med 1997. O’Connor HM. Arch Neurol 1996. Headache 1991. 53:36–40. cardiovascular disease. D’Antonio J. McEwen JI. Lipton RB. Saxena PR. 18:218–222. 28. Curry C. Friedman BW. Zebic S. et al. Speciali JG. 2:597–602. . Zuniga AS. Treatment of migraine with intramuscular chlorpromazine. Ann Emerg Med 1999. 37. Arthur DC. 33:560–562. 30. 40. Ergotamine and dihydroergotamine: history. Innes G. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Bigal ME. Mo J. 34. Brown MM. 25. Margul B. Am J Emerg Med 2000. Stanton JS. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective. French T. Acad Emerg Med 1998. Droperidol vs prochlorperazine for the treatment of acute headache. J Emerg Med 2004. Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inflammatory drug. crossover study. 40: 720–723. Mendizabal JE. Am J Emerg Med 1996. Bigal ME. Riffenburgh RH. 45. 47. Esses D. 49. 50:507–509. Gallagher EJ. Speciali JG. Karpitskiy VV. 38:621–627. Norton J. 61. Iannaccone R. Lipton RB. 50. 59. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. Silberstein SD. placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Miner JR. Yucel EC. Talu GK. Yucel A. prochlorperazine for benign headaches in the emergency department. Neurology 1998. Singh R. 42:519–522. Rothrock JF. Anderson AC. 57. Acad Emerg Med 2001. 48. Leibold RA. Bordini CA. 43:256–262. Schwartz TH. 38:18–22. March JA. Ann Emerg Med 1995. 26:145–150. Kailasam J. . Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Sohn RS. Neurology 2003. A prospective. double-blind. 52. Cephalalgia 2002. 41:976–980. Seim MB. A randomized. 22:345–353. Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: a randomized. Krymchantowski AV. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Headache 2004. Arch Intern Med 1996. Hayes JE. Chernyschev O. Arq Neuropsiquiatr 2001. double-blind. Duffy SJ. Brousseau DC. 54. Barbosa JS. Ann Emerg Med 2001. 41:847–853. 59:708–711. Treatment of pediatric migraine headaches: a randomized. Opioid therapy and headache: a cause and a cure. Intravenous valproate sodium (depacon) aborts migraine rapidly: a preliminary report. randomized. 5:573–576. 46. Gentry P. Headache 2001. Shrestha M. Tepper SJ. Beyond monotherapy: rational polytherapy in migraine. Young WB. Fish SJ.428 Diamond and Friedman 44. Smith SW. Lipton RB. Randomized. 53. Intravenous valproate sodium in the treatment of daily headache. Swarbrick J. 58. Pack S. double-blind trial of prochlorperazine versus ketorolac. randomized. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Neurology 2004. Peroutka SJ. Mathew NT. Tanen DA. 60. Controlled trial of ketorolac in tensiontype headache. 62. Peroutka SJ. Gracely RH. Ann Emerg Med 2003. Bijur PE. Goldstein J. Corbo J. Coppola M. Jones J. 56. Ann Emerg Med 2004. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Headache 2000. Lyon JA. Jones JB. 51. Moreden J. Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches. et al. Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. Behnke M. 44:136–141. 63. Chun E. Alam AS. 26:541–546. 24:51–54. 156:1725–1728. double-blind trial. Biros MH. Linakis JG. Reg Anesth Pain Med 1999. Edwards KR. Chisholm CD. 55. Miller S. Droperidol vs. Weaver CS. double-blind. placebo-controlled study. 60:315–321. Yealy DM. 8:873–879. Harden RN. Acute migraine treatment with droperidol: a randomized. Headache 1998. 62:1662–1663. Bigal ME. Ozyalcin S. Fink K. Headache 2002. Meadors L. Kolodner K. Rogers D. Dunn KA. double-blind trial. placebo-controlled trial. Erdine S. 14:262–264. Raskin NH. Hershey AD. Maytal J. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. 43:1026–1031. 43:621–627. 65. Schneeweiss S. Emergency management of migraine: is the headache really over? Acad Emerg Med 1998. imaging. Headache 2003. 37:377–382. Nagelberg J. Johnson K. Powers SW. Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Kurth T. and treatment. 66. 70. Kelly KM. Treatment of status migrainosus: the American experience. Headache 2000. Headache 2003. Blonsky J. Incidence and predictors for chronicity of headache in patients with episodic migraine. Raskin NH. Neurology 2004. 71. 73. 5:899–905. Headache 1997. Lee JS. Headache 1990. 40:25–29. Wang SJ. Blumenthal HJ. 14:157–160. Neurology 1986. 107:E62. 36:995–997. 72. Weisz MA. et al. Beaulieu S. Beveridge RC. Age as a risk factor for inadequate emergency department analgesia. Kabbouche MA. Young WB. Saenz V. Maizels M. Headaches in a pediatric emergency department: etiology. LeCates SL. Katsarava Z. 69. . Pediatrics 2001. Ducharme J. Silberstein SD.Migraine in the Emergency Department 429 64. Jones JS. Treatment of primary headache in the emergency department. 67. Impact of a group-based model of disease management for headache. 62:788–790. McNinch M. Kan L. 68. Wirjo J. Mayer RL. Am J Emerg Med 1996. 30(suppl 2):550–553. Droperidol treatment of status migrainosus and refractory migraine. Vockell AL. . As a consequence. CDH disorders may be primary or secondary. several separate proposals for the classification of CDH have emerged. Albert Einstein College of Medicine. Epidemiology and Population Health. U. The Montefiore Headache Center. classification has been controversial (7. and The New England Center for Headache. classification is based on the underlying pathology.27 Progression Forms of Migraine Marcelo E. while the second edition (ICHD-2) (8) has detailed diagnostic criteria for all four types of primary CDH of long duration.2). INTRODUCTION Chronic daily headache (CDH) of long duration is a clinical syndrome defined by headaches that occur for four hours a day or more. on 15 days a month or more. and has a very different definition. New York. new daily persistent headache (NDPH). For the secondary disorders. CDH is one of the most common and disabling headache presentations in neurology centers. Although vastly improved. Bigal Department of Neurology. We discuss TM as the result of episodic 431 . HC. U.A. The Silberstein and Lipton (S-L) criteria have been most widely used (2). Richard B. The term chronic migraine (CM) was introduced in place of TM.A.S. moving it to the appendix. In this chapter we focus on TM. as discussed below. Albert Einstein College of Medicine. Many patients with CDH are severely impaired (5).8). Connecticut. CDH sufferers usually have higher disability than those with episodic migraine (6). and subclassify each of these into subtypes ‘‘with medication overuse’’ or ‘‘without medication overuse’’ (Table 1). over more than three months (1. it afflicts 4% to 5% of the general population (3. the first edition of the International Classification of Headache Disorders (ICHD)-1 (7) included only CTTH. For the primary CDH disorders. recent studies show that the ICHD-2 remains cumbersome for the classification of adults with CDH (9). New York. Lipton Departments of Neurology. and The Montefiore Headache Center.S.4). More recently. New York. New York. chronic tension-type headache (CTTH). The S-L criteria divide primary CDH into transformed migraine (TM). Of these. the ICHD-2 has been considering revising the CM criteria. and NDPH (Chapter 31) are covered in detail elsewhere. CTTH (Chapter 30). Stamford. and hemicrania continua (HC). 7 New daily persistent headache 4. Sufferers usually report a process of transformation over months or years.2 Without overuse 4.8 Hemicrania continua 4. In a study by Mathew et al. EPIDEMIOLOGY OF THE CDHS The epidemiology of CDH has been described in a number of population samples based in Europe. TM is by far the most common type of CDH. and the United States (Table 2) (10). and as headache increases . TRANSFORMED MIGRAINE Most patients with TM report a past history of episodic migraine. headache center. In this setting.1 With overuse 4.4% (Norway) to 4. the Far East. as we will discuss in the following section. the clinical presentation. TM represented 87.4% of the cases of CDH (15). We highlight the strategies for the treatment of TM. From 35% to 50% of CDH sufferers in the population have TM (3).432 Bigal and Lipton Table 1 The Classification of the Chronic Daily Headaches According to the Silberstein and Lipton Criteria Daily or near-daily headache lasting more than 4 hr for more than 15 days/mo 1.2 Without overuse 4.2 Without overuse migraine that progressed over time. The prevalence of CDH is remarkably consistent among studies. and HC is equally rare.11). Clinic-based studies show that CDH response occurs in 10% to 20% of the patients in European headache clinics.8 Transformed migraine 1. The incidence among migraine sufferers in subspecialty care is 13% (13).8. Among subjects with episodic headaches at baseline.9% and 20% vs. of TM is different in adolescents than in adults.7. and potential strategies to avoid its development. the prevalence is 4. TM is more common in adults.2.1 With overuse 2.S. In the United States.2.2 Chronic tension-type headache 2.1 With overuse 1.1%. The relative frequency of the different headache subtypes presenting in a headache clinic is different in adults and in adolescents. CTTH and NDPH are more common in adolescents than in adults (10% vs. In a large study conducted at a U. (16).1 With overuse 4.7. studies show that 50% to 80% of the patients presenting in a headache clinic have TM (15–18).2 Without overuse 2.8. In the United States. Furthermore. 3% developed CDH within one year (12). 77% of the patients with CDH had TM.7% (Spain) (4. 0.8. ranging from 2. Adolescents with TM have a higher frequency of migraine attacks than adults (19). respectively). 10%. although this is likely an underestimation (14).8. The incidence of CDH was investigated in a prospective study in the United States. 0 34 38 Analgesic overuse based on Silberstein (45) criteria. 4þhr/day 15þ/mo Daily CTTH only 18–65 14þ 65þ 20þ 12þ 15þ 65þ 15þ 20þ 4.6 2.7 1.4 2.1 2.4 3.2 2.7 3. female to male prevalence ratio. chronic tension-type headache.2 2.3 2. Abbreviations: CTTH.0 Case definition Age range Total CTTH TM F:M 1.9 2. 4þhr/day 15þ/mo 15þ/mo >180/yr 15þ/mo. TM. F:M. 43.2 4.4 3.1 4.7 3.6 1.4 2.3 2.8 8.383 2096 3377 833 10.3 3.1 1.Table 2 Prevalence of Very Frequent Headaches in Adult Populations Using Silberstein–Lipton Criteria (Ordered by Date of Publication) Prevalence (%) N 2.343 1883 1533 51.6 Analgesic overuse (%) 25 25 Progression Forms of Migraine Author (year of publication) Country Scher (1998) Castillo (1999) Wang (1999) Hagen (2000) Ho (2001) Lu (2001) Prencipe (2001) ´ Lanteri-Minet (2003) Takeshima (2004) 1.7 1.5 United States Spain China Norway Singapore Taiwan Italy France Japan 13. Source: Modified from Ref. 433 .585 5758 15þ/mo 15þ/mo.4 1. transformed migraine. or combination analgesics on 10 days a month or more). Multiple risk factors may be involved in these cases (see chapters for risk factors for CDH). These findings suggest that CM (15 or more days of migraine per month) is the first stage of migraine chronification in most patients. associated symptoms become less severe and frequent (14–17). p < 0. where at least eight of the days fill criteria for migraine or probable migraine. on more than 15 days per month. the proportion of migraine attacks decreased with age (with a proportional increase of tension-type headache attacks). the frequency of migraine attacks diminishes. applying instead probable CM plus probable medication-overuse headache. the ICHD-2 reserves the diagnosis of CM from patients overusing acute medications (simple analgesics on 15 days a month or more or ergotamine. The findings of this study support what is seen in clinical practice and has been taught by headache specialists for many years (Saper et al. In the clinical setting. Subsequently. and both are different evolutive stages of migraine chronification. but transformation may occur without overuse (18).9%) are not (19). triptans. migraine transformation most often is related to acute medication overuse. and coding of the antecedent episodic migraine (Table 3).434 Bigal and Lipton in frequency. We have recently proposed that CM is classified in those subjects with headache lasting more than four hours. the ICHD-2 criteria for CM require that headaches meeting criteria for migraine without aura occur on 15 days a month or more. . TM in adolescents is replete with migraine attacks. First. it was higher in those with shorter interval from the onset of migraine to the onset of CDH (less than five years. and more days of headache resembling tension-type headache than of migraine. and most attacks will lack migraine features. opioids. In the population. The Phenotype of TM Is Not the Same in Adolescents and Adults Differences exist regarding the clinical presentation of TM in adolescents and adults. a diagnosis of NDPH should be assigned (data in press). Second. If the headache begins abruptly.0001). To classify TM. from 71% below the age of 30 years to 22% aged 60 or above. The concept that early in the process of transformation most headache days fill criteria for migraine. CM Is the Early Stage of TM In a recent study of 402 subjects with TM. which does not recognize TM as a separate entity.003). most adults with TM are overusing acute medication (84%). Revising the definition of CM: The terms TM and CM have been used synonymously in the past but this is no longer appropriate: CM has a specific definition in the ICHD-2. personal communication). The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles CTTH. Most adults with TM have less than 15 days of full-blown migraine per month. and in those with a more recent onset of CDH (less than six years. the headache attacks get less typical.. the S-L criteria require 15 days or more of headache (not necessarily migraine) and one link to migraine. most cases of TM are not related to medication overuse (12). Second. Two main differences exist between the S-L (TM) and ICHD-2 (CM) systems. and as disease evolves. with some attacks of full migraine superimposed (2). while most adolescents (58. These findings have implications for the classification of CDH and for our understanding of the natural history of migraine and biology of the transformation process (20). Thus. p ¼ 0. for at least three months. CM is the earlier stage of TM. e.) Progression Forms of Migraine Transformed migraine/ chronic migraine Transformed migraine Description: Migraine headache more than or equal to 15 days/mo for more than or equal to 3 mo and no drug overuse Diagnostic criteria: A. Headache fulfilling criteria C and D for 1. IHS.Table 3 Diagnostic Criteria for Transformed/Chronic Migraine Current ICHD-2 Chronic migraine Headache Proposed Criteria (Bigal et al. Average headache duration of more than 4 hr/day (if untreated) C.6.. Does not meet criteria for IHS chronic tensiontype headache (2. Headache frequency of more than or equal to 15 days/mo for 3 mo B. the default rule is to code such patients according to the antecedent migraine subtype (usually 1. Abbreviations: ICHD.1 migraine without aura.2 migraine with aura.5).1 Migraine without aura) plus 1. International Classification of Headache Disorders. hemicrania continua (4. Not attributed to another disorder When medication overuse is present (i.7 Probable medication–overuse headache. a 435 . fulfilling criterion B for any of the subforms of 8.8) E. or 1. 1. or new daily persistent headache (4.1 migraine without aura on more than or equal to 15 days/mo for over 3 mo B.5 Probable chronic migraine plus 8. on greater than or equal to 8 headache days D.2.2 Medication—overuse headache).3).6 probable migraine. hypnic headache (4. International Headache Society. Not attributed to another disordera A. Headache fulfilling IHS criteria for 1.7). the iron levels were increased in migraine sufferers. Pathophysiology—TM as the Result of Progression of Disease General Considerations Although the source of pain in primary TM is unknown and may be dependent on the subtype. women with migraine with or without aura were at a higher risk of deep white matter lesions. Kruit et al. possibly demonstrating progression of the disease. The white matter lesions increased with attack frequency. p < 0. contribute to the process (22): (i) Abnormal excitation of peripheral nociceptive afferent fibers in the meninges. It is closely related to the trigeminal nucleus. 25. compared with controls. free-radical cell damage. An imaging study has shown that iron deposition occurs in the PAG area in subjects with chronic headaches (23). (iv) Spontaneous central pain generated by activation of the ‘‘on cells’’ in the medulla.436 Bigal and Lipton Figure 1 Evolution of the frequency of headache in subjects that stopped (group 1) or continued analgesic overuse (group 2) after 1 year of follow-up. compared with controls. In this study. used a cross-sectional design to study Dutch adults aged 30 to 60 years. was also supported by an adolescent study. . and (vi) Central sensitization. where those with recent onset CDH were much more likely to have 15 or more migraine days per month (74. They showed that male subjects with migraine with aura were at an increased risk of posterior circulation infarct. Additionally. (iii) Decreased pain modulation from higher centers such as the periaqueductal gray (PAG) matter. These findings may be directly attributable to iron-catalyzed. The authors suggested that iron deposition may reflect progressive neuronal damage related to recurrent migraine attacks. recent work suggests that the following mechanism.5% vs. and in CDH headache sufferers compared with migraineurs.8%. It can be hypothesized that repetitive central sensitization of the trigeminal neurons correlate with iron deposition in the PAG area and.001) (21). (v) Decreased serotonin levels. migraine attacks predispose to disease progression. (ii) Enhanced responsiveness of trigeminal nucleus caudalis neurons. The PAG area is related to descending analgesic network and is important in controlling pain and providing endogenous analgesia. therefore. Evidence of migraine progression also comes from a recent neuroimaging study (24). alone or in combination. It is suggested that repeated central sensitization episodes are associated with permanent neuronal damage. CDH prevalence was inversely associated with educational level. (13). Having less than a high-school education was associated with more than a threefold risk of CDH compared with those with a graduate school–level education [OR ¼ 3. the strongest risk factor for the development of CDH was obesity [OR ¼ 5. are risk factors for migraine progression.01–2.14. Importantly. or widowed individuals [OR ¼ 1. obese migraine sufferers have more severe and frequent headache attacks. overuse of analgesics or other acute-care medications figures prominently (4. and with medication overuse (12). separated.65 (1. it is for CDH. withdrawal headache has been shown in a controlled trial of caffeine withdrawal (28). We recently have shown that although obesity is not a risk factor for migraine. TM and Medication Overuse In most clinical studies of CDH. There are a number of issues with this association that evoke controversy.9–3. using individual studies plus meta-analysis. showed that around 75% of migraine sufferers develop central sensitization (sensitization of the second-order trigeminal neuron. We also found that although not a risk factor for migraine development. which. the risk of new-onset CDH increased nonlinearly with baseline headache frequency. in a longitudinal epidemiologic study.50 (1. and disease progression (26).Progression Forms of Migraine 437 Finally. Burstein et al. compared to normal-weighted subjects.6)]. longer for ergots (three years) and longest for analgesics (five years). preventive treatment refractoriness.15). found that the time required for the development of CDH was approximately five years of exposure to medication and a history of primary headache for ten years prior to that.8)]. Both preventive and acute-care treatment for . with previous head trauma. which is clinically manifested by the development of cutaneous allodynia) during the course of a migraine attack (25). Katsarava et al.3–2.50 (1. CDH was also associated with a self-reported physician diagnosis of arthritis [OR ¼ 2. Finally. A patient develops CDH.4–21.0)] and divorced. usually from three days to three weeks. Is overuse a significant factor in transforming episodic headache into TM? Or is the frequently observed overuse merely a response to chronic pain itself? Although medication rebound has not been demonstrated in placebo-controlled trials. elevated risk was primarily limited to controls with more than about two headaches per month. Risk Factors for the Development of CDH Limited evidence exists about risk factors for migraine progression.56 (2. obesity was comorbid to TM (27). Central sensitization not only explains the progression of attacks.9)] (12). but also may play a role in the progression of the disease itself. Scher et al. after consuming a critical dose of a single medication or a combination of medications for an extended period of time. then.53 (1.3)].2–1. which is shortest for triptans (one to two years).12.3)] or diabetes [OR ¼ 1. per se. A study found that the prevalence of CDH decreased slightly with age and increased in women [Odds Ratio (OR) ¼ 1.51 (1. Central sensitization appears to be associated with triptan refractoriness. (12) showed that 3% of individuals with episodic headache (headache frequency of 2 to 104 days/yr) progressed to CDH over the course of one year. Furthermore. Acute withdrawal of the offending medications worsens headache for a finite time. The authors concluded that the incidence of CDH in subjects with episodic headache is 3% per year.3–53. showed that when nonsteroidal antiinflammatory agents are used daily in large doses for medical conditions. The essential features of an effective treatment regimen include a combination of the following steps: 1. Discontinue all potentially offending medications and caffeine by outpatient or inpatient detoxification procedures 5. Both studies established two principles of medication overuse headache: (i) Even when the overused medication is used for reasons other than headache. low frustration tolerance. behavioral. chronobiologic therapy. followed by an intensive. If patients discontinue their overused medications. and treat psychiatric and somatic comorbidities 4. they . is beyond the scope of this chapter. (ii) Acute medication overuse induces TM only in those predisposed (i.29–31). as well as the treatment of comorbid disorders. In patients with primary TM. it may still be associated with the development of TM. it is important to identify the subtype of TM and evaluate for the presence of analgesic overuse and comorbidities.438 Bigal and Lipton the primary headache usually fail if the offending medication or medications are not terminated (13. et al. Institute a program of acute care and preventive pharmacologic therapy Discussing the nonpharmacologic treatment of TM. Use nonpharmacologic therapies when appropriate:      Biofeedback and relaxation therapy Cognitive behavioral therapy Individual/family counseling as necessary Dietary instructions.e. In an attempt to better understand the relationship between medication overuse and refractory headaches. Wilkinson et al. several fundamental management considerations are important for treatment success in patients with TM (33). and basic prospects to treat and prevent the development of TM. they do not induce CDH in subjects without preexisting primary headache disorders (32). All migraineurs who overused opioids developed CDH (19%). Treatment of Medication Overuse Most studies suggest the benefit and necessity of detoxifying the patient from the overused medication (when present). nonpharmacologic. Patients suffering from long-duration TM often present not only with acute medication overuse. and sometimes physical interventions is usually necessary for a favorable outcome. such as rheumatoid arthritis. Identify. whereas no nonmigraineurs who overused opioids did so. Bahra. those with preexisting episodic migraine). Educate the patient. The Treatment of TM Principles of Treatment As with other lifelong illness. Recently. but also with psychiatric and somatic comorbidity. long-term treatment plan (34–37). as well as physical and emotional dependence. establish expectations and a follow-up plan 2. A combination of pharmacologic. looked for CDH in 28 patients who underwent total colectomy for ulcerative colitis (28). and sleep hygiene Daily exercise program 3.. Herein we focus on the outpatient treatment of medication overuse. address. abrupt discontinuation may be followed by severe abstinence syndrome. and both were more effective than just tapering off the overused medication (37). lack of ability to fall and stay asleep may prevent appropriate medication reduction.i. but presumed to be related to decreased neurogenic inflammation in the meninges. the drug’s side effects. can speed the detoxification process. They are usually the same medications tried for migraine prevention. a very useful technique is to use a three. No mater what medication is being tapered. the patient’s preferences and headache profile. and zolpidem (33). This will prevent withdrawal symptoms (probably by decreasing the release of norepinephrine) and if given in high-enough doses. or t. phenobarbital can be tapered 15 to 30 mg/day. one approach is to taper the opioid 10% to 15% every day over 7 to 10 days. they are usually difficult to treat effectively (Fig. including tricyclic antidepressants. One approach is to taper the overused medication gradually while an effective preventive therapy is established. benzodiazepines.d. Establishing an Effective Preventive Treatment Most of the commonly used preventive agents for TM have not been evaluated in well-designed. dexamethasone starting at 4 to 12 mg/day. tizanidine.Progression Forms of Migraine 439 frequently improve considerably. Thereby.) for seven days. During opioid withdrawal. Table 4 summarizes the medications commonly used in TM. it is important to calculate the average daily dose of medication in order to slowly taper over time. For medications containing butalbital compounds or opioids. Table 5 summarizes an assessment . The mechanism of action is unknown.05 or 0.i. but also supplying a temporary bridge. A second adjunctive therapy is to use a short course of daily triptans in patients who are not overusing them. prednisone starting at 60 mg/day.d.to seven-day taper of oral steroids. there are three outpatient approaches to detoxification. to give the patient the maximum chance to improve without drastically worsening first. Clonidine can be given either by tablet or transcutaneously. Various sleep-promoting medication may help. The choice of a preventive drug is done based on its proven efficacy. Once this switch has been made. which is easier to withdraw.1 mg b. For opioids. For example. thereby avoiding withdrawal (33).d. and subsequently taper the transitional medication. for patients suspected of overusing butalbital compounds. A more controlled approach is to change the overused butalbital to longer-acting phenobarbital. double-blind studies. during opiod withdrawal. One approach is to reduce the dose of one tablet every three to five days. and if they do not. For each 100 mg butalbital.5 mg. one could use daily naratriptan (2. The clinician should select the drug with the best risk-to-benefit ratio for the individual patient and minimize the side effects that are most important to the patient.i. The second strategy is to abruptly discontinue the overused drug. b. atypical antipsychotics. Basically. an equivalent dose would be 30 mg phenobarbital in divided doses throughout the day. A recent study showed that transitional therapy with naratriptan was as effective as transitional therapy with prednisone. adding a preventive medication rapidly. and the presence or absence of coexisting or comorbid disease. institute a transitional medication (medication bridge) to break the cycle of headache. It usually helps to add clonidine 0. or methylprednisolone. The third approach is to combine the two strategies by eliminating the rebound medication rapidly. 1). tricyclic antidepressants.i. MAOIs.5–225 mg/day 15–45 mg/day 25–100 mg/day 50–200 mg/day 20–200 mg/day 30–240 mg/day 10–30 mg/day 120–720 mg 40 mg t.d. TCA. .05–0. 30–60 mg t.i. monoamine oxidase inhibitors. Abbreviations: CDH. 10–40 mg/day 2.d.5–3 mg/day 5–20 mg/day 10–40 mg/day 25–100 units (IM)/3 month 50–82 mg/day 400–600 mg/day 400 mg/day 75 mg b. intramuscular.i. selective serotonin reuptake inhibitors.5–10 mg/day 10 mg/day 2–12 mg/day 2–16 mg/day 1.d. Evidence for moderate efficacy from at least two well-designed placebo-controlled trials.440 Bigal and Lipton Table 4 Selected Preventive Therapies for Migraine That May Be Used in the Treatment of CDH Generic treatment doses Alpha2-agonists Clonidine tablets Anticonvulsants Divalproex sodium tabletsa Gabapentin tabletsa Levetiracetam tablets Topiramate tabletsa Zonisamide capsules Antidepressants MAOIs Phenelzine tablets TCA Amitriptyline tabletsa Nortriptyline tablets SSRIs Fluoxetine tablets Sertraline tablets Paroxetine tablets Venlafaxine tabletsa Mirtazapine tablets Beta-blockers Atenolol tabletsa Metoprolol tablets Nadolol tablets Propranolol tabletsa Timolol tabletsa Calcium-channel antagonists Verapamil tabletsa Nimodipine tablets Diltiazem tablets Nisoldipine tablets Amlodipine tablets Flunarizine Serotonergic agents Methysergide tabletsa Cyproheptadine tablets Pizotifen tabletsa Miscellaneous Monteleukast sodium tablets Lisinopril tablets Botulinum toxin A injection Feverfew tablets Magnesium gluconate tablets Riboflavin tablets Petasites 75 mga a 0.3 mg/day 500–1500 mg/day 300–3000 mg/day 1500–4500 mg/day 50–200 mg/day 100–400 mg/day 30–90 mg/day 30–150 mg/day 30–100 mg/day 10–40 mg/day 25–100 mg/day 10–30 mg/day 37. chronic daily headache. IM. SSRIs. and pain Depression and OCD Refractory depression Mania. 31. migraine and episodic tensiontype headache) are now conceptualized not just as an episodic disorder. angina. depression. and heart block Mania Unreliable patient Flunarizine Antidepressants TCAs 4þ 2þ Aura. Source: From Ref. but as a chronic episodic and sometimes chronic progressive disorder. epilepsy. some episodic headaches (i. safety. insomnia. anxiety. Preventing disease progression in migraine has already been added to the traditional goals of relieving pain and restoring . congestive heart failure. and diabetes Obesity Angina and vascular disease 441 Drug Beta-blockers Relative indication based on comorbidity Hypertension and angina Antiserotonin Pizotifen Methysergide Calcium-channel blockers Verapamil 4þ 4þ 2þ 4þ Orthostatic hypotension 2þ 1þ Constipation and hypotension Parkinson’s and depression Mania..e. and anxiety 4þ 2þ SSRIs MAOIs Anticonvulsants Divalproex/ Valproate Gabapentin Topiramate 2þ 4þ 1þ 4þ 4þ 2þ 4þ 2þ 2þ 2þ Liver disease and bleeding disorders Liver disease and bleeding disorders Kidney stones Based on studies for migraine. and anxiety Mania. Abbreviations: SSRIs. hypertension. and asthma Dizziness and vertigo Depression. Ratings are on a scale from 1þ (lowest) to 4þ (highest) based on the strength of evidence. and evidence for a number of agents that may be useful in the preventive treatment of TM based on the efficacy for episodic migraine. selective serotonin reuptake inhibitors.Progression Forms of Migraine Table 5 Choices of Preventive Treatment for Transformed Migraine* Efficacy in the treatment of migraine 4þ Adverse events 2þ Relative contraindication Asthma. monoamine oxidase inhibitors. PROSPECTS FOR PREVENTING HEADACHE PROGRESSION Based on recent data. mania. epilepsy. Ongoing research and new emerging therapeutic strategies should consider this change in the conceptual model of migraine and TM. MAOI. and anxiety Obesity. Raynaud’s disease. epilepsy. à of the efficacy. urinal retention. Schroevers M. Tepper SJ. Headache Classification Committee of the International Headache Society. Emerging treatment strategies to prevent disease progression include risk factor modification. Rapoport A. Pascual J. Headache 1994. REFERENCES 1. Lipton RB. Headache 2003. Scher AI. detox protocols Relaxation techniques. 4. 9. chronic daily headache.442 Bigal and Lipton Table 6 Risk Factors for TM Development and Strategies to Address Them Not readily modifiable Sex: female Low education/socioeconomic status Head injury Modifiable Attack frequency Central sensitization Obesity Strategies to address modifiable risk factors Preventive treatment Early acute migraine interventions Diet. Stewart WF. Sliwinski M. Tepper SJ. 6. Spierings ELH. addressing depression when present Assessing sleep disturbances. Headache 1998. 43(4):336–342. Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria. 8(suppl 7):1–96. 3. Classification and diagnostic criteria for headache disorders. 2. et al. 44(7):684–691. 5. Honkoop PC. 8. 34:1–7. 38:497–506. Silberstein SD. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Headache 1999. Bigal ME. 38:497–506. and facial pain. 47:871–875. Bigal ME. Headache Classification Committee of the International Headache Society. Silberstein SD. Liberman J. Mathew NT. Sheftell FD. use of preventive therapies. 40:306–310. Solomon S. (suppl 1):1–160. Lipton RB. biofeedback. treating sleep apnea when present Medication overuse Stressful life events Snoring Abbreviation: CDH. cranial neuralgias. Prevalence of frequent headache in a population sample. Munoz P. Second Edition. Classification of daily and neardaily headaches: proposed revisions to the IHS criteria. Headache 2004. Neurology 1996. Cephalalgia 1988. patients’ ability to function. Classification and diagnostic criteria for headache disorders. Lipton RB. Guitera V. . Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Cephalalgia 2004. and facial pain. Sheftell FD. Rapoport AM. Epidemiology of chronic daily headache in the ˜ general population. 7. using preventive medications that do not increase the weight Limiting the consumption of acute medications. Headache 2000. preventive treatment. cranial neuralgia. Chronic daily headache: a time perspective. Castillo J. Lipton RB. Ranke AH. and possibly the use of triptans as early as possible in the course of a migraine attack (Table 6). 43:179–190. Katsarava Z.Progression Forms of Migraine 443 10. Burstein R. Medication-overuse headache: a worldwide problem. 14. Liberman M. Nagesh V. 25. Kurth T. Ricci JA. Sorbi M. 32. Diener HC. et al. Lipton RB. Bajwa ZH. 41:629–637. Honkoop PC. In press. 26. Hagen K. Presentation of chronic daily headache: a clinical study. 106(1–2):81–89. 25(7):482–487. Lancet Neurol 2004. Perez F. Bigal M. Reuveni U. Cephalalgia 2005. Dodick DW. Dyb G. Bigal ME. Tepper SJ. Lipton RB. Bahra A. Goadsby PJ. Ann Neurol 2004. Scher AI. Lipton RB. Wilkinson SM. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Bigal ME. 19(6):483–497. Neurology. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. In press. Sheftell FD. Ransil BJ. Menon S. Cephalalgia 2005. Rapoport AM. Gelman N. An association between migraine and cutaneous allodynia. Chronic daily headache: nosology and pathophysiology. Zwart JA. Spierings EL. CNS Drugs 2005. Dowson AJ. Diener HC. Classifying migraine patients with primary chronic daily headache consensus statement from the American Headache Society. Medication overuse headache in patients with primary headache disorders: epidemiology. Bigal ME. Neurology 2001. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. et al. Factors associated with the onset and remission of chronic daily headache in a population-based study. Incidence and predictors for chronicity of headache in patients with episodic migraine. . Curr Pain Headache Rep 2002. Limmroth V. severity and disability. Migraine days decline with duration of illness in adolescents with transformed migraine. Bigal ME. 31. Scher AI. Heine JA. Headache 1998. Transformed or evolutive migraine. 62:788–790. Tepper SJ. Chronic migraine is the early stage of transformed migraine. Body mass index and headache: associations with attack frequency. 38:191–196. Fritsche G. Yarnitsky D. Liberman J. 27. Migraine days decline with duration of illness in adolescents with transformed migraine. Limmroth V. Neurology 2004. Welch KMA. 13. 25(7):482–487. Mathew NT. Headache 2001. Svebak S. Tepper SJ. 22. 27:102–106. Becker WJ. Rapoport AM. 63(5):843–847. Hofman PA. Headache 1987. 20. Stewart WF. 11. Goadsby PJ. Lipton RB. Goor-Aryeh I. 21. Sheftell FD. 55:27–36. Ann Neurol 2000. 23. Neurology 2004. 29. van Buchem MA. 19. Lipton RB. Welch KM. Migraine as a risk factor for subclinical brain lesions. Schroevers M. 17. Cephalalgia. Walsh M. Curr Opin Neurol 2002. 28. Dodick D. Primary chronic daily headache and its subtypes in adolescents and adults. Sheftell FD. In press. 47:614–624. 16. Pain 2003. 12. Kruit MC. Opioid use to control bowel motility may induce chronic daily headache in patients with migraine. et al. 22(6):432–438. 61(2):160–164. Burstein R. Risk factors for chronic daily headache. 57(9):1694–1698. management and pathogenesis. Rapoport AM. Holmen J. 15. Stewart W. 15(3):287–295. Lipton RB. Schneeweiss S. 24. Analgesic use: a predictor of chronic pain and medication overuse headache: the Head-HUNT Study. 41:303–309. Lipton RB. Neurology 2003. Jakubowski M. 18. Katsarava Z. Aurora SK. Limmroth V. Neurology. 30. Muessig M. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001. 3(8):475–483. 6(6):486–491. Lipton R. 291:427–434. Headache. JAMA 2004. Silberstein SD. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 2003. Overuse of symptomatic medications among chronic (transformed) migraine patients: profile of drug consumption. . In: Crombie IK. Seattle. Epidemiology of Pain. Tepper SJ. et al. Washington: IASP Press. Headache 1991. 61:43–47. Tepper SJ. Lipton RB. 42:483–490. Diener HC. Andrasik F. Subcutaneous sumatriptan in the treatment of headache during withdrawal from drug-induced headache. 39. 34. Scher AI. Transformed migraine and medication overuse in a tertiary headache center—clinical characteristics and treatment outcomes. Cephalalgia 2004. Grazzi L. 1:233–245. 36. Headache Care 2004. Moreira PF. Out-patient detoxification in chronic migraine: comparison of strategies. Migraine and headache. A meta-analytic approach. 23(10):982–993. Headache 2002. Rapoport AM. Sheftell FD. Stewart WF. Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Haab H. Sheftell FD. 35. Lipton RB. 31:205–209. 1999: 159–170. Cephalalgia 2003. Bigal M. Rapoport AM. D’Amico D. Krymchantowski AV. 38. 24(6):483–490. Arq Neuropsiquiatr 2003. Bigal ME. Peters C. ed. 37. Chronic daily headache—an update. Krymchantowski AV. et al.444 Bigal and Lipton 33. It is now generally accepted that migraine is a disorder where the initial dysfunction occurs centrally in the brain.A. Cleveland. However. Ergotamine tartrate.28 The Future of Migraine Therapies Todd Schwedt Department of Neurology.S. Arizona. the transmission of nociception along 445 . but also revolutionized in our understanding of the fundamental anatomy. which were introduced in 1884. and the scientific rationale that selective constriction of cranial arteriovenous anastomoses would correct the underlying cause of the pain of migraine headache (2–4). Triptans were developed as cranial vasoconstrictors to mimic the desirable effects of serotonin while avoiding its unfavorable adverse effects (2). David Dodick Mayo Clinic College of Medicine.S. The understanding that the common final denominator of migraine pain is the activation and. Advances in our understanding of the receptors expressed on trigeminal afferents and the neuropeptides most important in initiating and maintaining the pain of migraine has led to the development of highly selective receptor targets whose modulation would inhibit the release of these neuropeptides. the sensitization of peripheral and central trigeminal nociceptive pathways has led to the development of highly selective compounds designed to inhibit the release or antagonize the downstream effects of neuropeptides released at the trigeminovascular junction or at the central trigeminal synapse (Fig. triptans not only changed the way clinicians managed acute migraine attacks. The Cleveland Clinic Foundation. in many cases. Ergots. 1). was the mainstay of acute migraine therapy until the introduction of the triptans approximately 15 years ago (1). and molecular mechanisms involved in the initiation and transmission of pain associated with migraine headache. were the first class of medications that targeted what at that time was felt to be the etiology of migraine pain—vasodilation of the cerebral and extracranial vasculature. physiology. In this way. Scottsdale. a pure ergot alkaloid that was isolated in 1920. with the vascular changes being secondary to neuropeptide transmission at the trigeminovascular junction (5).A. INTRODUCTION Attempts to alleviate the suffering caused by migraine span millennia and encompass treatments as primitive as trepanation of the skull to increasingly specific medications. Ohio. U. The developmental rationale was based on the clinical efficacy of serotonin and methysergide. U. CGRP receptors are located on smooth muscle cells of blood vessels. A1. Nitric oxide release from the vascular endothelium may be stimulated by activation of 5HT-2B receptors. In the future. ORL-1. adenosine A1. nitric oxide. CGRP antagonists inhibit neurogenic vasodilation mediated by CGRP release from trigeminal nerve terminals. The same receptor targets exist at the central synapse within the trigeminal nucleus caudalis. vanilloid receptor. are thought to terminate migraine through neuronal and vascular effects along the trigeminal vascular system. This discussion will focus on some of these highly selective compounds. ionic and metabotropic glutamate receptors. as we learn the mechanisms involved in activating or disinhibiting the trigeminal system. opioid receptor–like receptor. NMDA/GluR5. which are 5-HT1B/1D/(1F) agonists. 5-HT. Abbreviations: CGRP. NO. VR1.446 Schwedt and Dodick Figure 1 Trigeminal receptor targets at the trigeminovascular junction. TRIGEMINAL RECEPTOR TARGETS Serotonin (5-HT) Receptor Triptans. calcitonin gene–related peptide. peripheral and central trigeminal pathways would be interrupted and pain would be ameliorated or terminated without the need for drugs or the inherent risks associated with drugs that cause vasoconstriction. Inhibition of neuropeptide [calcitonin gene–related peptide . serotonin. The majority of novel receptor targets for acute migraine therapy reside on the trigeminal nerve terminal endings and are devoid of vasoconstrictor effects. we will unquestionably move closer to the ultimate goal of developing safe and effective compounds to prevent the initiation of migraine attacks. Vasoconstriction of cranial blood vessels is believed to be mediated through the 5-HT1B receptor subtype. but also by activation of inducible and neuronal nitric oxide synthase. 60. 5-HT1F Receptor Most of the triptans currently used for the treatment of migraine are potent agonists at the cloned human 5-HT1F receptor (12). Phase I trials of orally and intravenously administered LY334370 showed its safety and tolerability (19. Headache response. meningeal. Selective 5-HT1F agonists have been shown to inhibit neurogenic inflammation in animal models of migraine (13–15). A randomized. dose-escalation study in which 39 subjects received doses from 1 to 100 mg (9). Two of 34 patients receiving the study medication reported chest pain and three had QTc prolongation on electrocardiography. placebo-controlled study using a 50 mg oral dose of PNU-142633 for the acute treatment of migraine with or without aura failed to show a significant treatment effect compared to placebo (10). Although this was a failed trial. drug discovery programs were established to search for compounds that selectively act at the 5-HT1D and 5-HT1F receptor systems while being devoid of activity at the 5-HT1B receptor. double-blinded study randomized migraine patients to receive 20.The Future of Migraine Therapies 447 (CGRP)] release. The most common adverse effects were headache and dizziness with no serious adverse events reported. The safety and tolerability of PNU-142633 was established in a phase I. the clinical failure of this compound may reflect the use of a poor 5-HT1D agonist at the human receptor than a failure to terminate migraine by agonizing the 5-HT1D receptor. There was no electrocardiographic evidence of cardiac ischemia after administration of the drug. Because of the presence of 5-HT1B receptors on peripheral and coronary vascular beds. and coronary arteries (8). the preclinical efficacy of 5-HT1D agonists supports continued development of this class of compounds. double-blind. neurogenic inflammation. and firing of trigeminal afferents is likely mediated by the agonist activity of triptans at 5-HT1D and 5-HT1F receptors located on the presynaptic nerve terminal endings at the trigeminovascular junction and central synapse (5. . and was a poor brain penetrant (11). dizziness. Initial in vivo tests suggested that LY334370 exhibits high selectivity for the 5-HT1F receptor with no significant 5-HT1A agonist activity (17.6). the potential for serious adverse vascular events limits the broad utility of triptans by posing safety concerns in certain populations (7). it was a relatively weak agonist when compared to sumatriptan in in vitro studies. Adverse events with oral doses up to 200 mg and IV doses up to 20 mg included transient and mild to moderate asthenia.18). Therefore. Consequently. A placebo-controlled. or 200 mg of LY334370 versus placebo for the acute treatment of migraine (21). and paresthesias. The selective 5-HT1F receptor agonist LY334370 has a high affinity for the 5-HT1F receptor with a more than 50-fold binding selectivity over all other serotonin receptors except 5-HT1A (16). single-dose. somnolence. pain-free. There is no evidence of a vasoconstrictive effect of the drug on carotid. 5-HT1D Receptor PNU-142633 is a highly selective 5-HT1D agonist with at least 1000-fold selectivity for the 5-HT1D receptor compared to the 5-HT1B receptor (8). As this compound was developed using gorilla 5-HT1D receptors.20). doubleblind. Preclinical study of PNU-142633 in animal models suggests that the drug is effective in blocking neurogenic inflammation and the increase in trigeminal nucleus blood flow normally elicited by stimulation of trigeminal afferents. . and sustained pain-free rates after two hours were significantly better in the 60 and 200 mg treatment groups as compared to the placebo group. and support the concept that drugs with a neuronal mechanism of action. d-. The heptadecapeptide nociceptin/orphanin FQ (N/OFQ—nociceptin) has been identified as the endogenous ligand for the ORL-1 (NOP1) receptor. and nocistatin. Unfortunately. Eighty percent of patients who received the 200 mg dose of LY334370 reported at least one adverse event. However. nitric oxide synthase (NOS). The relevance of these findings to human migraine is based on the recent observations that the A1 receptor protein is localized in human trigeminal ganglia and two selective A1 receptor agonists. 11 of 21 (52%) having sustained response. an N/OFQ antagonist. The lack of an effect on resting vascular tone and the inhibition of the nociceptive blink reflex make A1 receptor agonists potentially feasible for the acute treatment of migraine.448 Schwedt and Dodick sustained response. and pituitary adenylate-cyclase activating peptide. although opioid ligands do not activate the ORL-1 receptor (27). 8 of 21 (38%) pain-free. substance P. it has been suggested that it be included in the opioid receptor family with the name of NOP1 (26). or k-receptors (28). further study of this compound was halted due to systemic toxicity of the drug in animals. which are devoid of vasoconstrictor activity. The 200 mg treatment group showed the most benefit with 15 of 21 (71%) patients showing response. and appears to be a predictive preclinical animal model for effective acute antimigraine compounds. nociceptin inhibits neurogenic dural vasodilatation (31) elicited by stimulation of trigeminal sensory nerve endings innervating meningeal vessels (32). Due to structural similarities with the other known opioid receptors. Nociceptin immunoreactivity and ORL-1 mRNA have been detected in human and cat trigeminal ganglia where it was shown to be colocalized with CGRP. has been shown to reverse nociceptin-induced analgesia (33). thereby preventing activation of central trigeminal neurons (25). particularly dynorphin A. Furthermore. a rate higher than that seen with conventional triptans. suggesting a role in trigeminal sensory transmission and trigeminovascular regulation (30). Adverse events were similar to those recorded in phase I trials. and 7 of 21 (33%) with a sustained pain-free response at two hours. Recent findings suggest that the analgesic effect of adenosine may be mediated by the adenosine A1 receptor (22). These early studies suggest that agonists specific for 5-HT1F receptors are effective for the acute treatment of migraine. it does not bind to opioidergic m-. GR79236 (23) and GR190178 (24) have been shown to inhibit the peripheral release of CGRP in the cranial circulation as well as at the central trigeminal synapse. DRUGS TARGETING THE ORL-1 RECEPTORS A novel neurotransmitter receptor referred to as opioid receptor–like (ORL)-1 receptor has been identified. nor are the effects of nociceptin antagonized by naloxone (29). Nociceptin seems to be involved in several biological systems and may play a role in central nociceptive processing (29). Neurogenic vasodilation is mediated predominantly by CGRP release from trigeminovascular nerve terminals. may be effective acute antimigraine agents. ADENOSINE RECEPTORS Adenosine has an established antinociceptive effect in humans. While the evidence for elevated levels of glutamate in migraine sufferers is conflicting. GLUTAMATE RECEPTORS Glutamate. Of 45 patients who were enrolled in the study. The discovery that 5-HT1B/D/F receptor–positive neurons in the trigeminal ganglion (TG) are also glutamate-positive suggests that 5-HT1 agonists may inhibit the presynaptic release of glutamate (42). l-glutamate excites trigeminal nucleus caudalis (TNC) neurons (37). Capsaicin-induced dural vessel dilation is antagonized by capsazepine (VR1 antagonist) and a CGRP receptor blocker (CGRP8–37) (36). glutamate levels rise in the extracellular substrate of the TNC following noxious stimuli to the trigeminal nerve (38). In the clinical studies done to date. This finding suggests that VR1 receptor activation may lead to CGRP-induced vasodilation at the trigeminovascular junction. or placebo (n ¼ 16). given the recent evidence suggesting that approximately 70% of migraine sufferers experience central sensitization during acute migraine attacks (45). There is an emerging body of preclinical and human evidence to suggest that glutamate may play a pivotal role in the pathogenesis of acute migraine attacks. and metabotropic glutamate receptors have been identified on peripheral and central trigeminal pathways (39–41). N-methyl-D-aspartate. 6 mg subcutaneous sumatriptan (n ¼ 15). LY293558 is an AMPA/KA receptor antagonist and has been tested for the treatment of migraine and pain (46–48). single-attack study where patients received LY293558 1. Furthermore. This was a multicenter. Painfree rates were high for LY293558 (54%) and sumatriptan 6 mg (60%). and are present on neurons in the human trigeminal ganglia (34). and therefore. transient dizziness.2 mg/kg IV (n ¼ 13). randomized. and sedation.The Future of Migraine Therapies 449 The ORL-1 receptor may therefore offer another selective trigeminal receptor target for acute antimigraine drug development. VANILLOID RECEPTORS Vanilloid type 1 (VR1) receptors are activated by capsaicin. a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA). . Intravenous capsaicin promotes the release of the proinflammatory neuropeptides from trigeminal neurons and has been shown to cause dural extravasation and dural vessel dilation in the rat (35). has been implicated in the pathogenesis of migraine. the VR1 receptor is potentially a feasible target for the development of antimigraine compounds. and low for placebo (6%). and particularly in those with migraine with aura (43. 44 completed it. several studies have reported higher glutamate plasma levels in migraineurs compared to controls. the central role of glutamate in the development of central sensitization supports a role for this excitatory neurotransmitter in acute migraine attacks. adverse events reported with LY293558 included mild. especially during attacks. located on small and medium-sized neurons that are either unmyelinated C-fibers or thinly myelinated Ad-fibers. placebo).017 vs. In addition. and 25% for placebo. The potential role of LY293558 specifically in migraine has been investigated in a small pilot study in patients with moderate to severe migraine attacks (47). the most abundant excitatory neurotransmitter in the central nervous system. In animal models. Also in animal studies. 86% for sumatriptan 6 mg SC. Two-hour headache response rates were 69% for LY293558 (p ¼ 0. visual distortion.44). kainate (KA). improvement in nausea. weak oxygen radical. This data suggests that antagonizing the effect of CGRP may provide acute relief of migraine headache. human. BIBN 4096 BS is the first. the rate of sustained response over 24 hours.450 Schwedt and Dodick Collectively. Adverse events were reported in 25% of patients receiving the 2. two-thirds of which occurred after the 10 mg dose. highly potent. photophobia. were considered mild to moderate in severity. the rate of recurrence of headache. and consisted mostly of paresthesias. double-blind trial examined the effectiveness of BIBN 4096 BS for the acute treatment of migraine (56). All 10 patients receiving CGRP. respiratory rate. Intravenous doses between 0. or forearm blood flow. phonophobia. Animal studies and in vitro studies of human cerebral arteries have shown BIBN 4096 BS to be an effective antagonist at the CGRP receptor (54). CGRP levels are increased in the external jugular venous blood during spontaneous migraine attacks with normalization of levels after treatment with sumatriptan (50. In migraine sufferers. placebo-controlled. placebo-controlled.5 mg dose. stimulation of TG fibers results in release of CGRP. but only one patient in the placebo group. with a response rate of 66% as compared to 27% for the placebo. Eight of the 41 volunteers reported at least one adverse event. A group-sequential adaptive treatment assignment design was used to minimize exposure of patients to nonefficacious doses and to identify the lowest dose superior to placebo evidenced by a rate of response of at least 60%. NOS INHIBITORS Nitric oxide (NO) is an endogenously synthesized short-lived vasodilator. although tolerated best at doses below 10 mg. Response was defined as the reduction of severe or moderate headache at baseline to mild or no headache at two hours. the second messenger of NO. the effect of human CGRP infused intravenously was studied in 10 patients with frequent migraine headache (52). The 2. There were no clinically relevant changes in blood pressure. leading to neurogenic vasodilation (49). The safety and tolerability of BIBN 4096 BS was established in a double-blinded. experienced headache within 12 hours of infusion. crossover study.51). Overall. and the time to meaningful relief. CGRP RECEPTOR ANTAGONISTS CGRP is one of the several neuropeptides found within the sensory terminals of the trigeminal nerve. BIBN 4096 BS was also found to be superior to placebo in regards to: the pain-free rate at two hours. In a double-blind. and clinical trial data suggest a pathogenetic role for glutamate in acute migraine attacks and supports future research into the clinical effects of glutamate receptor modulators for the treatment of migraine. pulse rate. electrocardiogram. the safety and tolerability of BIBN 4096 BS was favorable. laboratory tests. Platelet levels of cyclic guanosine monophosphate. and functional capacity. Adverse events consisted of paresthesias and fatigue. and NO metabolites such as nitrate/nitrite are increased . All patients were headache free at the time of infusion. infusion of human CGRP induces migraine-like headache (50). and neurotransmitter that has been implicated in the pathogenesis of migraine headache (57). single-rising dose design study of healthy volunteers (55). randomized. this preclinical.1 and 10 mg were administered to 41 volunteers. There were no serious adverse events. In animals. randomized. A multicenter. nonpeptide CGRP receptor antagonist with a high affinity and specificity for the human CGRP-receptor–(53).5 mg dose was chosen. 61). The effect of an NOS inhibitor. have been demonstrated to cause a delayed (four to six hours) but typical migraine headache in migraine patients (60. with afferent input from the dura mater. Three of the 10 patients in the treatment group who responded by two hours required rescue medication for headache after two hours. significant alterations in the systemic arterial blood pressure and heart rate would be unacceptable. Intravenous infusions of glyceryl trinitrate (GTN). Although patients reported only minimal symptomatic adverse effects after infusion of 546C88. Identification of genetic variants that increase susceptibility to migraine and specific migraine subtypes will lend further knowledge regarding the pathophysiology of migraine headache and the most effective treatment options. 10 of 15 patients who had received the NOS inhibitor experienced headache relief as compared to 2 of 14 placebo-treated patients. The treatment group received intravenous infusion of 546C88. present to a large extent in dural macrophages and responsible for the delayed neurogenic inflammatory response seen after GTN infusion. As compared to placebo. the only known autosomal dominant migraine subtype. at 6 mg/kg. Extracellular impulse activity was recorded from neurons in the rat spinal trigeminal nucleus.59). the induction of dural mast cell degranulation and dural plasma protein extravasation (neurogenic inflammation) has been demonstrated in animal models after an infusion of GTN (62). L-NG methylarginine hydrochloride (546C88). PHARMACOGENOMICS Migraine is a complex genetic disorder. encoding a brain-specific P/Q-type calcium channel gene. was tested in a controlled study in which 15 patients received the experimental therapy and were compared to historical placebo controls (64). and inducible (65). However. infusion of an NOS inhibitor significantly reduced neuronal activity. . neuronal. likely governed by multiple genetic factors that may differ from patient to patient. While the mechanism underlying the ability of NO to induce migraine is unclear. and histamine. and the ATP1A2 gene on chromosome 1. a stimulator of NO release from vascular endothelium. during an acute attack of migraine without aura. This occurs because of delayed induction of gene and cytokine expression with the production of inflammatory mediators such as interleukin (IL)-1b and IL-6 (62). Two hours after infusion. has been mapped to the CACNA1A gene on chromosome 19 (66). suggesting that NO plays a role in the ongoing activity of sensitized neurons in the trigeminal nucleus.The Future of Migraine Therapies 451 at baseline in migraine sufferers and rise further during attacks (58. It is noteworthy that 546C88 is a nonspecific NOS inhibitor acting on all three types of NOS: endothelial. Four of the remaining seven patients in the initial response group had headache recurrence within 4 to 16 hours after infusion. The effect of NOS inhibition on neuronal activity in the trigeminal nucleus has been studied in the rat (63). This study suggests that NOS inhibitors may be effective in the acute treatment of migraine. The development of more specific NOS inhibitors that target inducible NOS. there were significant but asymptomatic increases in mean arterial pressures (maximum 17%) and decreases in heart rate (maximum 21%). Familial hemiplegic migraine. is desirable and may prove to be effective for the treatment of migraine. Understanding molecular mechanisms of migraine at an individual level will allow for the development of new classes of more specific acute and prophylactic migraine therapies. an exogenous NO donor. Multiple gain-of-function phenotypes result from the creation of a knock-in mouse model carrying the human mutation in the CACNA1A gene (67). has led to a host of molecular targets for acute migraine therapy that may not only prove effective. Both of these mutations cause disturbances in ionic flux across neuronal membranes. one could not postulate that DHE and sumatriptan would have differing effects in patients with these polymorphisms. Although the contribution of CACNA1A mutations in more common forms of migraine awaits further study.72). The identification of genetic mutations in familial hemiplegic migraine. and abnormalities in neuronal excitability. while molecules that selectively inhibit the firing of central trigeminovascular neurons may provide effective prevention for those with or without aura. Compounds that block cortical spreading depression may prove useful in those patients who have migraine with aura. as well as the neuropeptides involved in neurogenic vasodilation and central trigeminal activation. among other features. Future research in the pharmacogenomics of migraine may uncover novel therapeutic targets and the ultimate possibility of individualized treatment strategies (71. genetic profiling may become part of the standard diagnostic protocol for migraine patients. it can be postulated that pharmacotherapy targeting voltage-gated PQ calcium channels may be effective for the treatment of migraine. The discovery of receptor subtypes located on trigeminovascular afferents and their pharmacology. Polymorphisms of the serotonin receptor have been hypothesized to alter the effectiveness of serotonin agonists. An understanding of the mechanisms by which the trigeminovascular system becomes abnormally activated or disinhibited will undoubtedly lead to novel prophylactic therapies. From such data.452 Schwedt and Dodick encoding a sodium–potassium adenosine triphosphatase pump. as well as a reduced threshold and increased velocity of cortical spreading depression. The mice were noted to have enhanced neurotransmission at the neuromuscular junction. This finding implies a possible role for this gene and its product in the pathogenesis of cortical spreading depression. The neuronal voltagegated P/Q calcium channel also regulates the release of serotonin and excitatory neurotransmitters such as glutamate. but also be devoid of vasoconstrictor activity and therefore the potential for adverse vascular effects. . loci associated with increased susceptibility to migraine.70). As gene profiling becomes more available. This will allow for more informed decisions regarding optimal prevention and acute treatment of migraine. A pharmacogenomic study of a possible relation between 5-HT1B polymorphisms (G801C and T-261G) and effectiveness of sumatriptan in migraine treatment showed no significant difference (68). SUMMARY The foundation for advances in migraine therapy has been laid by a better understanding of the underlying anatomy and pathophysiology of this disorder over the past two decades. migraine treatment may become individualized according to a patient’s likelihood of responding to specific medications. As genetic mutations are better defined and testing becomes more cost effective. and receptor polymorphisms altering the binding of migraine medications have been important discoveries in the realm of pharmocogenomics. alterations in resting membrane potential. headaches that are due to recurrent activation of peripheral and central trigeminovascular pathways. Other polymorphisms have been shown to negatively affect binding of dihydroergotamine (DHE) and sumatriptan (69. Migraine is an inherited brain disorder characterized by. Differential pharmacology between the guineapig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands). Serotonin and migraine. Phebus LA. 21. 22(Abstr):1331. et al. brain penetration and activity in the neurogenic dural inflammation model of migraine. et al. in patients with acute migraine. Beresford IJM. Br J Pharmacol 2000. Adham N. et al. Gomez-Mancilla B. Cephalalgia 1994. Life Sci 1997. 127:468–472. Vandenhende F. et al. Granier LA. Med J Aust 1963. De Vries P. and efficacy of intravenous LY334370. Knuth DW. 98:25–30. 17. Humphrey PPA. 21(7):727–732. Adham N. 22(10):799–806. Granier LA. 346:257–270. 45:199–210. Safety and pharmacokinetics of high doses of LY334370. Centurion D. McCall RB. Cephalalgia 2001. et al. Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. Leibowitz MT. 18. Pregenzer JF. Cephalalgia 2003. Alberts GL. Kao HT. Olivier A. 19(10):851–858. Reekers M. 23(8):776–785. 8. 37(10):487–492. Circulation 1998. Cephalalgia 2000. The mode of action of sumatriptan is vascular? A debate. 10. Case B. Skingle M. 6. Saxena PR. An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy [Review]. Fleishaker JC. Proc Natl Acad Sci USA 1993. Safety and efficacy of PNU-142633. Cumberbatch M. et al. Proc West Pharmacol Soc 2002. 600:587–598. 2. PNU-142633F. Br J Pharmacol 1999. Whalley ET. Feniuk W. Humphrey PPA. Vandenhende F. Br J Pharmacol 1978.[see comment]. 15. 3. Johnson KW. Controversies in headache. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities. Villalon CM. Skljarevski V. Ramadan NM. 14. Lancet 2001. Johnson KW. 129(3):501–508. Curran DA. LY334370 is selective for the cloned 5-HT1F receptor. Phebus LA. Maassen VanDenBrink A. Brancheck JA. The effect of ergotamine on tissue blood flow and the arteriovenous shunting of radioactive microspheres in the head. N Engl J Med 2002. Gossen D. a selective serotonin 1F receptor agonist (SSOFRA). 12. Coronary side-effect potential of current and prospective antimigraine drugs. Cephalalgia 2002. Roon KI. Hamel E. Goadsby PJ. Calligaro DO. 20. 20(Abstr):351–352. Cephalalgia 1999. Pearson LK. Edvinsson L. Shepheard S. Chio CL. Migraine-current understanding and treatment. Cephalalgia 1999. Saxena PR. 4. Onkelinx C. 90(2):408–412. Phebus LA. 16. Goldstein DJ. Goadsby PJ. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis [Review]. Overshiner CD. Huff R. Bax WA. Neuroreport 1997. Schecter LE. et al. 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. 63:541–549. et al. 8(9–10):2237–2240. Lipton RB. Schaus JM. Offen WW. during and outside an acute migraine attack. 5. pharmacokinetics. 19. Fine RD. 9. Perren MJ. 1:814–818. Durkin MM. et al. Valdivia LF. Zgombick JM. Johnson KW. 19(Abstr):368. Bouchelet I. Cutler NR. No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Ferrari MD. 7. An evaluation of methysergide in the prevention of migraine and other vascular headache. Int J Clin Pharmacol Ther 1999. a selective 5-HT1D agonist. Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633. Soc Neurosci 1996. Zgombick JM. 11. 61(21): 2117–2126. 13. Lance JW. 14:401–410. Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial [see comment]. Ann New York Acad Sci 1990. . Pereira A. Pharmacokinetics and tolerability of a novel 5-HT1D agonist. de Suray JM. Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Johnston BM. et al. 358(9289):1230–1234. Safety.The Future of Migraine Therapies 453 REFERENCES 1. Im WB. Edvinsson L. et al. Salt TE. Okuda-Ashitaka E. AMPA-type glutamate receptor subunits 2/3 in the human trigeminal sensory ganglion and subnucleus caudalis from prenatal ages to adulthood. 28. Tallaksen-Greene SJ. Alam Z. 109:693–698. . The ORL-1 (NOP1) receptor ligand nociceptin/ orphanin FQ (N/OFQ) inhibits neurogenic vasodilatation in the rat. Kanje M. 33. Classification of adenosine receptors mediating antinociception in the rat spinal cord. Ambu R. 32. 125:1392–1401. 34. 23. Neuropharmacology 2002. J Neurol Sci 1998. 17:6611–6620. Markowitz S. 330:223–226. 29. Mech Ageing Dev 2002. Co-localization of 5-HT (1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. 7: 4129–4136. Hou M. Nocistatin. Hill RG. 31. 123:463–471. Penney JB. Waring RH. 88:923–930. 21: 1031–1036. Br J Pharmacol 2000. Young AB. Br J Pharmacol 1993. Xu X. Xu IS. Br J Pharmacol 1986. Akerman S. Williamson DJ. Neurosci Lett 2002. Sahara Y. Cephalalgia 2001. 43:991–998.454 Schwedt and Dodick 22. 131:34P. Brain 2002. Peptides 2000. et al. Hou M. Goadsby PJ. Br J Pharmacol 2003. Nature 1998. 37. Grandy DK. Pasternak GW. et al. AP. Neurosci Lett 1992. An ionophoretic study of the responses of rat caudal trigeminal nucleus neurons to non-noxious mechanical sensory stimuli. Bourson A. Lai ML. Pain 1996. Reinscheid RK. Goadsby PJ. a peptide that blocks nociceptin action in pain transmission. Quartu M. 81:29–37. Iida Y. 41. 27. Demonstration of nociceptin positive cells and opioid-receptor like-1 in human trigeminal ganglion. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural blood vessel diameter in the anaesthetized rat. Darland T. J Neurosci 1997. White TD. 21:402. Hoskin KL. 25. Noro N. Grass S. 12:1589–1591. Uddman R. Bereiter DA. Nothacker HP. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Ellis F. Sheehan MJ. Kaube H. 156:102–106. Wiesenfeld-Hallin Z. Excitatory amino acid release within spinal trigeminal nucleus after mustard oil injection into the temporomandibular joint region of the rat. 36. Coates J. 30. 40. Hargreaves RJ. Adenosine (A1) receptor agonists inhibit trigeminovascular nociceptive transmission. Steventon GB. 38. 141:79–83. Pharmacol Rev 2001. 39. Science 1995. Storer RJ. Uddman R. 35. 327:65–78. 24. 392:286–289. Ma QP. 26. Tajti J. 42. Hill RG. Goadsby PJ. Mogil JS. Sweeney MI. Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Edvinsson L. Cousins R. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. Benetti. Glutamate receptor subunits GluR5 and KA-2 are coexpressed in rat trigeminal ganglion neurons. Edvinsson L. Beitz AJ. Serra MP. Coombes N. Functional characterization of three adenosine receptor types. Saito K. Sawynok J. 270:792–794. Nakamura Y. Bartsch T. Del Fiacco M. J Physiol 1982. Soma K. The orphanin FQ system: an emerging target for the management of pain? Br J Anaesth 1998. Tajti J. Williams AC. J Neurosci 1987. Akerman S. Hao J. Nociceptin/orphanin FQ in spinal nociceptive mechanisms under normal and pathological conditions. Capsaicin receptor immunoreactivity in the human trigeminal ganglion. Relative intrinsic efficacy of adenosine A1 receptor agonists measured using functional and radioligand binding. Neuroreport 2001. Minami T. 53:381–415. 140:718–724. Cephalalgia 1997. Vanilloid type 1 receptor (VR1) evoked CGRP release plays a minor role in causing dural vessel dilation via the trigeminovascular system. Gurden MF. 67:451–459. Giles H. Moskowitz MA. Wilson DJ. 17:518–524. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Connor HE. Shepheard SL. 43. Iversen HK. tolerability and pharmacokinetics of BIBN 4096 BS. 48. Sperling B. Itawa S. Murakami F. et al. Pharmacological profile of BIBN4096BS. Kruuse C. et al. Edvinsson L. Ekman R. 56. Diener HC. Christiansen I. Neuroreport 1995. Hamel E. CGRP may play a causative role in migraine. 60. Neuropharmacology 2002. 33(1):48–56. Lassen LH. Lassen LH. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ferrari MD. Hallermayer G. et al. Jakubowski M. 59. a novel AMPA/GluR5 antagonist. Moreno MJ. 55:19–26. 57. Ekman R. Reuter U. 55. Gilron I. 52. Jansen-Olesen I. Jacobsen VB. 6(11):1475–1479. Safety. 28(2):183–187. is efficacious and well-tolerated in acute migraine. Wolters JM. Thomsen LL. LY293558. Cephalalgia 2002. 24: 596–602. 19:218–222. Cephalalgia 1998. 42(4):568–576. Ann Neurol 1990. Malessy MJ. 51. Ann Neurol 1988. Olesen J. the first selective small molecule CGRP antagonist. Ashina M. 62. 47. 24(8):645–656. Edvinsson L. Sang CN. Lassen LH. Goadsby PJ. 124:2490–2502. Goadsby PJ. Neurology 1990. Kono S. Messlinger KB. Anesthesiology 1998. Sang CN. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Haderslev PA. Thomsen LL. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. 45. Ann Neurol 1993. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine [see comment]. et al. Edvinsson L. 15(2):94–100. et al. Brain 2001. Chalimoniuk M. Max MB. et al. 58. 1:73–80. 49. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Shimomura T. the first selective small molecule calcitonin generelated peptide receptor antagonist. Doods H. De Col R. Abounader R. 63. 54. 129(3):420–423. 89:1060–1067. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. 64. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Clin Pharmacol Ther 2000. . Husstedt IW. 40:1582–1586. Hostetter MP. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Olesen J. Iversen HK. Koulchitsky SV. et al. Olesen J. 350(11):1104–1110. Bos KD. Cephalalgia 1998. 18(1):27–32. Cephalalgia 2004. The nitric oxide hypothesis of migraine and other vascular headaches. Neuroexcitatory plasma amino acids are elevated in migraine. 14(2):229–232. Bolay H. 46. 50. N Engl J Med 2004. Lee G. Bruyn GW. BIBN 4096 BS Clinical Proof of Concept Study Group. Burstein R. 23(2):193–196. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 2004. Olesen J. Cephalalgia 2004. Wu D. Eur J Neurol 1994. Odink J. Stepian A. Thomsen LL.The Future of Migraine Therapies 455 44. Olesen IJ. Histamine induces migraine via the H1-receptor. following single intravenous administration in healthy volunteers. 22(1):54–61. Lassen LH. 53. Wallihan RG. Ramadan NM. Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. 68(3):320–327. Platelet nitric oxide metabolites in migraine. Goadsby PJ. Olesen J. Wallenstein G. Cephalalgia 1999. 18:631–634. Neuroreport 2003. Br J Pharmacol 2000. 61. Collins B. Young CL. Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain. Gracely RH. Level of nitric-oxide dependent cyclic GMP in patients with migraine. Doods H. Iovino M. Hebert E. Cephalalgia 1995. Feifel U. Kotani K. Support for the NO hypothesis of migraine. Gothert M. Lassen LH. Cephalalgia 2002. van den Maagdenberg AM. Propping P. Zhang L. 68. Lappalainen J. et al. Neurogenic inflammation in the pathophysiology and treatment of migraine [Review]. Maassen VanDerBrink A. Neuron 2004. Headache 1998. Tournier-Lasserve E. Vergouwe MN.456 Schwedt and Dodick 65. 66. Dean M. 59:499–505. et al. A dose-response study of nitric oxide synthase inhibition in different vascular beds in man. Pietrobon D. Bland-Ward PA. Buhlen M. Bruss M. Iversen HK. expression. Honey AC. Bonisch H. 9(1):95–102. Humphrey PP. Lancet Neurol 2002. Pizzorusso T. 2002. 72. 70. Frants RR. 22:260–264. Ferrari MD. Neurology 1993. 27(2):274–279. 5-HT1B receptor polymorphisms and clinical response to sumatriptan. Ophoff RA. and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Ducros A. A CACNA1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Olesen J. Feniuk W. Saxena PR. Genomics 1995. Modified ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor. Study of an adenosine A1 receptor agonist on trigeminally evoked dural blood vessel dilation in the anaesthetized rat. 38:288–291. 67. 71. Connor HE. Identification. Moskowitz MA. 43(6 suppl 3):S16–S20. Bousser MG. Nothen MM. 41(5):701–710. . Eur J Clin Pharmacol 2003. 1(5):285–293. 69. The genetics of migraine. Pharmacogenetics 1999. 457 . not a disease. where headache diagnosis from a clinical interview was compared to the diagnosis from a prospective headache diary. The second edition of the ICHD (ICHD-2) (5) subdivided episodic TTH into an infrequent form (happening less than 1 day per month or less than 12 days per year) and a frequent episodic form (occurring between 12 to 180 days per year) (Table 1) (5). Denmark INTRODUCTION Tension-type headache (TTH) is the most prevalent primary headache (1) and is usually considered a ‘‘normal’’ headache type both by patients and their doctors. frequent episodic TTH and especially the chronic TTH may be disabling disorders. are frequently missed. Nevertheless.6–10). TTH is a substantial problem in the general population and represents a major confounder in the diagnostic and therapeutic process of the complicated headache patient. Because very recent epidemiological data clearly demonstrate a poor prognosis and a very high socioeconomic impact in patients with coexisting migraine and TTH compared to that in patients with pure migraine. the vast majority of patients present with migraine or secondary headaches as their main problem and due to very little academic or pharmaceutical interest. Glostrup Hospital. University of Copenhagen. higher socioeconomic impact. and decrease in the quality of life (3. Glostrup. poorer prognosis. Several instruments have been developed to help in the recognition of TTH both by doctors and their patients. sometimes associated with medication overuse. and distinguished between an episodic type that occurs in less than half of all days and a chronic type that occurs in half of all days or more and in the majority of cases daily. The Danish Headache Center. Furthermore. less than 50% of the patients who reported episodic TTH during the clinical interview were actually identified. The first edition of the International Classification of Headache Disorders (ICHD-1) (4) clearly delineated and defined the disorder. Where infrequent episodic TTH can be regarded as an irritant. but specific diagnostic tests are still lacking for the complicated headache patient with several different headache disorders. In a comparative study by Russell et al. the correct diagnosis and the precise treatment of TTH are very important (3). The opposite pattern was seen with migraine (2). such as TTH. less disabling headaches. in specialized headache clinics.29 Tension-Type Headache Rigmor Jensen Department of Neurology. The CDH definition proposed by Silberstein et al. In 1994. and much effort has been spent with various attempts to improve the diagnostic criteria of frequent headaches (3.33. Thus. new daily-persistent headache. Daily or near daily headaches account for 40% to 50% of the patients in specialized headache clinics (9. 10% to 25% had it weekly. and this affects the definition used in the epidemiological studies (35). especially in clinical practice.9. when subjects with infrequent TTH are excluded. It is our opinion that the definition of CDH is broad and unspecific without implying any possible etiology. The terms ‘‘chronic daily headache’’ or ‘‘CDH’’ are widely used in the literature but are not internationally accepted and are not included in either version of the ICHD. and hemicrania continua (12). Distinguishing chronic tension-type headache (CTTH) from migraine and CTTH from MOH is a substantial. Silberstein et al.31). (12) has become quite popular.30). . however. just as arterial hypertension is a common broad term irrespective of the underlying cause. between 4% and 5% (18. introduced the term ‘‘chronic daily headache (CDH)’’ to designate headaches lasting for four hours or more and occurring 15 days or more per month (12). In most studies. Many prefer to only designate the daily occurrence of various subgroups of headache.28.23. the CDHs are subdivided into transformed migraine.11–13). where it is easy to use but is not included in ICHD-2 (4). Herein we focus on the TTH as defined by the ICHD-2. The CDHs are discussed in Chapter 3 of this book. THE EPIDEMIOLOGY OF TTH Several epidemiological studies of various aspects of TTH have been published (14–29). Jensen The classification of frequent headaches by the ICHD-1 has been most controversial.20. There is considerable debate regarding terminology. tension-type headache. the vast majority of the general population (namely 51–59%) had infrequent TTH (one day per month or less) and did not require specific medical attention (29.34). comparison of the studies reveals a high degree of concordance between the prevalence of frequent episodic and chronic TTH. A very recent population study of adults reported an increase in frequent episodic and chronic TTH in accordance with a similar study from Sweden (29. of importance because management of these headaches is completely different (35). It is meaningless to discuss the prevalence of TTH if the frequency of attacks is not considered. 18% to 37% had TTH several times a month. It is.32).23). In the Danish epidemiological studies. and 2% to 6% of the population had chronic TTH usually lasting for the greater part of their lifetime (16. all based on the diagnostic criteria of ICHD-1 (3).27.458 Table 1 Episodic TTH: Headache Types Infrequent episodic TTH Infrequent episodic TTH associated with pericranial tenderness Infrequent episodic TTH not associated with pericranial tenderness Frequent episodic TTH Frequent episodic TTH associated with pericranial tenderness Frequent episodic TTH not associated with pericranial tenderness Abbreviation: TTH. although the prevalence in the general population is much lower. The vast majority of these patients may also have medication overuse headache (MOH). chronic TTH. As originally proposed. diagnostic challenge. Poor living conditions. the prognosis was fairly favorable. European population studies have shown a fairly uniform prevalence of TTH in various social groups (41. Studies of younger children have shown an equal prevalence in males and females. stress. it probably accounts for at least some of the disability due to headache disorders in general. but only few of these can be confirmed in a follow-up study (5). Racial differences have also been reported in the U. Sociodemographic Factors Related to TTH A number of demographic factors besides sex and age have been studied in TTH. sleeping problems. and medication overuse are usually considered as predictors for a poor outcome. Overall.S. There are at least two plausible reasons for a link between headache disorders and income. TTH is not separately listed. Socioeconomic Impact of TTH The socioeconomic burden of headaches includes direct costs associated with health care utilization and indirect costs associated with missed work due to sickness absence or reduced efficiency.Tension-Type Headache 459 Sex and Age Distribution of TTH The average age for the onset of TTH is between 20 and 30. . This is confirmed by pathophysiological studies indicating that peripheral and central sensitization play a prominent role. Functional impairment and abolished working capacities were described by at least 60% of persons with TTH and accounted for 64% of the reduction in working capacity due to headaches. study and prevalence of TTH was significantly higher in whites than in African-Americans. The prevalence seems to peak in the third to fourth decennium between the age of 20 and 39 and then declines with increasing age in both genders (27–30).40).37). but because of its high prevalence. whereas migraineurs usually had higher rates of absence from work (1. The mean duration of TTH was 10. and patients with frequent episodes of headache are at risk of developing the chronic and more treatment-resistant form of TTH (39.3 years in the German population study (28) and 17 to 20 years in clinical studies of chronic TTH (36. illustrating the life-time consistency of this disorder. whereas a large U. unlike migraine. the vast majority of patients with chronic TTH had evolved from the episodic form over many years (5. The male:female ratio of TTH is 4:5 indicating that. females are only slightly more affected (27–30).S. On the other hand. In most studies.27. study has reported an increased risk for chronic tension-type headache (CTTH) in less-educated or lower-income groups (27). This could lead to a downward drift in socioeconomic status. In a Danish 12-year epidemiological follow-up study. anxiety. Depression. or poor access to health care could lead to an increased prevalence of headache disorders. in both men and women (27). Alternatively frequent headaches might lead to difficulties with work or career advancement. the prevalence of CTTH is fairly uniform among races. with reduced frequency or remission in 47% of subjects with chronic TTH (5). with the female preponderance starting in adolescence (32). Natural History of TTH There is little information on the prognosis of TTH.42). slightly older than what is seen in migraine (27–30).43–47). coexisting active migraine.38). whereas the patients with the chronic forms report a constant pressing. the clinical picture of TTH is therefore not as well described as it is for most other primary headache disorders. the total use of medical services is however 54% higher for TTH. moderate headache that is unrelated to daily hassles. B. At least 10 episodes occurring on !1 but <15 days per month for at least three months (!12 and <180 days/year) and fulfilling criteria B–D Headache lasting from 30 mins to 7 days Headache has at least two of the following characteristics: Bilateral location Pressing/tightening (nonpulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Both of the following: No nausea or vomiting (anorexia may occur) No more than one of photophobia or phonophobia Not attributed to another disordera D. in contrast to 56% of migraineurs (46). and completely refractory to most analgesics (Table 2). some patients refer to it as a ‘‘band’’ or a ‘‘cap’’ compressing their head. C. and terms such as a sensation of ‘‘tightness. When the data are corrected for the markedly higher prevalence of TTH. Abbreviation: TTH.’’ ‘‘pressure. E. consultation rates in TTH sufferers were 39% compared to 63% in migraineurs.’’ or ‘‘soreness’’ are often employed. a History and physical and neurological examinations do not suggest any of the disorders listed in groups 5 to 12. but it is ruled out by appropriate investigations. lack the migraine-associated incapacitating symptoms of nausea and vomiting. while others Table 2 Diagnostic Criteria for Frequent Episodic TTH A. .’’ ‘‘nonpulsating’’ headache.460 Jensen Utilization of Medical Services Only 16% of patients with TTH have been in contact with their general practitioner for headache. usually their migraines. tension-type headache. and holidays. stress. and usually respond to simple analgesics. Estimates of socioeconomic loss due to TTH should therefore include direct costs as well as indirect costs associated with lost workplace productivity. or history and/or physical and/or neurological examinations do suggest such a disorder. THE CLINICAL PRESENTATION OF TTH Most patients with the episodic forms of TTH report that their headaches usually are mild in intensity and relatively short lasting. costing roughly four times more than that for epilepsy and more than twice the cost for migraine. and younger age or moderate-to-severe pain intensity increased the likelihood of medical consultation (21). Characteristics of Pain Patients usually describe their pain as a ‘‘dull. In Chile. or such a disorder is present but headache does not occur for the first time in close temporal relation to the disorder. it is one of the most costly to the society. As patients in headache clinics tend to focus on their most severe and most recent headaches. Although TTH is not the most visible syndrome. A pulsating character occurs ‘‘seldom’’ or ‘‘never’’ in 80% to 86% of the patients from clinical populations (50. where the mean intensity was 1. Even after careful diary review. Nevertheless. In the Spectrum Study after diary review. It must also be kept in mind that for the primary headache disorders such as migraine and episodic TTH. Thus.53. 63% of the original 75 subjects with disabling episodic TTH retained their diagnosis (55).1 Migraine without aura Not attributed to another disorder Abbreviation: TTH. In a population-based study. and that many patients may suffer from both TTH and from migraine. especially. The one-year– prevalence of TTH and the male:female ratio were similar in migraineurs and in nonmigraineurs. the pain was mild or moderate in 87% to 99% of subjects with ETTH (49). Subjects that fill all but one criterion for TTH should be classified as having probable TTH (Table 3). it seems clear that a significant proportion of people who have TTH suffer important disability as a result of their headache. This corresponds well with a recent clinical study of Zeeberg et al.54). as 76% of subjects with more than 30 days of headache per year report moderate or severe intensity compared to 50% of those with less frequent headache (49. Severity of Pain According to the ICHD.2 on a 0 to 3 scale (52). because it was present in 78% of 488 subjects with episodic tension-type headache (ETTH) from the general population (49).2 Frequent episodic TTH Episodes do not fulfill criteria for 1. in contrast to a migraine attack. although. These data would appear to confirm the clinical impression that TTH is a graded phenomenon with headache intensity increasing as headache frequency increases. there is still no gold standard for diagnosis and.4. the pain of TTH is typically of mild or moderate intensity (3. it may be experienced as periodically pulsating during severe pain episodes. tension-type headache.49).Tension-Type Headache Table 3 Diagnostic Criteria for Probable Frequent Episodic TTH Probable frequent episodic TTH Diagnostic criteria: Episodes fulfilling all but one of criteria A–D for 2. The severity of TTH increases markedly with increasing frequency. 461 mention a big ‘‘weight’’ over their head and/or their shoulders (48). pain does not always occur in the .51). The most frequent pain quality in TTH is thus nonpulsating and pressing. The Location of Pain The pain of TTH is typically bilateral. the severity criteria is debated because an early treatment may have a significant influence on the pain intensity. however. whereas the frequency of TTH attacks was higher and the episodes lasted significantly longer in the migraineurs compared to those who have never had migraine. The pressing quality was confirmed in later studies. 32% of patients with disabling episodic TTH were reclassified as having ICHD migraine (55). and this was reported by 90% of subjects in a Scandinavian population study (25). which is an all-or-none phenomenon that runs its course once started. The clinical characteristics of TTH in migraineurs and in nonmigraineurs were compared in a large epidemiological study of 4000 subjects (54). plays no role in routine practice and has now been omitted from ICHD-2 (4). Pain sensitivity assessed by pressure algometer and electromyography (EMG) recordings has been widely used in research. 18% of subjects with TTH according to the ICHD-1 have reported mild or moderate anorexia during the headache episode and only 2% were excluded due to nausea (25. confirming the impression from headache clinics. lateral pterygoid. masseter. pericranial tenderness should be assessed by manual palpation of the temporal. At a minimum. and yet there are no studies analyzing the frequency of such symptoms in relation to ICHD-2 (4). and trapezius muscles. Lack of aggravation of the pain by physical activities is typical of TTH.462 Jensen same location. the pain characteristics and the accompanying symptoms of the episodes of TTH were very similar in those with and without migraine.49). but due to high intersubject variability. as not only two. the presence of these accompanying symptoms had no influence on the pain characteristics. while presence of both symptoms is not allowed. although they may coexist in many patients (49. sternocleidomastoid.49). in contrast to only 4% of migraineurs (25). and trigger points are areas of localized deep tenderness where sustained pressure also induces referred pain in another area in the region. three or all four pain characteristics were fulfilled in subjects with episodic TTH irrespective of accompanying symptoms. Accompanying Symptoms Presence of nausea and vomiting actually rules out the diagnosis of infrequent or frequent episodic TTH. A ‘‘band-like’’ topography including frontal and occipital areas is however common. However. This criterion has been shown to be one of the best pain criteria to distinguish TTH from migraine. The physical examination should also include a manual palpation of the pericranial muscles to identify tender points and trigger points. and a careful physical and neurological examination. varying pain sites associated with varying intensities are often reported by the patients. Mild photophobia was present in 10% and mild phonophobia in 7% of episodic TTH subjects. Therefore. migraine may aggravate or even precipitate TTH. Nevertheless. In patients with TTH. and therefore it was concluded that TTH and migraine are separate disorders and not part of a continuum.54). increased tenderness in pericranial muscles is the most consistent abnormal finding and increases with increasing frequency and intensity of TTH. In the large epidemiological study.28) and 84% in a prospective diary study (56) reported no aggravation of pain by routine physical activity. their appearance was occasional (25. Nevertheless. but more frequently. it is mandatory to base the diagnosis on an extensive history of the evolution of the patient’s pain and other symptoms. PHYSICAL EXAMINATION IN SUBJECTS WITH TTH The diagnosis of TTH requires exclusion of other causative disorders. as 72% to 83% of subjects with the episodic form in population studies (25. where the vast majority of migraine patients also have coexisting TTH (52). Tender points are areas where manual pressure induces local pain. Photophobia or phonophobia may be present.56. The muscle insertion areas such as the mastoid process and the neck muscle insertions should also be palpated (39.57). Subjects with the episodic form have . although in most subjects.52. but are less tender than subjects with CTTH (56–58). because the prevalence of organic cervical spine lesions in TTH is equivalent to other headache disorders (60).61). but no headache specialists will claim that migraine and cluster headache are part of a continuum just because both headaches often are unilateral or respond to triptans. reported that a number of personality factors such as depression. central sensitization may play an important role for both primary headaches because it has been suggested that very frequent migraine attacks may induce a permanent central sensitization in . activation may predominantly be induced by stimuli from e. differ in gender ratio. the pain pathways may be shared in the two disorders. In most studies. A detailed genetic characterization of the headache patient may help us to improve the clinical description and perhaps also lead to a specific individualized treatment strategy. In a controlled study. pericranial vessels and brainstem structures.60) cervical radiological examination should not be recommended unless local pathology is suspected clinically. age distribution. Holroyd et al. be proposed that migraine may be a precipitating factor to TTH in genetically predisposed individuals. and somatization.61).62). and probably also vice versa. It may. Some traits are shared also in migraine and cluster headache.. In general. In population studies. it could be argued that the ‘‘continuum theory’’ is an artifact of referral bias in headache clinics.g. however. and clinical presentation (25. some of the psychosocial and personality factors suspected in the past to cause headache may be the result of specific coping strategies or the result of recurrent pain rather than the primary cause of the headache. stress and mental tension were the most frequently reported precipitating factors. the most important predictor for depression and psychopathology was chronicity. but the exact cause–effect relationship suggests further studies. anxiety. and a fairly high prevalence of depression and anxiety has been identified in chronic TTH. while nociceptive or non-nociceptive stimuli from pericranial tissues may be most important in TTH. psychological abnormalities in most TTH sufferers may be viewed as secondary to headache. PSYCHOLOGICAL ASPECTS OF TTH TTHs are generally reported to occur in relation to emotional conflict and psychosocial stress but the cause–effect relation is still unclear.Tension-Type Headache 463 increased total tenderness score (TTS) score compared to migraineurs and healthy controls. Thus. PATHOPHYSIOLOGY It has been suggested that TTH and migraine share some common biology as they frequently coexist in severely affected individuals. normalized again when patients were retested outside the pain period (45. In both epidemiological and clinical studies. In migraine. The most likely explanation of the pathophysiological similarities between migraine and TTH is that activation of the trigeminal system may be of pivotal importance in both the disorders. therefore. The cervical spine should be examined for restricted and painful movements. Therefore. It is most likely that migraine and TTH are closely linked but biologically different disorders. but occurred with similar frequency in TTH and migraine (54. TTH and migraine. In conclusion. These results are in keeping with the findings of largely normal personality profiles in subjects with episodic TTH (41. whereas (59. Likewise. which were highly abnormal during ongoing pain.27). Pharmacological Treatment Pharmacological treatment of the acute episode of TTH is most often done with the simple analgesics. TREATMENT Nonpharmacological Techniques It is an absolute prerequisite for successful treatment to establish an accurate diagnosis where the individual headache episode is identified and separated from migraine or a secondary headache. and inadequate sleep is also important. to examine them thoroughly. the process of central sensitization may be a common denominator for both migraine and TTH in their chronic manifestations. In particular. Spinal manipulation and acupuncture have also been extensively used but the amount of evidence is insufficient for final conclusion (65). hot and cold packs. Another important element in treating TTH patients is to take their complaints seriously. should also be done. avoidance of any possible trigger factors such as nonphysiological working positions. and problem-solving methods (66. Second.67). psychosocial stress. anxiety or depression. A recent controlled study reported the modest effect of a standardized eight-week physiotherapy program. Nonpharmacological treatment is widely used for TTH but is rarely evidence based. The present treatment strategy is largely empiric and can be divided into nonpharmacological treatment. As most patients with CTTH have started with ETTH one or two decades earlier.g. and to inform them about their headache because many of the patients have been met with medical ignorance and lack of interest for years. most frequently medication-overuse headache. whereas sensitization of pain pathways in the central nervous system due to prolonged nociceptive stimuli from pericranial myofascial tissues or a genetic predisposition seems to be responsible for the conversion of episodic to chronic TTH. This hypothesis may lead to future understanding of pathophysiology and treatment. To summarize. peripheral myofascial sensitization is probably of importance in ETTH. acute pharmacological treatment. improvement of posture. Furthermore. to show empathy.. both of which have proved to . unbalanced meals. A well-conducted. which included relaxation techniques and smooth stretching and daily muscle exercise at home (64). and pharmacological prophylaxis. cognitive restructuring. identification and treatment of significant comorbidities. which can precipitate and exacerbate headache. and as early as 1996. but the majority of these modalities have not been properly evaluated. which can precipitate headaches.464 Jensen the trigeminal system.40. Relaxation training is a self-regulation strategy that aims to provide patients with significant stress with an ability to consciously reduce muscle tension and general arousal.63). Physical therapy is the most common therapy and includes relaxation and exercise programs. and ultrasound and electrical stimulation. aspirin and acetaminophen. placebo-controlled study demonstrated significant and comparable efficacy of stress management therapy and amitriptyline with a tendency for greater improvement when the two treatments were combined (66). e. and typically includes relaxation training. identification of a high intake of analgesics is essential because other treatments are usually ineffective in the presence of medication overuse. Cognitive-behavioral therapy (stress management) aims also to reduce emotional and physiologic arousal. such sensitization has been demonstrated to play a major role in CTTH (39. . REFERENCES 1. Mirtazapine 15 to 30 mg/day had an effect similar to amitriptyline compared with placebo in nondepressed. difficult-to-treat patients with chronic TTH.g. recently demonstrated that aspirin (500 mg and 1000 mg) and acetaminophen (1000 mg but not 500 mg) were superior to placebo (70). sumatriptan may have some effect on coexisting TTHs in patients with migraine but not in those with ‘‘pure’’ TTH (55. Muscle relaxants have often been used in TTH. although weight gain and drowsiness were also reported (37). Iversen HK. Cephalalgia 1999. for more than 15 days per month. and several subsequent studies have confirmed this finding (73–80). it is very important to study the long-term history and to try and identify risk factors for chronicity. In conclusion. Jensen RA. 12(6):369–374. Since 1964. Rasmussen BK.Tension-Type Headache 465 be effective in several placebo-controlled trials (68. As in migraine.72). Other tricyclic and tetracyclic antidepressants may also be effective but there is insufficient evidence for this. Cephalalgia 1992. Steiner et al. it is yet unknown whether early intervention may prevent development of chronicity and large longitudinal studies in well-described populations are needed. Amitriptyline probably elicits its analgesic effect in TTH by reducing the transmission of painful stimuli from myofascial tissues and by reducing the increased excitability in the central nervous system (74–78). Rasmussen BK. TTH represents a wide variety of frequency and intensity. . Likewise there is no clear evidence of an effect of Botulinum toxin in TTH (85). Nevertheless. Recently mirtazapine. Prophylactic pharmacotherapy should be considered in all patients with CTTH without medication overuse and who do not respond sufficiently to nonpharmacological treatment. the majority of patients experience some side effects. 19(suppl 25):20–23. So it can be summarized that there is an urgent need for more efficacious drugs for the treatment of TTH without significant side effects. e. Presentation of a new instrument: the diagnostic headache diary. identification of frequent episodic TTH is very important in the patient with coexisting migraine as different headaches within the same individual complicate the treatment and outcome. Mirtazapine was effective also in some patients who had not responded to amitriptyline and was generally well tolerated. which is a relatively new so-called nonadrenergic and specific serotonergic antidepressant with a better tolerability profile than the tricyclic antidepressants. not only between patients but also within the individual over long time. Thorough information on an upper monthly limit of analgesics and NSAIDs is crucial to avoid medicationoveruse headache. was reported effective in chronic TTH (37). and use of combination analgesics should generally be avoided because of the risk of MOH and the patients should be thoroughly informed about this. The triptans do not have a clinically relevant effect in patients with ETTH (71). Frequent intake of simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs). Olesen J. 2. Although amitriptyline generally is fairly tolerated. Brennum J. It is especially important to identify MOH. simple analgesics and NSAIDs are still the mainstays in the acute pharmacotherapy of TTH. but only the centrally acting drug tizanidine has been tested with conflicting results (81–84). Russell MB.69). Nevertheless.71. especially weight gain. the tricyclic antidepressant amitriptyline has been the mainstay in the treatment of nondepressed patients with chronic TTH. As most cases of chronic TTH had evolved from the episodic forms. Epidemiology and socio-economic impact of headache. and to develop more focused and specific treatment strategies for TTH. To summarize. Chile. 16. Confirmation of the distinction between chronic migraine and chronic tension-type headache by the McGill Pain Questionnaire. 16(6): 407–411. Classification of daily and neardaily headaches: proposed revisions to the IHS criteria. 8. 25. 12. Mitsikostas DD. Epidemiology of chronic daily headache. 9(2):171–174. 7. Sociodemographic factors and primary headache syndromes in a Saudi community. Deregibus A. Rasmussen BK. 19. Rasmussen BK. Cassidy EM. Neuroepidemiology 1997. The International Classification of Headache Disorders 2nd Edition. IIias A. Juang KD. Silberstein SD. 18(8):552–558. Headache classification subcommitee of IHS. Karis HA. Fuh JL. Chronic daily headache and the revised international headache society classification. Curr Neurol Neurosci Rep 2001. 23. Tepper SJ. Cephalalgia 1998. Arch Neurol 1992. Quality of life differs among headache diagnoses: analysis of SF-36 survey in 901 headache patients. 1(2):118–124. Headache 1996. Colas R. Epidemiology of chronic daily headache. Favorable prognosis for the majority with migraine and tension-type headache. Pain 2001. Jensen R. Headache 2002. 65:580–585. Lipton RB. Monzon MJ. Neurol Sci 2003. . Lipton RB. Cranial Neuralgias Facial Pain 1988. Lavados PM. 8(6):236–240. 13. Pop PH. Hardiman O. The International Headache Society classification of chronic daily and near-daily headaches: a critique of the criticism. 22(6):432–438. Cephalalgia 1996. Tenhamm E. Tiedink HG. Kavuk I. Olesen J. Ogunniyi A. Bigal ME. 5. Papageoergiou C. 8(1):59–65. Jørgensen T. Diagnosis. Kalfakis N. 49(9):914–918. Manzoni GC. Cephalalgia 2001. 36(9):561–564. Cephalalgia 2002. Diener HC. Torelli P. Factors associated with burden of primary headache in a specialty clinic. 26. tension-type headache. 42(4):287–290. Jensen R. Lu SR. Cheung RT. Schroll M. Lavados PM. 89(2–3):285–292.466 Jensen 3. Cetindere U. Tomkins E. Pascual J. Chronic daily headache. Agelink MW. Epidemiology of tension-type headache in Santiago. Gierveld CM. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Tenhamm E. O’Keane V. Gatzonis S. An epidemiological study of headaches among medical students in Athens. Headache 2003. Yavuz A. 6. Curr Pain Headache Rep 2004. epidemiology. Neurology 2005. 7(6):455–459. Epidemiological aspects of headache in a workplace setting and the impact on the economic loss. Cephalalgia 2004. 15. Headache 2003. 24 (suppl 1):1–160. Mongini F. 21(7):733–737. Rasmussen BK. Curr Opin Neurol (1350–7540) 1994. Moradi F. 20. Classification and diagnostic criteria for headache disorders. Mathew NT. Abdul JM. Rapoport AM. and impact of tension-type headache. Rasmussen BK. Solomon S. 24. 43(6):638–644. 4. International Headache Society classification: new proposals about chronic headache. Prevalences of migraine and tension-type headache in adolescent girls of Shiraz (southern Iran). Interrelations between migraine and tension-type headache in the general population. 24(suppl 2):S86–S89. 22. Curr Pain Headache Rep 2001. 10. 18. Olesen J. Headache 1994. Jensen R. Raviola F. 21. Consulting behaviour in migraine and tension-type headache sufferers: a population survey in Santiago. 7:264–271. 14. Mongini T. 8 (suppl 7):1–96. Headache 2000. 34:1–7. 43(8):867–877. Prevalence of migraine. Eur J Med Res 2003. Headache Classification Committee of the International Headache Society. Castillo J. 16(1):48–52. Chile: a prevalence study. Eur J Neurol 2002. Wang SJ. Lainez MJ. Lyngberg AC. Ayatollahi SA. 11. 17. 40(6):473–479. 9. Epidemiology of migraine and tension-type headache. Curr Pain Headache Rep 2003. Thomas A. Sheftell FD. and other headaches in Hong Kong. Levin M. Ayatollahi SM. Olesen J. 5(6):529–536. Epidemiology of headache in a general population–a prevalence study. Jensen R. Characteristics of tension headache: A profile of 1420 cases. Curr Opin Invest Drugs 2002. Holroyd KA. Epidemiology of headache in an English district. Olesen J. Bendtsen L. 28(9):590–596. Croft PR. . Lipton RB. Headache 2001. Krymchantowski AV. Bech P. 40(1): 3–16. Friedman AP. Newman LC. Headache (0017–8748) 1988. Murray TJ. O’Donnell FS. Psychosomatics 1979. 11:129–134. Schwartz BS. Schroll M. Boardman HF. J Occup Environ Med (1076–2752) 1997. 43. Betti M. 44. Rasmussen BK. Arq Neuropsiquiatr 2003. Lipton RB. 23(6):420–428. Cephalalgia 2003. 3(3):449–453. Jensen R. 39:320–327. Eeg-Olofsson O. Jensen R. Gobel H. Rasmussen BK. Impact of migraine and tension-type headache on life-style. Rasmussen BK. Epidemiology of tension-type headache. Cordingley G. Sensitization: its role in primary headaches. Poulsen DL. Wang SJ. The epidemiology of headache in Germany: ¨ a nationwide survey of a representative sample on the basis of the headache classification of the International Headache Society. 28. Migraine and tension-type headache in a general population: psychosocial factors. 41. 42. 49. 20:131–137. Hill KR. J Epidemiol Community Health (0143–005X) 1992. Findlay H. risk factors. 279(5):381–383. Clinical features of chronic daily headache. Cephalalgia 2003. Olesen J. Bendtsen L. Simon D. Bigal ME. 46:443–446. Millson DS. 20:243–249. Cephalalgia 1996. 40. Thomas E. Lyngberg AC. 38. Bordini CA. Jensen R. 61(2B):364–367. Psychosocial correlates and impact of chronic tension-type headaches. Evaluation of the impact of migraine and episodic tension-type headache on the quality of life and performance of a university student population. 16:175–182. J Clin Epidemiol 1991. 35. Laurell K. 29. Jensen R. Cephalalgia 1991. Stewart WF. Stewart WF. 34. Lipton RB. Pryse-Phillips W. 31. Lu SR. Qualitatively altered nociception in chronic myofascial pain. Headache 2000. Is chronic daily headache a useful diagnosis? J Headache Pain 2004. Tugwell P. Jensen R. Olesen J. and medication use: A Canadian Population Survey. 47. 30. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Headache in schoolchildren: agreement between different sources of information. Schwartz BS. Speciali JG. 20(7):451–461. Bigal JM. Int J Epidemiol 1992. Nelson RF. Chronic daily headache in Chinese elderly: prevalence. 45.Tension-Type Headache 467 27. Edmeads J. 21(6):1–6. 65(2–3):259–264. et al. Larsson B. Rasmussen BK. Solomon S. Fuh JL. Jørgensen T. Soyka D. Stensland M. 39. 36. JAMA 1998. A population-based analysis of the diagnostic criteria of the International Headache Society. Langemark M. Jensen R. Has the prevalence of migraine and tension-type headache changed over a 12-year period? Eur J Epidemiol 2005. Headache (0017–8748) 1992. Initiating mechanisms of experimentally induced tension-type headache. 33. Neurology 2000. consulting behaviour. 37. 5:87–93. Cephalalgia 1994. and biannual follow-up. Olesen J. Impact of headache on sickness absence and utilisation of medical services: A Danish Population Study. Primary headache diagnosis among chronic daily headache patients. Olesen J. Neurology 2004. Bendtsen L. Petersen-Braun M. Bendtsen L. Lipchik GL. 23(2):129–137. Can J Neurol Sci 1993. 32:325–329. 48. Pain 1996. 32. 44(11):1147–1157. 41(7):710–719. Rasmussen BK. Jensen R. Olesen J. Lost workdays and decreased work effectiveness associated with headache in the workplace. 62(10):1706–1711. 14:97–106. Clinical characterization of patients with chronic tension headache. 46. 54(2):314–319. Lipton RB. Cephalalgia 1992. Ricci JA. Andersson PG. Wober C. Stewart WF. 56. Lange R. Headache 1998. Systematic review of randomized clinical trials of complementary/alternative therapies in the treatment of tension-type and cervicogenic headache. In press. Cordingley GE. Langemark M. Lentz R. Rasmussen BK. Muscle tenderness and pressure pain thresholds in headache. Olesen J. Headache 1990. 38:10–17. Cephalalgia 2004. Epidemiologic and clinical characteristics of migraine and tension-type headache in Korea. Tension-type Headache. Brinck T. 64. Olesen J. 67. Factors associated with the onset and remission of chronic daily headache in a population-based study. 21(3):89–96. Russell MB. 69. et al. Aspirin in episodic tension-type headache: placebocontrolled dose-ranging comparison with paracetamol. Brennum J. 91(1–2):155–163. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study. Cephalalgia 2003. Nykanen M. The 5-HT1-like agonist sumatriptan has a significant effect in chronic tension-type headache. JAMA 2001. Jensen R. 53. Olesen J. 65. stress management therapy. Cephalalgia 1992. Stensland M. Jensen R. Management of chronic tension-type headache with tricyclic antidepressant medication. female hormones. Carlson BW. Lipton RB. Pain state as artifact in the psychological assessment of recurrent headache sufferers. Lange R. Kjeldsen M. 54. 285(17):2208–2215. France JL. Zeiler K. McDermaid CS. Stewart WF. 60. 63. 30(8):514–519. Vernon H. Brennum J. Eur J Neurol 1996. Headache 1998. ibuprofen and naproxen sodium in the treatment of tension-type headache. Mjellem N. Jacobs LD. 58. A cognitive-behavioral return-to-work program: effects on pain patients with a history of long-term versus short-term sick leave. 23(1):59–66. Olesen J. Kim JS. Olesen J. Active neck muscle training in the treatment of chronic neck pain in women: a randomized controlled trial. Torelli P. Linton SJ. Jensen R. 289(19): 2509–2516. Marhold C. Ursin H. Olesen J. Cady R. 51. 3:23–28. Muscular factors are of importance in tension-type headache. Scher AI. 52. Holroyd KA. 2000 Wolfe Award. Cephalalgia. 62. 67:501–506. et al. Clinical characteristics of migraine and episodic tension-type headache in relation to old and new diagnostic criteria. Nash JM. Efficacy of multidisciplinary treatment in a tertiary referral headache center. Headache 2000. 70. et al. Comparison ketoprofen. 12:375–379. Dahlof CGH. Cephalalgia 1996. 66. Pedersen B. A comparison of tension-type headache in migraineurs and in non-migraineurs: a population-based study. Pain 1996. Sensitization: a neurobiological theory for muscle pain. 55. Pain (0304–3959) 1993. Curr Treat Options Neurol 2001. 72. Schriver L. Physiotherapy for tension-type headache: a controlled study. 24(1):29–36. Wober-Bingol C. Rasmussen BK. 16:117–123. Roh JK. 40(10):783–791. .468 Jensen 50. sleep pattern and relation to lifestyle. 53:65–72. 7(3):142–155. 52:193–199. Takala EP. Pain 2001. 59. Jensen R. Ketoprofen. Ulrich V. 57. O’Donnell FJ. Migraine and tension-type headache in a general population: precipitating factors. Voelker M. Pain 1993. Tension headache and the cervical spine–plain ¨ ¨ ¨ X-ray findings. Jensen R. 3(2):169–180. Holroyd KA. Steiner TJ. Iversen HK. Ylinen J. Hagino C. Ahn YO. 38(5):356–365. Bendtsen L. Complement Ther Med 1999. paracetamol and placebo in the treatment of epi¨ sodic tension-type headache. Pain 2003. Melin L. et al. 71. and their combination: a randomized controlled trial. Olesen J. Endresen IM. Pain 1993. Elsevier 1993:413–427. Jensen R. 106(1–2):81–89. 53:229–235. A Population Study. Haaland EM. Hursey KG. Zeeberg P. 61. 68. 12:152–154. Hansen PE. Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache. Drugs Exp Clin Res 1995. JAMA 2003. Lipchik GL. Tumura R. 75. 20(6):603–610. 74. Shimomura T. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial. A non-selective (amitriptyline). Nelson C. Chronic tension-type headache: amitriptyline ¨ reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings. 91(3):195–199. 32:509–513. Awaki E. Catarci T. 7(6):466–474. Effects of tizanidine administration on exteroceptive suppression of the temporalis muscle in patients with chronic tension-type headache. Olesen J. Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition. Jensen R. Gobel H. 34:455–457. Nakashima K. Kassak K. Lake AE III. 82. Ashina S. Electroencephalogr Clin Neurophysiol 1996. Bronfort G. 61:285–290. Takahashi K. Kowa H. Sakuma K. Winner PK. Headache (0017–8748) 1992. Tizanidine in chronic tension-type headache: a placebo controlled double-blind cross-over study. J Manipulative Physiol Ther 1995. 31:601–604. 78. Cantrell DT. Pain 2001. a combined serotonin and noradrenaline re-uptake inhibitor. White JR. but not a selective (citalopram). Gobel H. Jensen R. Murros K. 79. 101:418–422. Cerbo R. Ashina S. 85. J Neurol Neurosurg Psychiatry 1996. Fabbrini G.Tension-Type Headache 469 73. Heinze-Kuhn K. 42(6):470–482. Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications. Saper JR. Chronic daily headache prophylaxis with tizanidine: a double-blind. Shimoda M. . Ashina M. 83. Bendtsen L. Heinze A. Headache (0017–8748) 1994. 76. 59:241–249. 18:148–154. 80. Austermann K. Wang Y. Amitriptyline. placebo-controlled. Cephalalgia 2000. Headache 1998. Curr Pain Headache Rep 2003. Boline PD. Headache (0017–8748) 1991. 81. serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. Bendtsen L. 108(1–2): 108–114. Jensen R. Anderson AV. Bendtsen L. Spinal manipulation vs. multicenter outcome study. Current and potential future drug therapies for tension-type headache. Fogelholm R. 77. Bendtsen L. Hansen C. Barbanti P. Takahashi K. Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache. Pascali MP. Pain 2004. reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache. 84. 38(6):453–457. et al. Pain (0304–3959) 1994. Botulinum toxin A in the treatment of headache syndromes and pericranial pain syndromes. Treatment of tension-type headache with tizanidine hydrochloride: its efficacy and relationship to the plasma MHPG concentration. Jensen R. Olesen J. Headache 2002. Hamouz V. . the daily frequency of attacks. The headache disorders within this group include cluster headache. These disorders must also be differentiated from a variety of other primary headache disorders and organic causes that can mimic the phenotype of any one of these disorders. PATHOPHYSIOLOGY Although the underlying genesis of the TACs is not completely known. The clinical manifestations are thought to reflect activation of the trigeminal and cranial autonomic (parasympathetic) pathways. Table 1). represent a group of primary headache disorders manifested by pain in the somatic distribution of the trigeminal nerve and by autonomic signs that reflect activation of the cranial parasympathetic pathways. U. Scottsdale.S. Hemicrania continua is a continuous headache that should be considered in the differential diagnosis of other chronic daily headache disorders of longer duration (more than four hours). The cell bodies in the superior salivatory nucleus give rise to parasympathetic preganglionic efferents that course within the facial nerve (cranial 471 . The attacks are separated by pain-free intervals. and the response to various medications (Fig.A. and relatively short-lasting (seconds to three hours) episodes of severe unilateral pain that is often confined or maximal in the orbital/periorbital region. respectively. INTRODUCTION Trigeminal autonomic cephalgias (TACs). These disorders are highly disabling and eminently treatable. They are differentiated from each other based on the duration of the individual attacks. and the short-lasting unilateral neuralgiform pain with conjunctival injection and tearing (SUNCT) syndrome. the anatomic and pathophysiologic basis continues to be elucidated. 1. Arizona. but often recur on a daily basis either continuously (chronic) or for a defined period of time (episodic) with intervening remission periods. The central origin of the trigeminal and cranial parasympathetic pathways reside. a term coined by Goadsby and Lipton (1). The TACs are characterized by discrete. 1). in the caudal trigeminal nucleus and superior salivatory nucleus (Fig. underscoring the importance of an accurate diagnosis.30 Trigeminal Autonomic Cephalgias David Dodick Mayo Clinic College of Medicine. paroxysmal hemicrania. stereotyped. 472 Dodick Figure 1 Differentiating the trigeminal autonomic cephalgias. . À. Chronic cluster headache is less common and is .Trigeminal Autonomic Cephalgias Table 1 Differential Diagnosis of Trigeminal Autonomic Cephalgias Feature Sex ratio (M:F) Attack duration Attack frequency Autonomic features Indomethacin response Cluster headache 4:1 60 min (15–180 min) 1–8/day þþ – Paroxysmal hemicrania 1:3 20 min (2–45 min) 1–40/day þþ þþ SUNCT 2. These fibers pass through the geniculate ganglion and synapse in the sphenopalatine and otic ganglia. precipitates headache. which accounts for patients who experience autonomic symptoms without pain or vice versa. In episodic cluster headache. Each pathway can presumably be independently activated. þ. Activation of either the trigeminovascular or parasympathetic pathway can lead to reflex activation of the other pathway through a functional connection in the brainstem. and hemicrania continua (4–6).1:1 40 sec (5–250 sec) 1/day to 30/hr þþ – 473 Abbreviations: SUNCT. but the disorder can occur in both the young and old (7–9). attacks of pain occur daily for weeks or months (cluster period) before an attack-free period or remission occurs that can last from weeks to years (Table 2). Furthermore. nerve VII). no effect on headache. but by a series of animal and human experiments that have demonstrated the local release of trigeminal [calcitonin gene–related peptide (CGRP)] and parasympathetic [vasoactive intestinal polypeptide (VIP)] marker peptides during acute attacks. Significant elevations of CGRP and VIP within cranial venous blood have been measured in the ipsilateral external jugular vein during attacks of cluster headache or chronic paroxysmal hemicrania (CPH) (2. which may explain the rhythmic periodicity of these disorders. Postganglionic fibers travel in the greater superficial petrosal nerve to provide the vasomotor innervation of the cerebral blood vessels and the secretomotor innervation of the lacrimal glands and nasal mucosa. Although the mechanism by which the pathways are activated is unclear. these peptide levels return to baseline after the headache is terminated with medication.3). The mean age at onset is 28 to 30 years. On average. This region contains the suprachiasmatic nucleus (the human biological pacemaker). SUNCT syndrome. CLUSTER HEADACHE Clinical Features Cluster headache is aptly named because of the tendency for attacks to occur in groups or clusters separated by periods of remissions (freedom from symptoms). a cluster period lasts 6 to 12 weeks and remissions last for 12 months (7). short-lasting unilateral neuralgiform pain with conjunctival injection and tearing. recent evidence from functional neuroimaging studies has demonstrated activation in the periventricular hypothalamic gray matter in patients with cluster headache. The evidence that these anatomical pathways become activated in these disorders comes not only from the clinical phenotype of pain within the first division of the ophthalmic nerve and hypersecretion from lacrimal and nasal mucosal glands. Nocturnal predilection is common and patients are often aroused from sleep by an attack. Not attributed to another disorder characterized by attacks of pain that occur for more than a year without a remission period that lasts longer than two weeks (10). The pain is strictly unilateral and almost always remains on the same side of the head during cluster periods. and/or temporal pain lasting 15–180 min if untreated C. except for a partial Horner syndrome that manifests itself by ptosis or miosis (or both) and may persist after acute attacks. Generally. namely nitroglycerin and histamine. and occiput. Migrainous features may also accompany the cluster attack. Ipsilateral nasal congestion and/or rhinorrhea 3. alcohol almost invariably triggers a cluster attack within minutes. In a recent study. Aura symptoms. supraorbital. The onset of pain is abrupt or preceded by a brief sensation of pressure or mild discomfort. Rarely. have been described in association with the cluster attack (11.474 Table 2 Diagnostic Criteria of Cluster Headache According to the International Classification of Headache Disorders-2 (ICHD-2) Dodick Diagnostic criteria A. and may radiate into the forehead. Ipsilateral eyelid edema 4. patients are restless during the pain of cluster headache. 50% of patients reported nausea during an acute attack. At least five attacks fulfilling criteria B–D B. In a recent study. which characteristically occurs during rapid eye movement (REM) sleep. nearly 93% of patients during a cluster attack reported that they were restless (12).12). Other compounds. Severe or very severe unilateral orbital. lasting only for the duration of the attack. Ipsilateral conjunctival injection and/or lacrimation 2. and 36% osmophobia (12). the attacks of pain are highly stereotyped. A cluster headache attack lasts on average 45 to 90 minutes (15–180 minutes) and occurs one to three times daily (up to eight attacks per day). depression. cheek. A prospective study of the clinical and epidemiological characteristics of cluster-headache sufferers noted that 14% of patients reported migraine aura symptoms (12). allergies. the pain is maximal in the retro-orbital and periorbital region of the affected side. 56% photophobia. the autonomic features are short lived. Ipsilateral forehead and facial sweating 5. temple. Headache is accompanied by at least one of the following: 1. In contrast to migraine. even less frequently. Typically. 43% phonophobia. the pain may occur on the opposite side in a subsequent period and. Head trauma has . The mechanism underlying the provocative action of alcohol is not understood. food sensitivities. Stress. Ipsilateral miosis and/or ptosis 6. and hormonal changes appear to have little role in the pathogenesis of cluster headache. though uncommon. A sense of restlessness or agitation D. The autonomic signs and symptoms that accompany the pain can help establish the diagnosis of cluster headache. Attacks have a frequency from one every other day to 8 per day E. jaw. Once a cluster period begins. attacks may switch to the opposite side within the same cluster period. It is important to note that autonomic signs and symptoms may be absent in up to 3% of patients with cluster headache (13). also act as potent triggers. The chronic form may develop spontaneously or evolve from episodic cluster headache. Whether the disease is in the episodic or chronic phase. 15). etc. tearing. and nasal rhinorrhea and obstruction. circadian periodicity with the potential for multiple attacks within a 24-hour period. Hypnic headache typically occurs in elderly persons (above 60 years of age). circannual periodicity with attacks occurring daily for periods of weeks or months.Trigeminal Autonomic Cephalgias 475 been recognized legally as a cause of cluster headache. are cluster-like attacks that are presumed to be caused by a structural lesion. as well as an ipsilateral Horner syndrome. Clues that may indicate a symptomatic cluster headache include (18)  absence of periodicity  a low-grade background headache that does not subside between attacks  inadequate or incomplete response to therapy Cluster headache may be confused with migraine. Box 1 Differential diagnosis of cluster headache Adenoma of the pituitary Arteriovenous malformation Carotid artery aneurysm Impacted molar teeth Meningioma of the upper cervical cord Metastatic lung cancer Nasopharyngeal carcinoma Parasellar meningioma Vertebral artery aneurysm . hypnic headache. During an attack. Patients often prefer not to lie flat. and only occurs during sleep (19). but whether there is medical merit to this remains to be determined (14. and palate are relatively rare. cheek. is often bilateral. although rare. abbreviated duration (45–180 minutes). motor restlessness and pacing during attacks. and very prominent cranial autonomic symptoms. cluster patients frequently report symptoms that are perceived to be migrainous (nausea.) and some even describe aura symptoms. In addition. Ipsilateral facial sweating and flushing and ipsilateral swelling of the temple. Differential Diagnosis The main diagnostic considerations in patients with presumed cluster headache are other TACs. phonophobia.17). The confusion is in part due to the fact that migraine is characteristically unilateral and up to 50% of migraine sufferers report cranial autonomic symptoms. Neurological examination findings in patients with cluster headache are normal except for the possibility of an ipsilateral partial Horner syndrome. or certainly not of the same intensity as cluster headache. and the headache is mild to moderate in intensity. Examples of these lesions are included in Box 1 (16. Symptomatic cluster headaches. There are no cranial autonomic features. and secondary causes of cluster-like syndromes. The features that are most useful in distinguishing cluster from migraine include the rapid peak in pain severity (often less than five minutes). there often is prominent ipsilateral conjunctival injection. photophobia. migraine. but may not necessarily pace. 25). Zolmitriptan. respectively. with 74% of patients having complete relief within 15 minutes compared with 26% of those given placebo (class 1) (23). randomized study that compared the effectiveness and satisfaction of subcutaneous sumatriptan 6 mg with intranasal sumatriptan 20 mg. 49 of 52 treatments provided complete relief of pain within 15 minutes.6 minutes after subcutaneous injection (class 3) (27). Sumatriptan has not been demonstrated to be effective when used in a preemptive manner. In an open-label study. dihydroergotamine. were 29%. oxygen inhalation was also shown to be effective for the symptomatic treatment of a cluster attack (class 1) (21). Headache response rates at 30 minutes. A beneficial response was noted within 30 minutes in 57% of the attacks treated with sumatriptan 20 mg nasal spray. 57%. In an open. however. 39 of 52 patients (75%) given 100% oxygen via facemask at 7 L/min experienced complete or near-complete relief within 15 minutes (class 3) (20). The difference was statistically significant only for 10 mg zolmitriptan compared with placebo. Oxygen. and 47% for placebo and 5 and 10 mg of zolmitriptan. In several long-term open-label studies. In some patients. The beneficial effects of intranasal sumatriptan. with a mean ‘‘time to pain relief’’ of 9. controlled study of oxygen versus air inhalation. zolmitriptan. acute attacks of cluster headache necessitate the use of fast-acting symptomatic therapy. The use of hyperbaric oxygen in the treatment of cluster headache has practical limitations. particularly tobacco abuse. 6 mg of sumatriptan administered subcutaneously was significantly more effective than placebo. octreotide (subcutaneous). and placebo. rather than abort the attack. oxygen inhalation may merely delay. Mild or no pain at 30 minutes was reported by 60%. sumatriptan was still effective after continued use for several months (class 3) (24. but it is contraindicated in patients with ischemic heart disease or uncontrolled hypertension. In the only double-blind. defined as a 2-point or greater decrease from baseline on a 5-point pain intensity scale. Zolmitriptan is an effective oral agent for the acute treatment of episodic cluster headache (class 1) (29). Oxygen inhalation is one of the most effective symptomatic treatments for cluster headache. hyperbaric oxygen (2 atm for 30 minutes) was effective within 5 to 13 minutes in six of seven patients (class 2) (22). Subcutaneous sumatriptan is a highly effective acute treatment for cluster headache. compared with the placebo response of 26% (class 1) (28). nor has it been effective when used as a prophylactic agent (class 1) (26). Oxygen inhalation. have been further corroborated by a recent study demonstrating its efficacy in cluster attacks lasting longer than 45 minutes (28). . In a double-blind. caution must be exercised because cluster headache predominates in middle-aged men who often have coexisting risk factors for cardiovascular disease.476 Dodick Treatment of Cluster Headache Acute (Symptomatic) Therapy Because of the sudden onset and short time to peak intensity. In a small placebo-controlled study. 40%. sumatriptan (subcutaneous and intranasal). In only 7 of 52 treatments with nasal spray in the nostril ipsilateral to the head pain was complete relief noted within 15 minutes. Sumatriptan. Thus. respectively. however. Sumatriptan is generally well tolerated. placebo-controlled study. zolmitriptan 5 mg. zolmitriptan was an effective oral agent for the acute treatment of episodic cluster headache (class 1). and 42% of patients given zolmitriptan 10 mg. and local anesthetics have provided acute relief from cluster headache attacks. In a placebo-controlled study that evaluated the efficacy and tolerability of oral zolmitriptan 5 and 10 mg in comparison with placebo in cluster headache. The headache response rate with subcutaneous octreotide was 52% compared to a placebo-response rate of 36% ( p < 0. zolmitriptan is detected in the plasma at two minutes postdose and in the brain at five minutes postdose (30–33). An intranasal preparation is now widely available. uncontrolled hypertension. Nonetheless. Somatostatin has been shown to inhibit the release of CGRP and VIP based on the results of two small.Trigeminal Autonomic Cephalgias 477 Zolmitriptan nasal spray may prove to be a more useful alternative than the tablet in patients with cluster headache. placebo-controlled trial. Octreotide was well tolerated with no reports of serious side effects. erratic bioavailability of oral ergotamine tartrate. The intranasal administration of local anesthetic agents such as cocaine (class 3) or lidocaine (class 3) has been reported to be effective (42. with a bioavailability of 40%. it has not been particularly useful in the acute treatment of a cluster attack. Intranasal absorption has been shown to account for approximately 70% of the total exposure to zolmitriptan in the first hour postdose (34). double-blind trials that suggested efficacy of intravenous somatostatin in cluster headache (39. await the results from a randomized. Dihydroergotamine administered intravenously has been shown to provide relief in less than 10 minutes (36). Octreotide.01). intranasal lidocaine applied by spray bottle or by dropping 4% viscous lidocaine in the nostril ipsilateral to the pain does not render the patient pain-free and produces only a modest decrease in pain in fewer than one-third of patients (class 3). A recent randomized double-blind placebo-controlled crossover study evaluated the use of octreotide. following intranasal administration. a pain-free response was observed in 27 of 36 attacks at 15 minutes (35). Dihydroergotamine. Topical Local Anesthetics. Thus. peripheral vascular disease. Because of the low. randomized. the currently available 2-mg commercial preparations of dihydroergotamine nasal spray may be effective (38).43). Patients were instructed to treat two attacks of at least moderate pain severity using subcutaneous octreotide 100 mg or matching placebo. The principles of preventive pharmacotherapy are to  begin treatment early in the cluster period  continue the treatment until the patient has been headache-free for at least two weeks . slow. Prophylactic Therapy The primary goals of preventive therapy are to produce a rapid suppression of attacks and to maintain this remission over the expected duration of the cluster period. All side effects resolved spontaneously and were generally short lived and mild in nature. Correspondingly.40). The pharmacokinetics of zolmitriptan nasal spray are consistent with a fast onset of action. kidney failure. a somatostatin analogue for the acute treatment of cluster headache (class 1) (41). Conclusive evidence for the efficacy and safety of zolmitriptan nasal spray will. or liver failure. however. in a recent single-blind observation trial involving five patients who treated 36 attacks of cluster headache with 5 mg zolmitriptan nasal spray. The main side effect observed was gastrointestinal upset in eight patients treated with octreotide compared with four patients treated with placebo. but pain intensity was markedly reduced with the drug compared with placebo (class 1) (37). A double-blind crossover trial compared intranasal dihydroergotamine (1 mg) with placebo and found no change in the frequency or duration of the attacks. Contraindications for all ergotamine derivatives include coexisting coronary artery disease. long-term treatment should be avoided. Prednisone. . have demonstrated that GON blockade in cluster headache patients can provide good to moderate short-term relief in 64% of patients (45). As with prednisone. a common method involves initiating treatment with prednisone 60 mg daily for three days. Corticosteroids (prednisone and dexamethasone) are the most rapidly acting prophylactic agents.3 mL 2% xylocaine in the region of the GON on the side ipsilateral to the pain experienced at least a 50% reduction in attack frequency in the first postinjection week compared with the preinjection week. More recently. followed by 10-mg decrements every three days. is a strategy that is also employed (class 3) (38). and it generally is not administered with methysergide because of the risk of potentiating the vasoconstrictive effects of both these drugs. Transitional Prophylaxis Transitional prophylaxis refers to the short-term use of corticosteroids.478 Dodick  taper the dose of the drug rather than abruptly withdraw it  restart treatment with the drug at the beginning of the next cluster period Herein we divide the prophylactic therapy into transitional therapy and maintenance prophylaxis. ergotamine. allowing for more restful sleep. nine patients who received the corticosteroid injection were attack-free. The literature supporting the use of corticosteroids is sparse and does not include the results of controlled trials. Four weeks after the injection. While strategies vary. followed by 4 mg daily for one week. ergotamine may be taken once or twice daily to a maximal daily dose of 3 to 4 mg. placebo-controlled study involving 23 patients with episodic cluster headache and seven patients with chronic cluster headache. These agents are the most effective initial prophylactic options to break the cycle of headache rapidly while waiting for longer-acting maintenance prophylactic agents to take effect (18). 92% of patients who received an injection of betamethasone 9. Thus. GON blockade provides clinicians with an alternative therapeutic option for the transitional treatment of cluster headache. Ergotamine tartrate is contraindicated within 24 hours of taking sumatriptan. In a recent double-blind. cluster attacks invariably recur. GON Blockade. Dexamethasone at a dose of 4 mg twice daily for two weeks. whereas only one patient in the placebo group had a similar improvement ( p ¼ 0. when the dose of dexamethasone is tapered. For periods shorter than two months. Ergotamine Tartrate. Ergotamine tartrate (2 mg) is also an effective agent for achieving rapid suppression of attacks when administered daily for a short period. Most clinicians limit the use of prednisone or dexamethasone to no more than two or three cycles per year. over an 18-day period. GON blockade was initially reported by Anthony as an effective means of providing temporary relief from cluster attacks (44). A response typically occurs within one to two days after therapy is initiated. or greater occipital nerve (GON) blocks. without any other preventive therapies. Ergotamine tartrate taken at bedtime may prevent attacks at night. Because of the adverse effects associated with corticosteroids.06 mg/dL and 0.0004) (46). Peres et al. corticosteroids are useful primarily for inducing rapid remission in patients with episodic cluster headache. sumatriptan.d.i.52). computed tomography or magnetic resonance imaging (MRI) of the abdomen. When used in patients with cluster headache. and other preventive agents. and this complication. which was too short for the results to be conclusive.g. pulmonary. The short-term side effects include nausea. and general screening laboratory tests] when methysergide is given for a prolonged period. maintenance prophylaxis is started at the onset of the cluster period and is given in combination with either corticosteroids or an ergotamine derivative. and binds to serotonin (5-HT2) receptors in the brain (38). Most clinicians consider verapamil the preventive therapy of choice for both episodic and chronic cluster headache. the study was terminated one week after treatment began. The initial dose of verapamil is generally 80 mg three times daily or 240 mg sustained-release daily. Methysergide has been reported to be effective for the prophylaxis of episodic cluster headache in approximately 30% to 70% of patients (class 3) (51. Although most clinicians believe that both the regular and extended-release preparations are equally efficacious. Dosages range from 240 to 720 mg daily in divided doses. has significantly curtailed its use. Lithium carbonate has been reported in open-label studies to be effective primarily for the treatment of chronic cluster headache. Nimodipine (30 mg four times daily) has been shown in two open trials to be effective (class 3) (49. but up to 12 mg may be given if tolerated. echocardiography. most clinicians abide by the recommendations of a one-month drug holiday between six-month treatment periods. The daily dose generally is 2 mg three times daily. Verapamil has a benign side-effect profile and can be given safely in conjunction with ergotamine derivatives. However. Verapamil. and pedal edema. but higher doses may be needed. pleural. Response rates from 38% to 82% have been reported (class 3) (53–55). The initial starting dose of lithium is either 300 mg twice daily or 450 mg sustained-release. Methysergide is a prodrug of methylergonovine. The drug markedly decreased the frequency of attacks and the consumption of analgesics during the 14 days and was well tolerated (class 1) (48). a brief review is warranted. A double-blind. 360 mg) (class 3) (47). Their mechanism of action in cluster headache has not been explained. placebo-controlled trial failed to demonstrate superiority of lithium (800 mg sustained release) over placebo (56) (class 2). muscle cramps. given its continued use worldwide. Calcium-channel blockers are a group of chemically heterogeneous drugs developed as cardiovascular agents that interact with L-type calcium channels. abdominal pain. A therapeutic response frequently . Long-term side effects include fibrotic reactions (retroperitoneal.Trigeminal Autonomic Cephalgias 479 Maintenance Prophylaxis ‘‘Maintenance prophylaxis’’ refers to the use of preventive medications throughout the anticipated duration of the cluster period.) over 14 days.. zolmitriptan. and cardiac). diarrhea. but it is continued after treatment with these initial suppressive agents has been discontinued. A double-blind. Calcium-Channel Blockers. placebocontrolled trial evaluated the efficacy of verapamil (120 mg t. no direct comparative trials have been conducted. however. 69% reported improvement by more than 75% during treatment with verapamil (mean daily dose. and recommend periodic imaging and laboratory studies [e. Often. crosses the blood–brain barrier. Lithium Carbonate. chest radiography. Although methysergide is no longer available in the United States. Methysergide. which occurs in about 1 out of 1500 patients. It is widely distributed throughout the body. In an open-label trial involving 48 patients. it is not widely used to treat cluster headache.50). nausea. thrombocytopenia. tremor. including nausea. the effective dose ranged between 500 and 2000 mg/day. which seriously limits its long-term use in cluster headache sufferers. placebo-controlled study. either as monotherapy (13 patients) or as an add-on therapy (36 patients). bloating. Conflicting results on the efficacy of topiramate for cluster headache were found in a study of 33 patients. treatment with divalproex sodium (mean dose. valproate sodium or divalproex sodium should be started at 250 mg b. alopecia.4 to 0. topiramate was associated with cluster remission in nine patients within three weeks of treatment initiation (61). altered taste. 26 patients (12 with episodic and 14 with chronic cluster headache) were treated with topiramate at a mean dose of 100 mg/day (range 25–200 mg/day) (62). Caution must be exercised when other drugs such as diuretics or nonsteroidal anti-inflammatory agents are given concomitantly. Nine patients reported complete remission of cluster headache and two patients reported marked improvement. polyuria. In general. In another open-label study.0 mEq/L. confusion. Topiramate. tremor. respectively (57). The serum concentration should be measured 12 hours after the last dose and should not exceed 1. extrapyramidal signs. However. and titrated up in 250 mg increments according to clinical response and tolerability. Other rare but concerning side effects associated with its use include pancreatitis. vomiting.3 mg/day.8 mEq/L. In an open-label study involving 10 patients (seven with episodic cluster headache. Unfortunately. sodium valproate was not shown to effectively prevent cluster headache (60). In an open-label study of 26 patients (21 with chronic and 5 with episodic cluster headache). In a retrospective assessment of 49 patients with cluster headache who received divalproex sodium daily (500–1500 mg). Several open-label studies suggest that topiramate may be an effective prophylactic therapy for patients with episodic or chronic cluster headache. Adverse effects include weakness. Side effects associated with sodium valproate included nausea. memory impairment. Renal and thyroid toxicity are well-known complications with this drug. Divalproex Sodium/Sodium Valproate. 73% of patients reported improvement (58). weight gain. two with chronic cluster headache. 22% of cluster patients reported negative side effects. and drowsiness. Cluster remission was observed in six patients (50%) with episodic and nine patients (64%) with chronic cluster headache. Reported side effects included paresthesia. and one with cluster–tic syndrome). and somnolence. and alopecia are other side effects. when treating patients with cluster headache. weight loss. which may limit the use of valproate in clinical practice.d. No significant differences in the median number . The mean dose of topiramate for cluster remission was 83. The effectiveness of sodium valproate (600–2000 mg/day in two divided doses) for the prevention of cluster headache was assessed in a second. Lithium has a narrow therapeutic window and has the potential for numerous side effects. Kidney and thyroid function studies must be performed before treatment and periodically during treatment. small open-label study of 15 patients (59). disequilibrium. less than those required for the treatment of bipolar disorders. and hepatic dysfunction.480 Dodick occurs within one month and often at serum concentrations of 0. and rash. nystagmus. and seizures. in a recent double-blind.i. somnolence. The mean time to remission was 14 days. diarrhea. ataxia. but several patients had complete headache cessation within the first few days of treatment. Polymorphonuclear leukocytosis may occur in patients taking lithium and may be mistaken for occult infection. Weight gain. 838 mg/day) resulted in mean decreases in headache frequency of 59% and 54%. In the open-label studies described. Remission of cluster headache was noted within three to five days in 5 of 10 patients who received melatonin compared with none of the 10 patients who received placebo. No improvement was noted in patients in whom capsaicin was applied to the nostril contralateral to the pain (class 2). and tamoxifen is too limited to support their routine use in the treatment of cluster headache. two patients reported mild drowsiness. The experience with these drugs and several others such as botulinum toxin.d. In a double-blind. Small open-label studies and case reports have indicated that the following drugs are effective for cluster headache: methylphenidate (class 3) (68). none of them reported new attacks. Several other drugs are being investigated for the treatment of cluster headache. In addition to the side effects described above. Clearly. intolerance. Melatonin is the most sensitive surrogate marker of circadian rhythm in humans and is under the control of the suprachiasmatic nucleus. In an open-label trial. placebo-controlled study. randomized controlled trials are needed. placebo-controlled trial (class 1) (67).i. in seven patients (21%). Refractory Cluster Headache Approximately 10% to 20% of patients with cluster headache experience chronic cluster headache that fails to respond to monotherapy. During this study. Gabapentin.d. eletriptan (class 3) (76). chlorpromazine (class 3) (73). and patients must be alert to the rare but concerning adverse events including acute myopia. cyproheptadine. depletes sensory neurons of substance P. histamine (class 3) (74). All patients were pain-free after a maximum of eight days following the initiation of gabapentin (64). many of these patients require rational polypharmacy or may be candidates for ablative neurosurgical procedures.Trigeminal Autonomic Cephalgias 481 of daily attacks were found between the run-in and treatment periods (63). for six months. Fusco et al. The efficacy of 10 mg of oral melatonin was evaluated in a double-blind. and frovatriptan (77–86). Capsaicin is not widely used for the treatment of cluster headache because other more easily administered and effective agents are available. Thus. demonstrated that capsaicin applied to the nostril ipsilateral to the pain produced marked improvement in 70% of 70 patients (51 with episodic headache and 19 with chronic cluster headache) (66). oligohidrosis. Those patients suffering from chronic cluster headache were instructed to continue gabapentin at 300 mg t. 12 patients previously shown to be refractory to other preventive therapies were treated with gabapentin initiated at 100 mg t. tizanidine (class 3) (70). baclofen (class 3) (69). and increased in three days to 300 mg t. Capsaicin. topiramate also causes kidney stones in 1% of patients. In the patients with episodic cluster headache. Melatonin. or contraindications to abortive or prophylactic medications. capsaicin was applied topically twice daily for seven days to the nostril ipsilateral to the pain and was shown to be superior to placebo in reducing the frequency and severity of the attacks (class 2) (65). no relapse had occurred in the three months following discontinuation of therapy.i. Capsaicin. Other Drugs. However.d. diltiazem.i. However. Further studies are warranted to verify the effectiveness of gabapentin for the prevention of cluster headache. given the conflicting results of some of these studies. At four months after the start of therapy. patients with episodic cluster headache with frequent cluster periods may develop relative drug resistance. the daily number of attacks was reduced by more than 50%. . and metabolic acidosis. pizotifen (class 3) (72). a constituent of hot peppers. leuprolide (class 3) (75). clonidine (class 3) (71). computed tomography. justifies the use of each of the drug options listed above. indomethacin. Normal cerebral MRI including foramen magnum MRI angiography and venography Experienced neurosurgical team Patient not pregnant Ethics Committee/Institutional Review Board approval Patient quits smoking and drinking alcohol Patient informed and gives written consent Abbreviations: IHS. in whom outpatient and inpatient therapy has failed. gabapentin. cluster headache. Although verapamil is the only drug for which there is placebo-controlled evidence for efficacy. Radiofrequency lesions have been utilized more than glycerol rhizotomy or balloon compression. Surgical Therapy Surgical therapy is a consideration only for patients with medically intractable cluster headache. lithium carbonate. Source: From Ref. and steroids Normal psychological profile No recent medical/neurological conditions contraindicating surgery including Normal neurological examination except for symptoms characteristic of CH (e. dihydroergotamine administered intravenously every eight hours over three days has been reported to be effective for some patients with intractable cluster headache (class 3) (87). melatonin. it is incumbent on the clinician to exhaust all potential medical options. . CH. Over the past few decades. chronic cluster headache. and these criteria can be generalized to the selection of patients for any surgical procedure (Table 3) (89). International Headache Society. sometimes in combination.. also suggests that outpatient intravenous dihydroergotamine is a safe and effective treatment for cluster headache (class 3) (88). methysergide. the debilitating nature of this disorder. The results of radiofrequency rhizotomy are somewhat Table 3 Patient Selection Criteria for Invasive Cluster Headache Surgery IHS-defined CCH for at least 24 mo Attacks should normally occur on daily basis Attacks must have always been strictly unilateral Patients must be hospitalized to witness attacks and document their characteristics All state of the art drugs for CH prophylaxis must have been tried in sufficient dosages (unless contraindicated or have unacceptable side effects) alone and in combination.482 Dodick Before a surgical procedure is considered. topiramate. 89. valproate. Procedures aimed at lesioning or decompressing the trigeminal ganglion or nerve have been better evaluated. persistent Horner’s syndrome) Normal CT scan (base of the skull window). In addition to a combination of prophylactic therapies. A recent study. CCH. combined with the potential for serious morbidity associated with destructive surgical procedures. Some patients have a response to medications used in combination rather than to the maximal dosage of a single medication. These comprise verapamil. CT. or patients in whom contraindications or intolerance sufficiently limits the use of effective prophylactic therapy given sequentially and in combination. various surgical procedures have been used to treat chronic cluster headache that is refractory to medical therapy. where applicable.g. Criteria for patient selection for deep brain stimulation have recently been proposed. Most clinicians hesitate to recommend this procedure.7 years) (97). Given the results of recent functional imaging data. Satisfaction with the procedure was reported by 10 of the 17 of those patients who did not require preventive medications after surgery. reported complete or near-complete relief of pain in 12 of 14 patients who had a sensory trigeminal rhizotomy through the posterior fossa approach (class 3) (96). with or without section of the intermediate nerve. alone or in combination with microvascular decompression or section of the intermediate nerve. 15 of 17 patients who underwent sectioning of the trigeminal sensory root at the level of the brainstem experienced complete or nearcomplete relief in the immediate postoperative period. the overall efficacy. weakness of the masticatory muscles. Some patients have remained pain-free for up to 20 years. It is noteworthy that 7 of the 14 patients who had a partial nerve root section required a second procedure for complete relief. anesthesia dolorosa. death. Four patients remained pain-free beyond eight months. for chronic cluster headache was recommended by Lovely et al. Long-term follow-up (5. Complications included epistaxis (12%). and jaw deviation. Kirkpatrick et al. radiofrequency lesioning of the sphenopalatine ganglion via an infrazygomatic approach was performed in 66 patients (class 3) (93).6 years. safety. Accordingly. These procedures require an experienced surgical team. Gamma-knife radiosurgery was shown to be effective in six patients with medically refractory cluster headache (class 3) (94). An initial postoperative benefit (greater than 90% relief) was noted by 50% of patients and relief greater than 50% was noted by 73% of first-time surgical patients. The results were marginal. concluded that complete section was more likely to provide sustained relief than partial section of the root. which suggest that the cluster headache generator is located in the posterior inferior hypothalamic gray matter. in selected medically refractory cases (class 3) (98). cheek hematoma (17%). Microvascular decompression of the trigeminal nerve. aggressive long-term ophthalmologic follow-up is critical for all patients having radiofrequency rhizotomy. and durability of the procedure are not clear.Trigeminal Autonomic Cephalgias 483 encouraging. Several authors have reported favorable results in patients with refractory chronic cluster headache after section of the sensory trigeminal nerve at the root exit zone (class 3). In a recent study. 28 patients (two with bilateral cluster headache) underwent 39 operations of the trigeminal nerve. with 40% of the patients experiencing relief and only 30% of those with chronic cluster headaches obtaining complete relief. in fewer than 4% of patients. The recurrence rate is about 20% (class 3). Repeat procedures were ineffective. Because this study has not been duplicated. The best results have been noted in patients with complete analgesia or dense hypoalgesia. In one. and 76% went on to have long-term benefit (mean follow-up period 6. and painful facial dysesthesias or anesthesia dolorosa are potential adverse events. Stroke. Transient complications may include diplopia. In a recent observational study. A total of 19 patients have received . and partial maxillary nerve lesion in 6% of patients. hyperacusis.3 years) demonstrated a decrease in the good-to-excellent relief to 46%. Kirkpatrick et al. Leone et al. were prompted to employ deep-brain stimulation of this area. The mean duration of follow-up was 5. Additional studies are needed before microvascular decompression can be considered as a first-line operative treatment for chronic cluster headache. Longer-term complications include corneal anesthesia and. In their series. with nearly 75% of patients having good-to-excellent results (class 3) (90–92). The time to effective relief was either immediate or within one week. as a first-line surgical treatment (95). ice-pick pain. Larger series will be needed to determine the safety and long-term efficacy of this procedure. more rarely. In a retrospective study of 84 patients. Attacks of severe unilateral orbital. the headaches lasted less than 30 minutes in more than half of the patients (103). PAROXYSMAL HEMICRANIAS Paroxysmal hemicranias are characterized by frequent. the pain may alternate sides or. During attacks. In a recent report of 78 patients. Ipsilateral conjunctival injection and/or lacrimation 2. the age at onset varies from 6 to 81 years. at a mean age of 34 (102). Headache is accompanied by at least one of the following: 1. the mean duration of the attack was 13 minutes (range. 3–46 minutes) and the mean frequency of attacks was 14 per day (range. The pain is described as a ‘‘throbbing. At least 20 attacks fulfilling criteria B–D B.’’ or ‘‘stabbing’’ pain that ranges from moderate to excruciatingly severe in intensity. one or more ipsilateral autonomic symptoms or signs occur. The pain is strictly unilateral in most patients. Ipsilateral forehead and facial sweating 5. and the disorder usually begins in adulthood. The female-to-male ratio is approximately 2:1. in which fewer than 6% of headaches last less than 30 minutes and more than 90% of patients have fewer than three attacks per day (104–108). Occipital nerve stimulation has recently been demonstrated to be efficacious in a 45-year-old man with chronic cluster (101). although periods with lower frequency may occur E. The mechanism by which stimulation of this area is able to suppress attacks from occurring is not well understood. supraorbital. Ipsilateral eyelid edema 4. The durability of this procedure remains to be further elucidated (class 3). The pain occurs predominantly in the anterior region of the head (orbital or temporal) and usually lasts between 2 and 45 minutes. or temporal pain lasting 2–30 min C. However. although in some. 6–40) (102). with the only difference being that EPH has pain-free remissions. Ipsilateral miosis and/or ptosis D. the mean duration of the attack was 21 minutes and the mean frequency of attacks was 11 per day (range.100).484 Dodick deep-brain stimulation with favorable results in 18 (class 3) (99. 4–38) (104). One patient died of an intracranial hemorrhage after the surgery. Lacrimation and nasal congestion are the most common Table 4 Diagnostic Criteria of Paroxysmal Hemicranias According to the International Classification of Headache Disorders-2 Diagnostic criteria A. Attacks have a frequency above 5 per day for more than half of the time. This is in contrast to cluster headache.’’ ‘‘pulsatile. The procedure may provide clinicians an alternative option to more aggressive procedures with less neurologic morbidity. The clinical profiles of CPH and episodic paroxysmal hemicrania (EPH) are similar. Ipsilateral nasal congestion and/or rhinorrhea 3. Attacks are prevented completely by therapeutic doses of indomethacin F. occur bilaterally.’’ ‘‘boring. short-lasting unilateral headaches (Table 4 ). In a prospective study of 105 attacks. Not attributed to another disorder . indefinite treatment is often required for patients with CPH or hemicrania continua. Patients who require a continuous high dose of indomethacin and those who require increasing doses after an initial response to a lower dose may have an underlying lesion and need careful evaluation (113). a bedtime dose of sustained-release indomethacin may be useful to prevent these attacks. EPH differs from CPH in having attack phases that are interrupted by longer lasting remission phases. Some patients are so exquisitely sensitive to indomethacin that skipping even one dose will allow the headache to recur.8 years. Therefore. highlighting the need for a careful clinical evaluation of patients who otherwise appear to have a typical clinical picture and response to medication. Similar to episodic cluster headache. Patients may have a partial response but not complete relief if the dose is not optimal. Treatment failure should be considered only if a patient has not had a response to a dosage of 300 mg/day. methysergide. Some patients with symptomatic CPH due to intracranial or pulmonary lesions have been reported to have a response to modest doses of indomethacin (114. lamotrigine. remissions range from 1 to 36 months. 48 hours (109). dose adjustments are necessary to treat the clinical fluctuations that occur sometimes in these disorders. including other nonsteroidal anti-inflammatory drugs. Maintenance doses between 25 and 100 mg are usually adequate for suppressing the headache.Trigeminal Autonomic Cephalgias 485 accompanying features and are often robust. If the headache is refractory to indomethacin therapy. However. 42% experienced a mean decrease of 56% in the dosage of indomethacin (41 mg 619 mg/day) required to maintain a pain-free state (110). but who fail to or cannot tolerate indomethacin. it should be decreased gradually to ascertain the lowest effective dose. Interindividual differences exist in the dose and timing needed to abolish the headaches and likely are due to differences in bioavailability and individual sensitivity. Treatment is usually initiated at a dosage of 25 mg three times daily with meals. The average interval between drug ingestion and relief of pain in patients with hemicrania continua is approximately 30 minutes and for those with CPH. who were followed for an average of 3. Although longterm. It is recommended that after an effective dose has been established for several weeks. If headache relief is not obtained within 48 hours after initiation of treatment. corticosteroids. several drugs have been reported effective. Conjunctival injection and rhinorrhea also occur in upto one-third of patients.112). the response to treatment is invariably swift. indomethacin is usually continued for approximately two weeks beyond the expected duration of the headache period. In patients with EPH.115). from the perspective of a clinician evaluating and treating .5 months. a periodic attempt to withdraw the medication is useful because long-term remissions have been described (103. In subjects with a phenotype that resembles CPH. About one-third of attacks occur during nocturnal sleep in both disorders. Indomethacin is the treatment of choice for paroxysmal hemicranias. the diagnosis should be reconsidered. Most patients report complete headache relief within 24 hours and frequently within eight hours. and the marked response to this drug has been considered the sine qua non for establishing the diagnosis. typical cases of CPH have been described in which the headache was unresponsive to indomethacin (103. Because nocturnal attacks or exacerbations are frequent. acetaminophen with caffeine. gabapentin. After an appropriate dose has been attained. Occasionally. the dosage should be increased to 50 mg three times daily.109–111). dihydroergotamine. In a recent study of 26 patients with hemicrania continua or CPH. The headache phase can last from 2 weeks to 4. and attacks have been reported to occur in association with REM sleep. and lithium carbonate (116–120). rhinorrhea. exclusively unilateral. . or coughing. therefore. Attacks of unilateral orbital. The attack frequency between and among individual sufferers varies considerably. while nasal congestion. occurring as infrequently as once a day or less to more than 30 attacks an hour. though these periods can range from one week to seven years. eyelid edema. the cranial autonomic symptoms occur in synchrony with the pain. the majority of patients can trigger attacks by touching the face or scalp. and facial redness or sweating are less commonly reported. restlessness is not a feature of SUNCT syndrome (124). ptosis. with a presumptive Table 5 Diagnostic Criteria of SUNCT According to the International Classification of Headache Disorders-2 Diagnostic criteria A. Attacks occur with a frequency from 3 to 200 per day E. Nausea. All patients. or temporal stabbing or pulsating pain lasting 5–240 sec C. vomiting. in contrast to trigeminal neuralgia. washing. nocturnal attacks are seldom reported. shaving. Ipsilateral conjunctival injection and lacrimation are almost always present. SUNCT SYNDROME SUNCT is a rare primary headache disorder that is more common in males (2:1) and usually begins between the ages of 40 and 70 years (range 10–77 years) (Table 5). Unlike in CPH. periorbital.486 Dodick patients in routine clinical practice. or frontal location. or burning pain (121). Unlike cluster headache. although some report a persistent dull interictal discomfort (123). chewing. The temporal pattern of SUNCT is quite erratic. a response to indomethacin should not be considered either necessary or sufficient to make a diagnosis of CPH or hemicrania continua or of any primary headache disorder. Differential Diagnosis Secondary SUNCT has been reported in several patients with lesions in the posterior fossa or pituitary gland (125. The individual attacks of pain are very brief.126). photophobia. moderate or severe. maximal in the orbital. Most patients are completely pain-free between attacks. or with certain neck movements (124). miosis. Pain is accompanied by ipsilateral conjunctival injection and lacrimation D. The pain peaks and resolves abruptly (122). and often described as an electric shock or as a stabbing. with no predictable timing between symptomatic and remission periods. short-lasting unilateral neurogliform pain with conjunctival injection and tearing. and are often robust. and phonophobia are not normally associated with SUNCT syndrome. most patients have no refractory period between successive triggering stimuli. eating. lasting less than 40 seconds on average (5–200 seconds). supraorbital. talking. brushing teeth. Like other TACs. However. Remissions typically last a few months. Symptomatic periods generally last from a few days to several months and occur once or twice annually. Not attributed to another disorder Abbreviations: SUNCT. Like trigeminal neuralgia. piercing. At least 20 attacks fulfilling criteria B–D B. and baclofen have been reported to be ineffective (128). Open-label lamotrigine 100 to 200 mg has been reported to be highly effective in seven patients. Triptans. . methysergide. 2. A review of paroxysmal hemicranias. microvascular decompression and percutaneous trigeminal ganglion compression have been reported to be effective in three patients (75. Edvinsson L. which are associated with trigger zones in the face and occur in middle or old age. Primary stabbing headache (PSH). surgery should only be considered as a last resort in patients who are truly refractory to medical therapy. For patients with medically intractable SUNCT. 120:193–209. dihydroergotamine. beta-blockers. Because of the considerable overlap in the clinical phenotype. Goadsby PJ. prednisolone. differentiating SUNCT from trigeminal neuralgia can be very challenging. Both are characterized by frequent unilateral stabbing or electric-like shocks of pain of brief duration. Brain 1994. However. REFERENCES 1. ergotamine. Goadsby PJ. Given the uncertain efficacy of trigeminal procedures together with the potential for complications. including trigeminal nerve root section (129). the pain of trigeminal neuralgia is rarely confined to the ophthalmic division of the trigeminal nerve or accompanied by robust cranial autonomic features (124. Human in vivo evidence for trigeminovascular activation in cluster headache: neuropeptide changes and effects of acute attacks therapies. SUNCT can be differentiated from paroxysmal hemicrania by the brevity of attacks (seconds) and by a trial of indomethacin. including new cases.Trigeminal Autonomic Cephalgias 487 diagnosis of SUNCT should have an MRI of the brain with attention to the sellar/ parasellar region and posterior fossa.76). patients with SUNCT syndrome do not respond to indomethacin or medications typically effective for patients with cluster headache. and further broaden the therapeutic and clinical background of this syndrome.127). lithium. Lipton RB. which may be mistaken for SUNCT. suggesting that treatment with lidocaine can be considered when acute intervention is required to suppress a severe exacerbation of SUNCT. tricyclic antidepressants. SUNCT syndrome and other short-lasting headaches with autonomic features. 117:427–434. Treatment Unlike other TACs. Partial improvement with carbamazepine has been observed in several patients (128). and until results for randomized controlled trials become available. nor are they usually exclusive to one side. It has been recently demonstrated that intravenous lidocaine can completely suppress attacks of SUNCT (74). differs in that the attacks last only one to three seconds and they are not usually confined to the orbital/periorbital region. patients with PSH do not report cranial autonomic symptoms. two patients with SUNCT were reported to have failed to respond to similar decompressive or ablative procedures. it is considered the treatment of first choice (68–70). In addition. calcium-channel antagonists (verapamil and nifedipine). phenytoin. However. Gabapentin and topiramate have also been reported in isolated cases to be effective and should be considered as alternative therapeutic options for patients with SUNCT (71–74). Brain 1997. Cephalalgia 1995. Cluster headache—clinical findings in 180 patients. 91:606–617. Heinze A. Silberstein SD. Buchel C. et al. Bono G. 51:908–911. Fusco BM. Sumatriptan nasal spray (20 mg/dose) in the acute treatment of cluster headache. 46:791–794. van Vliet JA. Cluster headache after head injury. May A. 20. Posterior hypothalamic and brainstem activation in hemicrania continua. 4. et al. Di Sabato F. Neurology 1998. 21. (suppl 41):1. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. 11. Bahra A. Pain 1993. Monstad I. Edvinsson L. Goadsby PJ. Fogan L. Zweifler RM. 27. A clinical comparison of cluster headache and migraine. 352:275–278. Gobel H. 20:787–803. Cephalalgia 1998. Ekbom K. 26. pathophysiology. 28. Cohen AS. Acute therapy for cluster headache with sumatriptan: findings of a one-year long-term study. J Pain Symptom Manage 1993. Hypnic headache: clinical features. Buchel C. Neurology 2003. Frackowiak RS. 42:362–363. Cluster headache: a prospective clinical study with diagnostic implications. Niknam R. Clin Pediatr (Phila) 1994. Micieli G. Headache 1995. Goadsby PJ. Headache 1981. 58:354–361. Reik L Jr. Hardebo JE. Arch Neurol 1985. Campbell JK. Dodick DW. et al. 16:448–450. Nappi G. Matharu MS. 10. Kudrow L. Cephalalgia 1992.488 Dodick 3. 8. Bahra A. Cluster headache attacks treated for up to three months with subcutaneous sumatriptan (6 mg). Lancet 1998. Acta Neurol Scand 1970. The Subcutaneous Sumatriptan International Study Group. 32:504–506. Treatment of migraine attacks with sumatriptan. Dawson GA. 21:1–4. Micieli G. Ward N. Terzano MG. et al. 19. Treatment of cluster headache. Cavallini A. Acta Neurol Scand 1970. Headache 2004. . Ekbom K. 12. et al. N Engl J Med 1991. Bahra A. Headache 1987. Ann Neurol 1999. 35:607–613. 44(8):747–761. et al. et al. Bahra A. and treatment. et al. 17. Krabbe A. 8:155–164. et al. 25. 15. 33:241–242. Neurology 2000. 16. Diagnosis and treatment of cluster headache. Mendizabal JE. 52:243–245. 7. et al. Evers S. Martin V. 15:230–236. 18. Patterns of cluster headache with a note on the relations to angina pectoris and peptic ulcer. A double-blind comparison of oxygen v air inhalation. Cephalalgia 2000. Hyperbaric oxygen therapy in cluster headache. May A. Cluster headache: Horton’s cephalalgia revisited. Manzoni GC. Accompanying symptoms of cluster attacks: their relevance to the diagnostic criteria. Umana E. Lindner V. 6. D’Cruz OF. Goadsby PJ. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Goadsby PJ. 60:905–909. Hypothalamic activation in cluster headache attacks. Neurology 2003. Neuropeptide changes in a case of chronic paroxysmal hemicrania—evidence for trigemino-parasympathetic activation. 27:509–510. 60:630–633. Ekbom K. 3:21–30. South Med J 1998. 24. Goadsby PJ. 18:487–489. Headache 1992. 5. Cluster headache following head injury: a case report and review of the literature. et al. et al. McGonigle DJ. Cluster headache with aura. Rozen TD. 325:316–321. 13. Wirth O. 54:219–221. 12:165–168. Turkewitz LJ. Dahlof C. 9. 46:225–237. Micieli G. Cephalalgia 1983. May A. Pelaia P. Cephalalgia 1996. Cluster headaches in childhood. 22. 14. Cluster headache. Neurology 2002. Rozen TD. 23. Preemptive oral treatment with sumatriptan during a cluster period. Response of cluster headache attacks to oxygen inhalation. Krabbe A. Mathew NT. Uemura N. Headache 1989. et al. 43. Peres MF. Local anesthetic abortive agents. Seybold ME. Arrest of attacks of cluster headache by local steroid injection of the occipital nerve. Meeran K. 42:496–498. Migraine: Clinical and Research Advances. Levy MJ. et al. Spierings EL. Marabini S. 54:1832–1839. Kittrelle JP. Jespersen LT. D’Amico D. 43:S159. Methysergide. 30. Preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray in healthy volunteers. Limited efficacy of methysergide in cluster headache: a clinical experience. J Clin Pharmacol 2002. Kailasam J. Ann Neurol 2004. Headache 1987. Onishi T. 48. Siow HC. Zingmark PH. 45. 47. Krabbe A. New York: Springer-Verlag. 42:1237–1243. Hinterberger H. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. 29:167–168. 42. Frediani F. 56: 488–494. 35. Basel: Karger. 44. Eur J Neurol 2003. Gabai IJ. 31. 38. Headache 1983. Wall A. et al. Sicuteri F. Prophylactic treatment of cluster headache with verapamil. 9(suppl 10):404–405. In: Rose CF. 10:76. Cephalalgia 1989. 44:483. A double-blind trial versus placebo. Pain relief by somatostatin in attacks of cluster headache. Bergstrom M. Andersson PG. Headache 1982. et al. 34. et al. Cocaine as an abortive agent in cluster headache. . Zolmitriptan demonstrates good pharmacokinetic consistency between and within individuals following intranasal administration. CNS Drugs 1994. Duvauchelle T. Pain 1984. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. et al. Neurology 2000. 22:520–522. 331 p. Headache 2003. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Cephalalgia 2002. Dixon R. Zolmitriptan (Zomig) nasal spray in cluster headache attacks: a single-blind observation—a preliminary report. 51. Neurology 2004. Lundberg PO. Lanie JW. 1985:169–173. Updating in Headache. Grouse DS. de Carolis P. Oral zolmitriptan is effective in the acute treatment of cluster headache. Curran DA. Nimodipine in episodic cluster headache: results and methodological considerations. Cephalalgia 2003. 22:69–73. et al. 18:359–365. Bahra A. Neurology 1992. 42:22–31. Yates R. Barre F. Br J Clin Pharmacol 2004. Stiles MA. Nairn K. et al. Matharu MS. Rossi P. An open label positron emission tomography study to investigate the distribution of intranasally administered [11C] zolmitriptan into the CNS. 2(3):199–207. et al. 62:A80–A81. 23:266–277. 23:734. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. 36. 54:1382–1385. 57:679–680. Zolmitriptan is detectable in plasma 2 to 5 minutes after administration by nasal spray. et al. Van den Heede M. Neurology 2000. 37. 39. Suboccipital (GON) injection with long-acting steroids in cluster headache: a double-blind placebo-controlled study. Seifer T. 52. Cephalalgia 1986. Gedal M. 41. Mathew NT. Berlin. 49. 1:74–122. 33. Arch Neurol 1985. Hardebo J. Hovsepian L. Leone M. True nasopharyngeal absorption of zolmitriptan following administration of zolmitriptan nasal spray. Hardenberg J. et al. Headache 2004. Res Clin Stud Headache 1967. 32. Baldrati A. et al. Sjaastad O.Trigeminal Autonomic Cephalgias 489 29. Anthony M. Yates R. 40. Greater occipital nerve blockade for cluster headache. et al. Charlesworth B. Geppetti P. Hedlund C. Agati R. Gedal M. Cluster headache. Cluster headache. 50. ed. 46. 27:397–399. 6:51–54. 1985:xxv. Pharmacologic management of cluster headache. Gawel MJ. Meyer JS. Ambrosini A. Silberstein SD. Pfaffenrath V. Tizanidine for chronic cluster headache [letter]. Cephalalgia 2000. Cohen AS. 17:460. 60. Topiramate in cluster headache prophylaxis: an open trial. Headache 1977. Neurology 1999. Freitag FG. A patient with SUNCT cured by the Jannetta procedure. et al. Marabini S. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Urban G. Viruega A. 21:996–999. Rapoport A. Headache 2002. Freitag FG. et al. Diederich N. Leone M. Leandri M. Santonja JM. Gadoth N. 40:408. D’Amico D. 75. Kudrow L. 56. Cephalalgia 1983. Hering-Hanit R. Moschiano F. 38:710–712. SUNCT syndrome responsive to intravenous lidocaine. 21:132–139. Diamond ML. Ekbom K. 3:109–114. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Bono G. Lithium prophylaxis for chronic cluster headache. 74. Wheeler SD. Sodium valproate in the treatment of cluster headache: an open clinical trial. 58. 62. Cephalalgia 2004. et al. 59:321–325. 17:673–675. Boes CJ. SUNCT responsive to gabapentin. 13:114–116. 16:494–496. Headache 1998. et al. Fusco BM. Lanfranchi M. 72. Couturier EG. Pain 1994. Goadsby PJ. 40:48–51. 23:1001–1002. Peepr B. Drug-resistant cluster headache responding to gabapentin: a pilot study. Usai S. Carrazana EJ. Two new SUNCT cases responsive to lamotrigine. Cephalalgia 2001. Matharu MS. 73. Cephalalgia 2000. Cephalalgia 1997. Topiramate in the prophylactic treatment of cluster headache. Goadsby PJ. 71. Hering R. Manzoni GC. 55. 9:195–198. Leone M. Headache 2003. Headache 2000. Mueller LL. Matharu MS. Lithium carbonate in cluster headache: assessment of its short. Gardella L.490 Dodick 53. Dodick D. 24(11):985–992. Lamotrigine in the treatment of SUNCT syndrome. D’Andrea G. Possible usefulness of lamotrigine in the treatment of SUNCT syndrome. Bosch EP. Marks DR. 68. Preventative effect of repeated nasal applications of capsaicin in cluster headache. A case of a patient with SUNCT syndrome treated with Jannetta procedure. Divalproex sodium in the treatment of migraine and cluster headaches. Steiner TJ. D’Alessandro R. 58(8):1307. et al. Mellick GA. 63. Bousser MG. Cephalalgia 1989. et al. A negative trial of sodium valproate in cluster headache: methodological issues. Divalproex sodium in the preventive treatment of cluster headache. Lainez MJA. et al. Phuoe D. Neurology 2002. 61. 57. 17: 15–18. Cephalalgia 2002. Lenaerts M. 53:234–236. Graff-Radford SB. 65. 53:1093. Cephalalgia 1997. Diamond S. Granella F. 79. 77. 69. 57:1723–1725. Headache 1981. Cluster headache management with methylphenidate (Ritalin). Gottlieb A. Hering R. 43:784–789. Maggi CA. SUNCT syndrome responsive to gabapentin. Kuritzky A. Cephalalgia 1993. 59. 67. 66. J Am Osteopath Assoc 2002. SUNCT syndrome: prolonged attacks. refractoriness and response to topiramate. 20:515–517. Cephalalgia 2001. Leone M. 53:1609. 42(6):525–526. 21:744–746. Cephalalgia 1996. 22:205–208. Cephalalgia 2003. et al. Baclofen in cluster headache. Headache 2000. Rigamonti A. 54. 78. Gallagher RM. Arch Neurol 1996. Pascual J. Padla D. Topiramate-treated cluster headache. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Massiou H. Rigamonti A. Salvador A. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cadaldini M. Dodick DW. Hunt CH. Cruccu G. 64. Granella F. 22:205–208. Neurology 1999. Neurology 2001. 70. Pascual AM. 20:845–847. Ponz A. Rojas H. El Amrani M. 76.and long-term therapeutic efficacy. et al. D’Andrea G. Mellick LB. Luzzani M. Ghiotto N. . Magnoux E. Eletriptan for the short-term prophylaxis of cluster headache. J Neurosurg 1997. Franzini A. Treatment of intractable cluster. Dodick DW. 87. Cephalalgia 1984. duration and time of occurrence of attacks. Occipital nerve stimulation for chronic cluster headache. 20:289. O’Brien MD. Poggioni M. 38:3–9. Dodick DW. 61:537–544. 95. Grazzi L. Sjaastad O. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Cephalalgia 2000. Headache 1988. Freitag FG. Headache 1980. Franzini A. 35:193–196. 91. Headache 1998. 97. et al. Long-term followup of hypothalamic stimulation to relieve intractable chronic cluster headache. Percutaneous radiofrequency trigeminal gangliorhizolysis in intractable cluster headache. Neurology 2004. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study. Dodick DW. 104. Jarrar RG. Zlotnik G. Vigl M. 3:159–203. 98. 20:128–131. 102. 4:53–56. N Engl J Med 2001. . Kirkpatrick PJ. 44:249–255. 3:S569–S571. 92. Black DF. Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. et al. Cephalalgia 1993. May A. Neurology 2004. 62:A356 [Abstract]. Outpatient intravenous dihydroergotamine for refractory cluster headache. Sicuteri F. Silberstein SD. Hypothalamic modulation of nociception and reproduction in cluster headache. Gamma knife treatment of refractory cluster headache. Mayo Clin Proc 1986. Russell D. et al. 37:559–560. et al. Attanasio A. Antonaci F. Leone M. Frovatriptan for the treatment of cluster headaches. et al. 62:A355 [Abstract]. 44:361–364. Zebenholzer K. Headache 2004. Headache 1997. Sanders M. Headache 1986. et al. Br J Neurosurg 1993. Hurt W. et al. 38:590–594. 13:253–257. Bussone G. Onofrio BM. 82. Long-term results of radiofrequency rhizotomy in the treatment of cluster headache. Leone M. Schulman EA. Headache 1995.to 70-month follow-up evaluation. 83. Headache 1989. Mathew NT. Van denheeden. 89. Chronic paroxysmal hemicrania: severity. Avery GS. Pozo-Rosich P.Trigeminal Autonomic Cephalgias 491 80. Mather PJ. Franzini A. Naertens AS. Caviness VS Jr. I. Ford RG. Ford KT. Prager J. The clinical spectrum of chronic paroxysmal hemicrania seen at the Mayo Clinic from 1976 to 1996 (abstract). Kotsiki SX. Campbell JK. Trigeminal nerve section for chronic migrainous neuralgia. Headache 1998. Siow HC. Nicolodi M. 103. 31:525–532. et al. 85. Lovely TJ. 345:1428–1429. Cluster headache: response to chlorpromazine. 101. Speight TM. 84. Boes C. et al. 24(12):1045–1048. Diamond S. Surgical treatment of chronic cluster headache. Headache 2004. Cephalalgia 2004. Cephalalgia 2004. Silberstein SD. 26:42–46. 94. D’Amico D. 86. Deep brain stimulation of posterior hypothalamus in chronic cluster headache. 88. Zuurmond WW. Taha JM. 29:648–656. Wober C. 60:1360–1362. MacCabe JJ. Swaid S. 28:328–331. Leone M. 81. Renacle JN. 93. Leone M. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12. 96. Drugs 1972. Pizotifen (BC-105): a review of its pharmacological properties and its therapeutic efficacy in vascular headaches. Therapeutic trials of leuprolide. 100. The surgical management of chronic cluster headache. 87:876–880. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Jannetta PJ. Neurology 2003. 24(11):934–937. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. Headache 1991. Adv Stud Med 2003. Tew JM Jr. 7:483–490. 99. O’Brien P. 90. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. 21:508. 21:507–508. Hemicrania continua: a possible symptomatic case. 124. 36:108–110. Cephalalgia 2001. Lamotrigine efficacy in migraine prevention (abstract). Headache 1996. 113. Kruszewski P. Hemicrania continua: ten new cases and a review of the literature. Pareja JA. Peres MF. SUNCT syndrome or trigeminal neuralgia with lacrimation. Speciali JG. Hemicrania continua in a black patient—the importance of the non-continuous stage. SUNCT syndrome: duration. 116. Headache 1997. Dodick DW. Boes CJ. Joubert J. Rozen TD. et al. 21:374. Peres MF. Dose and efficacy of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua (abstract). Swanson JW. 130. Neurology 1994. 127. J Neurol Neurosurg Psychiatr 2003. Headache 1991. Bordini CA. com/cgi/external_ref?access_num¼8984088&link_type¼MED. Pareja J. Caminero AB. 31:480–482.492 Dodick 105. Antonaci F. Funct Neurol 1992. 114. SUNCT syndrome secondary to prolactinoma [Case Reports. 56(suppl 3):A452. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome: a review. Chronic paroxysmal hemicrania and hemicrania continua. et al. 31:20–26. Levy MJ. Kruszewski P. Neurology 2001. A clinical review. Pareja JA. 21:82–83. Ming JM. .bmjjournals. 107. Stolt-Nielsen A. SUNCT syndrome. 123. Nahmias S. Symptomatic cluster. Cephalalgia 2001. Antonaci F. 121. frequency and temporal distribution of attacks. Noronha A. Interval between indomethacin administration and response. Cephalalgia 2001. Headache 1996. et al. 7(4):308–318. 45:2302–2303. Siow HC. Sjaastad O. 35:363–367. Relief of continuous hemicrania by gabapentin: a case report (abstract). Bordini C. 115. 22(3):201–204. 56(suppl 3):A452. 126.http://jnnp. Pareja JA. Pascual J. Atypical temporal patterns. Neurology 2001. ‘‘Hemicrania continua’’: a clinical review. 117. Alcantara MC. Young WB. 33:551–554. Funct Neurol 1992. 119. Pareja JA. Hemicrania continua with aura. Goadsby PJ. 36:161–165. Matharu MS. 33:485–487. Sjaastad O. Matharu MS. Matharu MS. Cephalalgia 2002. 12:57–59. Headache 1995. 7:471–474. Journal Article]. Eross EJ. Hemicrania continua: an indomethacin-responsive case with an underlying malignant etiology. Goadsby PJ. An overview. 106. Pascual J. Mariano HS. Two cases of medically and surgically intractable SUNCT: a reason for caution and an argument for a central mechanism. 120. 37: 195–202. Sjaastad O. Sjaastad O. Neurology 1993. 128. 111. Headache 1993. Cephalalgia 1992. 35:138–142. Indomethacin-resistant hemicrania continua. Hemicrania continua and symptomatic medication overuse. et al. 44:2111–2114. Headache 1996. Hemicrania continua is not that rare. Sjaastad O. Headache 1991. Silberstein SD. Stovner LJ. due to mesenchymal tumor. Kuritzky A. Soloman S. 112. Silberstein SD. 74(11):1590–1592. 110. 129. Kruszewski P. CPH and hemicrania continua: requirements of high indomethacin dosages—an ominous sign? Headache 1995. Goadsby PJ. Neurology 2001. Black DF. 7:103–107. 108. Newman LC. Boes CJ. 109. SUNCT syndrome: trials of drugs and anesthetic blockades. SUNCT syndrome. Hemicrania continua. Stovner LJ. Headache 1993. Curr Pain Headache Rep 2003. 57:948–951. 122. Wheeler SD. 36:20–23. Chronic paroxysmal hemicrania (CPH) and hemicrania continua: transition from one stage to another. Sjaastad O. Sjaastad O. Sjaastad O. Cephalalgia 2001. Lipton RB. Cohen AS. Appelbaum J. 118. Merry RT. Trigeminal neuralgia and ‘‘SUNCT’’ syndrome: similarities and differences in the clinical picture. Sanchez del Rio M. Pareja JA. Antonaci F. Joubert J. 43:1270. 125. Neurology 1995. Episodic paroxysmal hemicrania responsive to calcium channel blockers. Hannerz J. Poster P1233. Headache 2002. Meadors L. Claveria LE. Kailasam J. and cluster headache with topiramate. 138. Efficacy of topiramate for the prevention of cluster headache. Headache 1992. de Seijas EV. 132. Prophylaxis of migraine. 137. Adolescent chronic paroxysmal hemicrania responsive to verapamil monotherapy. 135.Trigeminal Autonomic Cephalgias 493 131. Sandrini G. Sjaastad O. Antonaci F. 34:597–599. Headache 1994. 40:436–437. 133. Antonaci F. Ericson K. September 4–7. J Neurol Neurosurg Psychiatr 1992. 42:796–803. Wamil AW. Chronic paroxysmal hemicrania: orbital phlebography and steroid treatment. 134. Trucco M. Cephalalgia 1987. Jimenez-Jimenez FJ. McAbee G. Warner JS. Shabbir N. Wheeler SD. 136. 55:166. 2004. Hering-Hanit R. 35:549–550. transformed migraine. Coria F. Presented at 8th Congress of the European Federation of Neurological Societies. France. Mathew NT. Headache 1994. 32:39–40. 139. A piroxicam derivative partly effective in chronic paroxysmal hemicrania and hemicrania continua. Acetazolamide for the treatment of chronic paroxysmal hemicrania. Hemicrania continua: a case responsive to piroxicam-beta-cyclodextrin. Headache 1995. McLean MJ. Bergstrand G. A case report. Rofecoxib-responsive hemicrania continua (abstract). 34:209–210. Headache 2000. Paris. 7:189–192. . . Roosevelt Hospital Center. and Christine L. the proper treatment of these disorders is predicated upon establishing the correct diagnosis. Although included under the rubric of other primary headaches. New York. INTRODUCTION Although migraine and tension-type headaches are the most common headache disorders encountered in clinical practice. Lay The Headache Institute. but not all. this headache is associated with other headache disorders. As noted in the criteria for these disorders in the second edition of the International Classification of Headache Disorders (ICHD-2) (1). Secondary stabbing headache has been associated with intracerebral meningiomas and temporal arteritis (6. Newman.d brings relief in most. some of the syndromes listed within this classification may in fact have secondary etiologies. often coming on in middle or later years of life.i. In patients 495 .5). recognition of other less common primary headache syndromes is important.7).A. the diagnosis of the primary headache can only be given after secondary causes have been excluded. up to 50 times/day. such as migraine. New York. Furthermore. some of the conditions described in this chapter respond dramatically to therapy with indomethacin but not to agents typically prescribed for the other more common primary headaches. This chapter reviews the clinical features and treatment options for several of these rarer disorders.’’ the new ICHD-2 (1) term for idiopathic stabbing/icepick headache. some patients develop repetitive volleys of painful attacks. lasting days at a time (4). which may be bilateral or unilateral and may vary in location. U. chronic paroxysmal hemicrania and cluster (3). often misdiagnosed and mismanaged.1) ‘‘Primary stabbing headache. PRIMARY STABBING HEADACHE (ICHD-2 CODE 4. with a lifetime prevalence of 2% (2). Broner. very brief (1–10 seconds) sharp/stabbing pain. Women are more commonly affected than men and although the attacks are usually self-limiting. Susan W. is a benign headache disorder. cases (4. It typically is described as a paroxysmal. hemicrania continua (HC).S. The pattern and frequency of attacks are quite variable and in more than 50% of cases. The ICHD-2 criteria (1) for primary stabbing headache are listed in Table 1. because the sufferers tend to be desperate.31 Other Primary Headaches Lawrence C. Indomethacin 25 to 50 mg t. it may relate to a sudden increase Table 2 ICHD-2 Criteria for Primary Cough Headache Previously used terms: Benign cough headache. PRIMARY COUGH HEADACHE (ICHD-2 CODE 4. International Classification of Headache Disorders. success has been reported with melatonin. or such disorder is present. Description Transient and localized stabs of pain in the head. which occur spontaneously in the absence of organic disease of underlying structures of the cranial nerves Diagnostic criteria Head pain occurring as a single stab or a series of stabs and fulfilling criteria B and C Exclusively or predominantly felt in the distribution of the first division of the trigeminal nerve Stabs last for up to a few seconds and recur with irregular frequency ranging from one to many per day No accompanying symptoms Not attributed to another disorder Note: History and physical and neurological examinations do not suggest any of the disorders listed in groups 5–12 and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations. Other reported causes of symptomatic cough headache include carotid or vertebrobasilar diseases and cerebral aneurysms. Diagnostic neuroimaging plays an important role in differentiating secondary cough headache from 4. sneezing. the throbbing pain is maximally felt at the vertex. . Abbreviation: ICHD.2) Primary cough headache typically affects men over 40 years of age and while often described as a severe headache of sudden onset. International Classification of Headache Disorders. occipital or temporal areas and associated neurological features or nausea/vomiting are absent. lasting one second to 30 min Brought on by and occurring only in association with coughing. Often bilateral in location. some sufferers may continue to experience a dull ache for several hours afterward.496 Table 1 ICHD-2 Criteria for Primary Stabbing Headache Newman et al. Valsalva-maneuver headache Description Headache precipitated by coughing or straining in the absence of any intracranial disorder Diagnostic criteria Headache fulfilling criteria B and C Sudden onset. straining and/or Valsalva maneuver Not attributed to another disorder Note: Cough headache is symptomatic in about 40% of cases. Within seconds of coughing. and the large majority of these present Arnold-Chiari malformation type I. While the precise etiology is unknown. frontal. however. in doses ranging from 3 to 12 mg daily (8). The headache usually subsides within minutes. it is by definition benign. unable to tolerate indomethacin. Abbreviation: ICHD.2 Primary cough headache. straining or other Valsalva maneuvers an immediate headache is experienced. The criteria for primary cough headache are listed in Table 2. but attacks do not occur for the first time in close temporal relation to the disorder. ) is often the best choice. it is theorized that venous distention following exercise or arterial distention as a result of exercise (especially in a warm environment) may be at the root of the cause.’’ they remain distinct entities in the ICHD-2 classification (1). brain tumor [both malignant and benign (meningioma/acoustic neuroma)]. straining or bending over. secondary exertional headache often begins later in life. While cough and exertional headache are often linked as ‘‘Valsalva maneuver headache. Abbreviation: ICHD.i. Other secondary causes include Chiari malformation. but unlike cough headache. subdural hematoma. . A positive response to indomethacin may be seen in secondary cases and is therefore not diagnostic of primary cough headache. In a small case series. A ‘‘first-ever’’ presentation of exertional headache requires a work-up to rule out SAH or arterial dissection. not surprisingly. Indomethacin is the treatment of choice in those patients who frequently experience cough headache and the sustained release formulation (75 mg q. with subsequent release of vasoactive peptides leading to downstream neurogenic Table 3 ICHD-2 Criteria for Primary Exertional Headache Description Headache precipitated by any form of exercise Diagnostic criteria Pulsating headache fulfilling B and C Lasting 5 min to 48 hr Brought on by and occurring only during or physical exertion Not attributed to another disorder Note: On first occurrence of this headache type it is mandatory to exclude subarachnoid hemorrhage and arterial dissection. Neuroimaging is mandatory in distinguishing the secondary causes from primary cough headache. is of long duration. the headache is associated with neurological features such as meningismus.i. The headache is of sudden onset and often bilateral in location.d. Secondary cough headache has been described in Chiari malformation. The ICHD-2 criteria for primary exertional headache are listed in Table 3.Other Primary Headaches 497 in intracranial pressure with traction on pain-sensitive structures from a downward displacement of cerebellar tonsils. occurs with exertional effort as may occur during physical exercise. International Classification of Headache Disorders. While the pathophysiology of primary exertional headache is unknown. the diagnosis must be questioned. lasts longer (24 hours to weeks) and in cases of subarachnoid hemorrhage (SAH). In addition to unilaterality. the pain is often pulsatile and of longer duration (5 minutes to 48 hours). PRIMARY EXERTIONAL HEADACHE (ICHD-2 CODE 4.d. particularly when the headache is unilateral (9). cerebral aneurysm and carotid or vertebrobasilar disease (9). neuroimaging to rule out a posterior fossa or craniocervical junction abnormality should be undertaken in a patient presenting with new exertional headache. When cough headache occurs in a younger patient. is strictly unilateral or is associated with other features. neoplasm (primary and metastatic) and platybasia (9). lumbar puncture provided prompt relief (10). weight-lifting. or b.3) Primary exertional headache. As in cough headache. In ICHD-2. The pain is excruciatingly severe. Rather. These headaches resemble tension-type headaches in that they are characterized by a dull ache in the muscles of the head and neck. primary headache associated with sexual activity is now separated into preorgasmic and orgasmic headaches (1). however. at the moment of orgasm. These headaches begin abruptly. in the absence of any intracranial disorder Preorgasmic headache Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contraction and fulfilling criterion B Occurs during sexual activity and increases with sexual excitement Not attributed to another disorder Orgasmic headache Sudden severe (‘‘explosive’’) headache fulfilling criterion B Occurs at orgasm Not attributed to another disorder Note: On first onset of orgasmic headache it is mandatory to exclude conditions such as subarachnoid hemorrhage. benign vascular sexual headache. These headaches have also been referred to as benign sex headache. Other NSAIDs may be empirically tried. usually starting as a dull bilateral ache as sexual excitement increases and suddenly becoming intense at orgasm. and may be frontal. a dull type. Preorgasmic headaches (previously classified as the dull subtype) occur in approximately 20% of sufferers. occipital. inflammation (11). Treatment with indomethacin or ergotamine around 30 minutes prior to exercise may be helpful.4) Headaches with sexual activity affect men more often than women. and can be prevented or reduced by deliberate muscle relaxation. Three varieties of these headaches were described in the first edition of the ICHD (15). these subtypes are not classified as such. On occasion this type of Table 4 Criteria of Primary Headache Associated with Sexual Activity Description Headache precipitated by sexual activity. or generalized.13). Some patients describe an awareness of tightness of the muscles of the jaw and neck occurring during sexual activity. Orgasmic headaches (previously called the explosive subtype) are the most common. . beginning as sexual excitement builds. PRIMARY HEADACHES ASSOCIATED WITH SEXUAL ACTIVITY (ICHD-2 CODE 4.498 Newman et al. and a postural type. and may be caused by an increase in blood pressure. coital cephalalgia. the ICHD2 (1) has classified these as primary headaches associated with sexual activity (12–14). or benign orgasmic headaches. it has also been reported to occur more commonly during illicit sexual encounters (12. most often described as explosive or throbbing. It is estimated that 50% of these sufferers also have preexisting migraine headaches (16). accounting for approximately 75% of cases. As they are not solely precipitated by sexual intercourse (similar headaches provoked by masturbation and during nocturnal emissions have been reported) or with orgasm. an explosive type. Preorgasmic headaches are bilateral. These criteria are listed in Table 4. while other patients experience them at infrequent intervals throughout their lifetime. Rarely. One patient has been reported in whom treatment with the calcium channel blocker diltiazem 60 mg t. For most patients.17). . or prophylaxis with the b-blocker propranolol 40–200 mg daily. with meals often prevents attacks. Often patients can lessen the severity of an impending attack by stopping the sexual activity as soon as the headache begins.19). These headaches typically last from one minute to three hours. This headache resembles the headache that follows lumbar puncture in that it worsens with sitting or standing and is relieved by recumbency. Headaches often recur during several encounters over a brief period of time and never return again.d. these headaches are now classified as headaches attributed to spontaneous low cerebrospinal fluid (CSF) pressure. The duration of an untreated attack and in-between attacks varies among patients. arterial dissection and lesions of the posterior fossa. affecting approximately 5% of sufferers.28). and cervical spine (9. and may on rare instances occur during a daytime nap (24. HH usually begins late in life with a mean age at onset of 61 Æ 10 years (range 30–83 years). Table 5 lists the ICHD-2 criteria for HH. which spontaneously develops during sexual activity. Indomethacin 25 mg t. The postural variety is the least common subtype. the headache is hemicranial (28–30). Other options include the use of oral ergotamine tartrate taken a few hours prior to when sexual activity is planned.d. A report of a nine-year-old girl with probable HH has been reported. primary headache disorder that usually begins after 50 years of age. which unfortunately may interfere with sexual function (18. In the largest case study HH was diagnosed in 0.i. Raskin (21) first described the disorder in 1988. The pain in HH is usually localized anteriorly and less often involves the lateral aspects of the head or felt as a diffuse headache. It may be caused by a rent in the dura. and spontaneously resolve in 15 to 180 minutes. but longer attacks of up to 10 hours have been reported. are diffuse and throbbing.5) The hypnic headache (HH) is a rare. This rare subtype is no longer included in the ICHD classification of headaches associated with sexual activity. sleep-related. More than four attacks per week occurred in 70% of the cases and about half of them had daily attacks (range one per week to six per night) (24). although the headache frequency did not meet International Headache Society (HIS) criteria (26). Usually the pain resolves within one to two hours (range 15–180 minutes). On occasion it involves the occiput or radiates into the neck. For patients who suffer from frequent. The diagnosis of primary headache associated with sexual activity is predicated upon the exclusion of secondary causes such as SAH. CSF pathways. however. these are self-limited disorders. The frequency of the attacks is high. The mainstay of treatment of the primary forms of headaches associated with sexual activity is reassurance. Instead. recurrent episodes preventive strategies should be employed. The condition is more prevalent in women (65%) than in men. The headaches of HH occur at a consistent time each night. THE HYPNIC HEADACHE SYNDROME (ICHD-2 CODE 4. both of the patient and their partner.i. the course may be unpredictable. recurrent.07% of all headache patients assessed annually at a specialty clinic reflecting the rarity of this syndrome (23). usually between 1:00 to 3:00 AM.Other Primary Headaches 499 headache may be associated with nausea and vomiting. more than 90 cases have been subsequently reported (22–25). was successful (20). The headaches begin abruptly. Other agents that have been reported to effectively treat HH include bedtime doses of caffeine (40–60 mg tablet. In 1986. or as a cup of coffee) (23. some will choose to delay usage of medications (23). Indomethacin appears to be of utility for patients in whom attacks are strictly unilateral (34).33). but nausea. it is often poorly tolerated. and indomethacin 25 to 75 mg (33–35). Following tumor resection. In the second report. Severe headaches with abrupt onset are often associated with a sinister underlying secondary cause. photophobia. and periodically during treatment. The disorder was first described in 1984 (36). International Headache Society. the patient had a nine-month history of typical HH. Treatment is initiated with 300 mg at bedtime and can be increased to 600 mg at bedtime within a week. and awakens patient At least two of the following characteristics: Occurs >15 times/mo Lasts !15 min after waking First occurs after the age of 50 No autonomic symptoms and no more than one of nausea. and remains the most indicated treatment for HH (21. Lithium was the first. diarrhea. A brain magnetic resonance imaging revealed a large posterior-fossa meningioma. Two reports of probable secondary HH have been described. there was complete resolution of the headache (31). that thunderclap headache (TCH) exists as a primary subtype is controversial. Description Attacks of dull headache that always awaken the patient from sleep Diagnostic criteria Dull headache fulfilling criteria B–D Develops only during sleep. Abbreviation: IHS. No associated autonomic symptoms accompany the pain. but criteria have been suggested in the ICHD-II (1) and are listed in Table 6. Lithium serum concentrations should be monitored as well to avoid toxicity. and polyuria. Although lithium has higher efficacy rates than other medications. In one. Headaches remitted following a spinal blood patch (32).500 Table 5 IHS Criteria for Hypnic Headache Newman et al. Day and Raskin coined the term ‘‘thunderclap headache’’ when describing a patient with a severe. HH-like headaches occurred in the setting of intracranial hypotension.24. Side effects include tremor. rapidly developing headache who had normal computed tomography (CT) of the brain . PRIMARY THUNDERCLAP HEADACHE (ICHD-2 CODE 4.6) Primary thunderclap headache (PTCH) is a severe headache of sudden onset that may persist for several hours. increased thirst. but also reported brief episodes of giddiness. or phonophobia Not attributed to another disorder Note: Intracranial disorders must be excluded.33).22. By reassuring the patients of the benign nature of the headache. photophobia and phonophobia may rarely be present. Distinction from one of the trigeminal autonomic cephalgias is necessary for effective management. Renal and thyroid function should be assessed prior to initiating therapy. flunarizine 5 mg (22.33). although one-third of patients may experience recurrent PTCH over the following months to years. It may occur spontaneously while at rest.42). The majority patients have a normal neurological examination. It comes on suddenly. the headache may linger at a lower level. There . Patients often describe TCH as the worst headache of their life. rarely. PTCH is often self-limiting. nausea. According to ICHD-2 criteria (1). lumbar puncture. Initial work-up should include a head CT. Some patients have a prior history of migraine. although rarely. peaks in intensity within one minute. and arterial dissection amongst others. The differential diagnosis includes SAH (12% of patients with SAH present with the worst headache of their life).39. yet two subtypes of PTCH may exist: one with no angiographic abnormalities and a second subtype with diffuse segmental vasospasm (37. The disorder was first described in 1981 (5) and officially named in 1984 (47). nimodipine may lessen the risk (45. a consistent location or quality of pain has not been described. and/or vomiting. Normal CSF and normal brain imaging are required. HEMICRANIA CONTINUA (ICHD-2 CODE 4. there are no treatment recommendations. magnetic resonance imaging and conventional. Secondary causes of TCH should be aggressively sought. although in one-third of reported cases. Long-term follow-up in patients with PTCH and unruptured aneurysms thus far has not revealed a tendency to bleed (41. reaching maximum intensity in <1 min Lasting from 1 hr to 10 days Does not recur regularly over subsequent weeks or monthsa Not attributed to another disorderb Headache may recur within the first week after onset. cerebrospinal fluid and brain imaging must be normal. In patients with angiographic evidence of segmental vasospasm. CT.46). Patients may experience repeated bouts in the first two weeks. but in whom angiography revealed an unruptured aneurysm with diffuse vasospasm (37). focal deficits have been reported (39). The headache may be associated with light and sound sensitivity. pituitary apoplexy. b a 501 and lumbar puncture. neck stiffness.7) HC is another primary headache that is responsive to treatment with indomethacin. Because PTCH is usually a self-limited disorder. the headache was precipitated by exertion (38). central nervous system vasculitis should be considered. PTCH is a diagnosis of exclusion. Abbreviation: CSF. Clinically. in others it may presage the development of migraine. but this remains controversial (43). and typically lasts several hours. cerebral venous sinus thrombosis. or magnetic resonance angiography of the brain. and when appropriate. PTCH may be part of the migraine continuum.Other Primary Headaches Table 6 Diagnostic Criteria for Thunderclap Headache Severe head pain fulfilling criteria B and C Both of the following characteristics Sudden onset.40). As mandated by the ICHD-2 criteria. Recurrent TCH with vasospasm leading to stroke has been reported (44). These criteria make no mention of the need for angiography. cerebrospinal fluid. Patients usually describe this baseline discomfort as dull. Two temporal profiles of HC exist: an episodic form with distinct headache phases separated by pain-free remissions. lacrimation. continuous headache of mild-to-moderate intensity. aching. Headache for >3 mo fulfilling criteria B–D All of the following characteristics Unilateral pain without side-shift Daily and continuous. Because of the presence of autonomic features that accompany the painful exacerbations. Most patients experience strictly unilateral headaches without side shift. or history and/or physical and/or neurological examinations do suggest such disorder. The pain is maximal in the ocular. temporal. and a chronic form in which headaches persist without remissions (25. these painful exacerbations never reach the level experienced by cluster headache sufferers. HC is chronic from onset in 53% of patients. HC was not included in the first edition of the ICHD guidelines (15). HC was considered to be one of the trigeminal autonomic cephalgias (25). in 35% the disorder began as the episodic subtype and evolved into the chronic . Superimposed upon this background discomfort.502 Table 7 Diagnostic Criteria for HC Newman et al. exacerbations of more severe pain. conjunctival injection. or such disorder is present but headache does not occur for the first time in close temporal relation to the disorder. although three patients in whom attacks alternated sides (50–52). and three bilateral cases have been described (53–55). chronic daily headaches in sub-specialty practices (48). Migrainous symptoms. and phonophobia may also accompany the exacerbations of pain. and it is not associated with other symptoms. However. The age of onset ranges from 11 to 58 years (mean 34 years). and nasal congestion) occur ipsilateral to the pain. Many patients report primary stabbing headaches (stabs and jabs). and maxillary regions. HC is thought to be under-recognized in the general population. vomiting. Abbreviation: HC. photophobia.57). Although significantly more intense than the baseline pain. or pressing. such as nausea. These exacerbations may occur at any time and frequently awaken the patient from sleep. hemicrania continua. and a feeling of sand or an eyelash in the affected eye (foreign body sensation) (49). one or more autonomic symptoms (ptosis. During these flare-ups. The disorder demonstrates a female predominance with a femaleto-male ratio of approximately 2:1. but it is ruled out by appropriate investigations. HC is characterized by a unilateral. without pain-free periods Moderate intensity. Criteria for HC are listed in Table 7. but is a common cause of refractory. unilateral. lasting 20 minutes to several days are experienced by the majority of sufferers. the ICHD-2 (1) includes HC within the other primary headaches section. a are now more than 100 reports of HC in the literature. Clinically. but with exacerbations of severe pain At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain Conjunctival injection and/or lacrimation Nasal congestion and/or rhinorrhoea Ptosis and/or miosis Complete response to therapeutic doses of indomethacin Not attributed to another disordera History and physical and neurological examinations do not suggest any of the disorders listed in groups 5–12.56. however. and vomiting that may occur during exacerbations. indomethacin should be given for slightly longer than the usual headache phase and then gradually tapered. Similarly. by focusing on the associated photophobia. nighttime dosing with sustained-release indomethacin often prevents nocturnal exacerbations. occurring within one to two days after the effective dosage is reached. either acutely or over a maximum of three days. in one week if there is no response or only partial benefit. nor the associated phenomena typically reported with migraine accompany this baseline pain. and the diagnosis of HC can then be made. In patients suffering from the episodic form of HC. HC may be misdiagnosed as migraine. the disorder may be incorrectly diagnosed as cluster headache. neither the ipsilateral autonomic features of cluster.8) New daily-persistent headache (NDPH) is a headache that develops de novo.i. one in whom an initially chronic course evolved into the episodic form. During the active headache cycle.d. In patients with the chronic sub-type. phonophobia. If the physician focuses on the ipsilateral autonomic features that accompany the painful exacerbations. and celecoxib (61). NEW DAILY-PERSISTENT HEADACHE (ICHD-2 CODE 4.i. patients report that skipping or even delaying doses of indomethacin may result in the prompt re-emergence of symptoms. The gastrointestinal side effects of indomethacin can be mitigated with antacids. at times doses as high as 300 mg daily may be required. piroxicam (25). ibuprofen. Organic mimics of HC have been reported: a mesenchymal tumor involving the sphenoid bone. criteria for HC but failed to respond to indomethacin or other agents have been described (62). nausea. and skull base created symptoms of HC (25). rofecoxib (60).Other Primary Headaches 503 form. The diagnosis of HC may be masked by medication overuse headache (59). Indomethacin is the treatment of choice for HC.58). an unremitting headache will remain. . unremitting headache. It has features of both migraine and tension-type headache: it is usually bilateral. Patients who have otherwise met. HC is distinguished from cluster and migraine by the presence of a continuous baseline headache of mild-to-moderate severity. Headache resolution is usually prompt. with discontinuation of the overused agents. Therapy is usually initiated at a dose of 25 mg t. and response to therapy with indomethacin is necessary for establishing the diagnosis (1). These agents should always be considered for those patients requiring long-term therapy. phonophobia. or mild nausea. and paracetamol with caffeine. Two atypical presentations of HC. Dosage adjustments are occasionally necessary to treat the clinical fluctuations that are sometimes seen with HC. Although the ICHD-2 requires indomethacin responsiveness as a diagnostic criterion. HC is frequently misdiagnosed as another primary headache syndrome. of mild-to-moderate intensity without worsening by physical activity.d. This has been termed ‘‘indomethacin-resistant hemicrania continua’’ but as such would not meet ICHD-2 criteria (1) for the disorder. and increased to 50 mg t. in 12% it begins and remains episodic (48). or histamine H2 receptor antagonists. other agents have been reported to induce a partial response. Maintenance with doses ranging from 25 to 100 mg usually suffices. These include naproxen. clinoid process. and then persists as a daily. and a patient with episodic HC with a clear seasonal pattern have been described (48. although response may take as long as two weeks. pressure-like. and may be accompanied by photophobia. paracetamol. misoprostel. long-term indomethacin dosing is required. These headaches were usually bilateral. . there may be two forms of NDPH: a self-limited subtype and a refractory. new daily-persistent headache.69).504 Table 8 Diagnostic Criteria for NDPH Newman et al.65). neoplasm. lightheadedness. The current ICHD criteria are listed in Table 8. Whereas the initial report of NDPH suggested a benign outcome. an unambiguous description of this recollection is part of the criteria. chronic meningitis. Medications reported to have some efficacy include topiramate and gabapentin (65). Such onset or rapid development must be clearly recalled and unambiguously described by the patient. No consistent pain location is described in the reported cases of NDPH.67). Otherwise code as 2. and photo. in fact. continuous. or history and/ or physical and/or neurological examinations do suggest such a disorder but it is ruled out by appropriate investigations. Secondary mimics of NDPH include low. tizandine. Over subsequent years.71–73). a The patient typically can recall the day of onset and. with the peak age in the second to fourth decades. Headache for >3 mo fulfilling criteria B–D Headache is daily and unremitting from onset or from <3 days from onseta At least two of the following pain characteristics: Bilateral location Pressing/tightening (non-pulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Both of the following: No more than one of photophobia. with most patients becoming headache-free regardless of treatment (63). In men.or high-pressure CSF headaches. fluvoxamine and paroxetine (67). and concentration difficulties are also described (63. subsequent descriptions suggest a more intractable course (65). baclofen. amitriptyline. Neck pain. further cases were identified and various investigators published proposed criteria (64. Additionally. and phenelzine (72). NDPH appears to be a relatively rare disorder with a female predominance.65). Indeed. blurred vision. NDPH was first described in 1986 (63). or mild nausea Neither moderate or severe nausea nor vomiting Not attributed to another disorderb Headache may be unremitting from the moment of onset or very rapidly build up to continuous and unremitting pain. A high percentage of patients have features typical of migraine. Abbreviation: NDPH. valproic acid. cerebral venous sinus thrombosis. or such disorder is present but headache does not occur for the first time in close temporal relation to the disorder. The age of onset in women ranges from 13 to 73.70). posttraumatic headache. with the peak age in the third to fifth decades (62.3 Chronic tension-type headache. a significant number of adolescents with chronic daily headache have been found to meet criteria for NDPH (68. SAH. postinfectious headache. virally-induced trigeminal nerve damage (66.and phonophobia. vomiting. The initial report described 45 patients with no previous headache history who developed daily headaches from onset. phonophobia. invoking a possible autoimmune etiology or even perhaps direct. persistent subtype (65). and associated with nausea. There is some data suggesting an infectious etiology to the disorder. Two studies have found elevated Epstein–Barr Virus titers in these patients.66.2 Medication-overuse headache and its subforms). the age of onset ranges from 14 to 67. and giant cell arteritis (65. b History and physical and neurological examinations do not suggest any of the disorders listed in groups 5–12 (including 8. Sexual headaches: case report. each of the headaches included within this subcategory have as part of their diagnostic criteria the mandate that their diagnosis can only be made after secondary causes have been appropriately excluded. Gubbay SS. Headache 1988. 30:203–205. Edis RH. 4. Dodick D. 8(suppl 7):1–160. 38:710–712. 17. Clinicians must. Headache 2001. Neurology 1995. J Neurol Neurosurg Psychiat 1991. The International Classification of Headache Disorders. Stewart-Wynn EG. 46:1520–1524. Ramussen BK. Uncommon headaches: diagnosis and treatment. Oterino A. 2nd ed. A study of coital related headaches in 32 patients. remain vigilant as many of these syndromes may have an underlying secondary cause. cranial neuralgias and facial pain. 15:45–68. REFERENCES 1. Berciano J. 15. 10. 9. Cluster headache variant: spectrum of a new headache syndrome. Pareja JA. Suppl 1:1–160. 8:19–26. Mascellino AM. 20. Idiopathic stabbing headache (jabs and jolt syndrome). Rozen TD. Neurogenic model of migraine. Headaches related to sexual activity. 12. Porter M. Iglesias F. Arch Neurol 1981. 11. 38:138–141. Bonamini M. Jacome DE. Medina JL. Neurology 1996. Akpunonu BE. Silbert PL. 7. Cephalalgia 1995. 61:865–866. Masturbatory-orgasmic extracephalgic pain. Headache 1994. 8. Ahrens J. 54:417–421. and is especially rewarding for the health-care professional as well. 41:599–601. however. 45:1784. et al. Masturbatory-orgasmic pain. 28:534–536. 18. 15:277–280. and treatment with calcium channel blocker. 34:214–216. Buzzi MG. 14. Cephalalgia 1995. The hypnic headache syndrome. primary headaches. Arch Neurol 1981. Cephalalgia 1988. Neurology 2003. Stabbing headache as the presenting manifestation of intracerebral meningioma: a report of two patients. 6. Schwartz RK. 2. Pascual J. Current Pain Headache Rep 2004. 8:333–341. 16. 31:141–145. 38:705–709. proper diagnosis and treatment significantly improves the lives of patients with these disorders. Lance JW. Robbins L. Kumar KL. Neurology 1980. Vazquez-Baquero A. Indomethacin-responsive headache syndromes. exertional and sexual headaches: an analysis of 72 benign and symptomatic cases. Differential diagnosis and treatment. Cough. 21. 5. 16:93–96. J Gen Int Med 1993. Benign coital cephalalgia. Raskin NH. Rujiz J. Classification and diagnostic criteria for headache disorders. Epidemiology of headache. Cephalalgia 2004. J Neurol Neurosurg Psychiat 1976. 3. Raskin NH. Melatonin as treatment for idiopathic stabbing headache. 13. Icepick-like pain. 5(suppl 3):300–301. Newman LC. Indeed. The cough headache syndrome: treatment. Reuler JB. Many of the syndromes discussed here demonstrate a unique response to treatment with indomethacin. Moskowitz MA. Lay CL. Jancovic J. . 39:1226–1230. Cephalalgia 1985. Headache 1998. Diamond S. Selwyn DL. Cephalalgia 1996.Other Primary Headaches 505 CONCLUSION The disorders discussed in this chapter are by definition. Raskin NH. Deisla C. 19. Headache Classification Committee of the International Headache Society. review. Headache Classification Committee of the International Headache Society. Headache 1991. Benign vascular sexual headache and exertional headache: inter-relationships and long term prognosis. Takeuchi T. Peatfield RC. Headache 2004. Phildelphia: Lippincott Williams and Wilkins 2006:847–850. Cephalalgia 2000. Hypnic headache: another indomethacin responsive headache syndrome?. Harling DW. Thunderclap headache: is it migraine?. 43:1007–1008. 43. 44. Evers S. The hypnic (‘‘alarm clock’’) headache syndrome. Gould JD. 20:132–135. 25. The hypnic headache syndrome: report of three new cases. Newman LC. Freeman WD. Dodick DW. Headache 1995. The hypnic headache syndrome: a benign headache disorder of the elderly. Painful states: a neurological commentary. 40:1904–1905. 6:226–232. Brazis PW. Mendoza ND. 28. 60(6):905–909. Abbott RJ. Nonaneurysmal thunderclap headache with diffuse. 35:1–6. Wang SJ. 38. 40:412. Mosek AC. Barreiro. Welch KMA. Dodick DW. Lancet 1988. Van Hille PT.506 Newman et al. Mosek AC. Lancet 1986. Silberstein SD. Long-term follow-up of 71 patients with thunderclap headache mimicking subarachnoid haemorrage. 45. Headache 2003. Headache 2000. Ramadan NM. Ballaban-Gill K. 36. Jones JM. 2:1247–1248. Kerkhoff H. Brain 1997. Nowak DA. including new cases. 31:32–53. Goadsby PJ. 26. Headache 2000. van Gigjn J. Huston J. 34. Neurology 2003. Slivka A. 62(8):1414–1416. Lu SR. 33. Solomon S. Soler R. Ivanez V. Britton JW. Fischer CM. Dodick DW. Morales-Asin F. Hypnic headache and intracranial hypotension. The hypnic headache syndrome. 39. Neurology 2004. Strum JS. 120:193–209. The Headache. 18:157–158. In: Olesen J. Cephalalgia 1997. Recurrent thunderclap headache associated with reversible intracerebral vasospasm causing stroke. SUNCT syndrome and other short-lasting headaches with autonomic feature. Unilateral hypnic headache: a case study. 42. 40:830–835. 40. Lipton RB. Goadsby PJ. Campbell JK. Brown RD. 31. pathophysiology. 23:218–222. Gould JD. Philbrook B. Necessity for searching for cerebral aneurysm in thunderclap headache patients who show no evidence of subarachnoid hemorrhage: investigation of m8 minor lead cases on operation [Japanese]. 24. and treatment. 24:437–441. 3d ed. Unilateral hypnic headache: a case study. Newman LC. Nimodipine for treatment of primary thunderclap headache. Tfelt-Hansen P. 29. 2:68–70. 22. Cephalalgia 1998. Solomon S. Mauri JA. Lirng JF. Cephalalgia 1999. Thunderclap headache. 46. et al. Kojima S. 9:87–90. Silberstein SD. Current Pain Headache Rep 2002. 17:310. Neurology 1997. Clinical and angiographic features of thunderclap headache. Reversible segmental cerebral vasoconstriction (Call-Fleming syndrome): are calcium channel inhibitors a potential treatment option? Cephalalgia 2003. A review of paroxysmal hemicranias. 35. Lipton RB. segmental. Thunderclap headache: symptom of unruptured cerebral aneurysm. Raskin NH. Fuh JL. 41. Macdonell RA. Neurology 1990. Cephalalgia 1989. Headache 2004. Capobianco DJ. Kasahara E. Lipton RB. 18:225–226. Cephalalgia 1998. Hypnic headache: clinical features. Day JW. and reversible vasospasm. Henneken S. Posterior fossa meningioma presenting as hypnic headache. Capobianco DJ. Cephalalgia 1998. Hypnic headache in childhood?. Liao YC. Mostacero E. Iniguez C. Hypnic headache syndrome: a case with good response to indomethacin. Clin Neurosurg 1984. 23. 32. 18:152–156. Iwasaki M. Rodiek SO. Wijdicks EF. . Goadsby PJ. Lamer T. 49:1749–1751. Hypnic headache: another indomethacinresponsive headache syndrome?. No Shinkei Geka 1996. Grossberg BM. multifocal. 19:1–6. 37. 30. Dodick DW. 44:497. eds. Peatfield RC. 44:498. 27. Espada F. Dodick DW. Jones JM. 20:130–131. Lay CL. Trucco M. 42:530–531. Neurology 2004. Chronic paroxysmal hemicrania (CPH) and hemicrania continua: transition from one stage to another. Vanast WJ. 1:411–415. Nahmias S. Solomon S. Rozen TD. Boes C. New daily persistent headache. 64. 49. 70. New daily persistent headache. Hemicrania continua and symptomatic medication overuse headache. Medical Clinics of North America. 7:169–170. et al. Cluster and related headaches. Tatsumi C. 14:307–308. Antonaci F. Petit H. Sjaastad O. Cephalalgia 1987. Hemicrania continua: a case responsive to piroxicam-beta-cyclodextrin. Gladstein J. Pasquier F. Lipton RB. 2001:997–1016. ‘‘Hemicrania continua’’: a possible case with alternating sides. Peres MFP. 61. Philadelphia: WB Saunders. Hemicrania continua: ten new cases and a review of the literature. Antonaci F. 4:65–70. et al. 36:349–351. Solomon S. 63:843–847. Leys D. Evans RW. Marano E. Headache and painful lymphadenopathy in extracranial or systemic infection: etiology of new daily persistent headaches. Hemicrania continua responds to cyclooxygenase-2 inhibitors. 32:530–533. 22:66–69. ed. Silberstein SD. 48. Newman LC. Headache 2002. Sjaastad O. Curr Pain Headache Rep 2003. 67. Peres MF. 57. Nakano M. Headache 2004. Zuckerman E. Silberstein SD. Spears RC. Newman LC. Peres MF. In: Mathew NT. Hemicrania continua: attacks may alternate sides. Tyrell DL. 66. Hemicrania continua responsive to rofecoxib. Hemicrania continua is not that rare. 26:318. 9: 301–303. Primary chronic daily headache and its subtypes in adolescents and adults. Silberstein SD. Cephalalgia 1994. Tepper SJ. Neurology 2001. Mathew NT. Sjaastad O. Spierings ELH. 58. 22:551–554. effectiveness of drugbased treatment. Headache. Hemicrania continua: remitting stage evolved from the chronic form. 69. 72. 71. Russell M. 33:485–487. Vanast WJ. and prognosis of new daily persistent headache (NDPH): 30 cases in Japan. Cephalalgia 2002. J Neurol Neurosurg Psychiat 2002. Cephalalgia 1992. Headache 1994. . Cephalalgia 2000. Cephalalgia 2004. Lipton RB. 59. 24:955–959. 57:948–951. Santoni-Williams CH. Lipton RB. Indomethacin-resistant hemicrania continua. Iordanidis T. Goadsby P. 7:303–307. 54. Clinical features. Classification of daily and neardaily headaches: proposed revisions to the IHS criteria. Bigal ME. 62. Solomon S. Lipton RB. 56. Neurology 1994. Diaz-Mitoma R. 32:39–40.Other Primary Headaches 507 47. 63. Gennaro DR. Sandrini G. 34:1–7. Headache 1993. Holden EW. 44:2111–2114. Intern Med 1993. Headache 1986. The clinical characteristics of new daily persistent headache. Headache 1992. Hemicrania continua: the first bilateral case. Lancet 1987. Headache 1996. 53. Giampiero V. 60. Curr Pain Headache Rep 2003. Newman LC. 65. Headache 1993. Goadsby PJ. 7:218–223. Rozen TF. Cephalalgia 1989. 12:57–59. Young WB. Chronic daily headache in children and adolescents: a 2-year prospective study. 55. Li D. Hemicrania continua: a third case in which attacks alternate sides. Kuritzky A. 50. Headache 1992. 52. Pareja JA. Rapoport AM. Cephalalgia 1980. 35:161–162. Lipton RB. Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches. 32:237–238. 51. Newman LC. New daily persistent headaches definition of a benign syndrome. Silberstein SD. Hemicrania continua: another headache absolutely responsive to indomethacin. Hemicrania continua: a case report. 73. 44(8):821–823. Matsuyama. New daily persistent headache. Santoni JR. 72(suppl II):ii6–ii9. 68. Headache 1995. Takase Y. . particularly the patient with chronic daily headaches. Managing the headache patient. New York. New York. Marcelo E. they account for about one in five outpatient visits (1. and The New England Center for Headache. The Montefiore Headache Center. U. We have grouped these treatment failures into five broad categories (Table 1). New York. This issue takes three major forms: a secondary headache disorder goes undiagnosed.S. New York. We find it helpful to consider these categories when confronting treatment-refractory patients. INTRODUCTION Headache disorders are a leading reason for neurologic consultation in the United States. Albert Einstein College of Medicine. When a patient fails to respond as expected to an appropriate therapy or announces at the first consultation that he or she has already tried everything and nothing works. and The Montefiore Headache Center. U. Lipton Departments of Neurology. In this chapter.2). we summarize the common as well as uncommon reasons for headache treatment failure.S.A. REASON 1: THE DIAGNOSIS IS INCOMPLETE OR INCORRECT Perhaps the most common reason for treatment failure is that the diagnosis is inaccurate or incomplete. Secondary Disorders Go Undiagnosed Patients with intractable headache often live with both the hope and the fear that the doctor ‘‘missed something. Connecticut. We will consider these three forms of diagnostic error one at a time.A. The discussion that follows is organized around these categories of treatment failure with an emphasis on opportunities to improve patient outcomes. or two or more headache disorders are present and at least one goes unrecognized. it is important to identify the reason(s) for failure of that treatment. is difficult (3.32 When the Treatment of Headache Fails Richard B. a primary headache disorder is misdiagnosed. Albert Einstein College of Medicine.’’ This is also a concern for clinicians who care for 509 .4). Epidemiology and Population Health. Stamford. Bigal Department of Neurology. They are of particular concern in patients presenting to the emergency department. These disorders rarely cause chronic headaches. Acute medication overuse with rebound headache is probably the most common secondary disorder that causes intractability (3–6). or other intracranial catastrophes (9).510 Table 1 Possible Reasons Leading to Treatment Failure The diagnosis is incomplete or incorrect A secondary headache disorder goes undiagnosed A primary headache disorder present is misdiagnosed The number of headache disorders is not clear Important exacerbating factors have been missed Acute headache medication or caffeine overuse Hormonal triggers Dietary or lifestyle triggers Psychosocial factors Other medications Pharmacotherapy has been inadequate Ineffective drug Excessive initial doses Inadequate final doses Inadequate duration of treatment Combination therapy required Poor absorption Noncompliance Nonpharmacologic treatment has been inadequate Physical medicine Cognitive behavioral therapy Other factors Unrealistic expectations Comorbid and concomitant conditions Inpatient treatment required Lipton and Bigal patients with difficult-to-manage headaches. Detection of many of these disorders requires a systematic approach to the headache history and physical examination as well as a high index of suspicion. Temporal Profile of Headache Onset The temporal profile of the headache. We will highlight some of these critical issues. but can result in the intractability of an ongoing headache attack. A few examples are listed below:  A rapid-onset headache may suggest a subarachnoid hemorrhage (7).  Headaches that start after age 55 suggest an organic disorder such as a mass lesion or giant cell arteritis (11). The temporal profile of a headache can provide important clues to its etiology. . Rapid-onset headache also can be acute-onset migraine. Other less common secondary causes of intractable headaches are summarized in Table 2. as well as its nature and the circumstances of its onset. pituitary apoplexy (8).  Sphenoid sinusitis may cause a subacute intractable headache and may be missed radiologically unless appropriate studies are performed (10). is crucial for diagnosis. Giant cell arteritis is often underdiagnosed and is an important cause of preventable blindness in the elderly. including carcinoma Disorders of the trigeminal nerve.  Similarly. anemia.) Vasculitis/rheumatic/connective tissue disorders Miscelanias Mediastinal and thoracic processes including angina. exposure to carbon monoxide and other toxins Hormonal disturbances/endocrinologic disease (estrogen.  Fever suggests an infectious etiology. . Headache associated with substances or their withdrawal Overuse of acute headache medications (rebound or toxic drug overuse syndromes) Headache associated with cranium.When the Treatment of Headache Fails Table 2 Secondary Headaches That Mimic Chronic Benign Headache Syndromes 511 Headache associated with vascular disorders Cerebrovascular disease including carotid artery dissection and arteriovenous malformation Arteritis including giant cell arteritis Headache associated with nonvascular intracranial disorders Low CSF pressure syndrome (spontaneous or posttraumatic CSF ‘‘leak’’) High CSF pressure without papilledema Intracranial: Lyme disease. upper cervical joint. optic neuritis and other ocular disorders Occipitocervical disease. renal disease.  In contrast. including Arnold-Chiari Malformation Type I. etc. or an epidural block) (13).  When headache is worse in the morning. and some of them are listed and commented upon below:  Headaches that occur in the peripartum period may be due to dural sinus thrombosis (12). or sneezing suggests a hindbrain malformation. metabolic or systemic disturbances Hepatitis. eyes. it may suggest raised intracranial pressure. nose. etc. including chronic sphenoid sinusitis (or other sinus disease) Nasopharyngeal disorders. when headache is better in the morning and worse at night. jaw pathology Subacute angle closure glaucoma. including dental and oral disease. or other facial or cranial structures Otolaryngologic disease. mouth. or nerve (neuralgic) syndromes Headache associated with noncephalic infection. neck. thyroid disease. Concurrent Events or Provoking Activity Concurrent events and headache triggers may give clues to diagnosis. sinuses.  Orthostatic headache suggests headache attributed to low cerebrospinal fluid (CSF) pressure (from a spontaneous CSF leak. fungal meningitis. occipitocervical junction disorder. hyperprolactinemia. ears. teeth. mass lesions. human immunodeficiency virus. coughing. cerebrospinal fluid. superior vena cava syndrome Abbreviation: CSF. B12 deficiency. it may suggest low CSF volume headache (13). or increased intracranial pressure (14). root. headaches that are worse on awakening sometimes occur with obstructive sleep apnea (13).  Headache triggered by straining. encephalitis. a previous lumbar puncture. 512 Lipton and Bigal  Increasing pain while upright. Many patients with intractable headache have had multiple neuroimaging procedures. etc. lymph nodes. For truly intractable patients who fail many therapies. Diagnostic Testing. neck. a lumbar puncture is important to identify inflammatory or infectious changes that could indicate aseptic or chronic meningitis (including seronegative Lyme disease) (29). Cisternography or computed tomography (CT) myelography is indicated when low CSF pressure is the most likely diagnosis. ears. Obesity and pulsatile tinnitus are risk factors for idiopathic intracranial hypertension (IIH) (31). despite the fact that it can render an individual refractory to standard headache treatments (19). pus. or infection if the pain is periorbital (22). as well as idiopathic intracranial hypertension (IIH) (without papilledema) (30). including intravenous dihydroergotamine. or pressure may suggest sinus disease (23).  Search for opportunistic infections. and headache provoked by flexion or extension of the neck might suggest an occipitocervical junction disorder or a systemic medical illness (15). sphenoid sinus. oral cavity health.  A skin rash suggests Lyme disease. if prior studies are negative. drainage. a rare disorder sometimes termed ‘‘cardiac cephalalgia’’ (16). including toxoplasmosis and cryptococcal meningitis. visual function. In such cases. lumbar puncture should be avoided because it can worsen intracranial hypotension. (17). in patients who may have HIV infection or HIV risk factors (18). The strategies for investigation of secondary headaches are described in detail in Chapter 10. eye movement. including the occipitocervical junction. Neuroimaging does not obviate the utility of lumbar puncture in these circumstances (31). sella tursica.  Nasal blockage. submandibular pain (indicating styloid process factors.  The history often neglects recent dental procedures. Physical Examination. Root canals. In brief.  Postictal headaches might be of special importance especially considering that migraine and epilepsy are comorbid (20). neck pain. tooth extractions. Other dermatologic disorders might suggest the presence of a systemic or localized disease such as antiphospholipid syndrome. Sneddon’s syndrome. disc margin clarity. and pain and discomfort in the temporomandibular joint area may provide diagnostic clues (25).  A previous mild to moderate head or neck injury is frequently overlooked in the standard history. consider studies targeted to suspected sites of pathology. or bite disturbances may provoke or be associated with the development of intractable headache due to brain abscess (21). herpes zoster. such as eyes. Occipitocervical pain on palpation and movement.  Headaches associated with exercise may be an anginal equivalent. and others with trigeminal innervation. carotid artery tenderness masses). Nasopharyngeal carcinoma can produce chronic head and face pain and can be identified by detailed. and nasopharyngeal regions (26–28). The physical examination should focus on the organs that are important in headache provocation. . expert examination of the nasopharynx or neuroimaging (24). or sarcoidosis (17). A diagnosis of posttraumatic headache may lead to additional treatment including trigger point injections and facet joint and cervical nerve blocks.  Consider ocular disturbances such as subacute angle closure glaucoma. exacerbations are more typically accompanied by nausea. we will review some primary headache disorders often missed in neurologic practices. The hypnic headache syndrome is a primary headache disorder of the elderly. photophobia. One example is the well-recognized association described as the cluster-tic syndrome. All these disorders are described in detail in previous chapters. and a greater attack frequency (often five or more attacks per day) (37. In contrast to cluster headache.36). patients have both cluster headache and trigeminal neuralgia and need treatment for both disorders. Both disorders are characterized by chronic unilateral pain with superimposed painful exacerbations. lacrimation. Herein. or 120 mg of verapamil at night can be useful. sometimes from rapid eye movement sleep. the painful exacerbations are often associated with ipsilateral autonomic features such as conjunctival injection.33. or diffuse and lacks the intense. a trial of indomethacin may be warranted when conventional treatment for cluster headaches or trigeminal neuralgia fails (40). and phonophobia (34. Both disorders are characterized by short-lived. Responses to indomethacin are usually very clear and easy to evaluate in PH. Like cluster headache. throbbing. When headache is controlled.42). attacks increase in frequency over time. the PHs show a female preponderance. and ptosis (32. the dose can generally be lowered and headache control is maintained. hypnic headache pain is usually bilateral. . usually occurring in individuals over the age of 60 (41. patients with hemicrania continua usually do not have antecedent history of episodic migraine. If the headaches are longstanding. In atypical patients. Hemicrania continua (32. In typical patients. The hypnic headache syndrome responds promptly to an evening dose of lithium carbonate 300 mg or to slow-release lithium. A recent case series suggests that unilateral hypnic headache is more common than previously believed (43). Paroxysmal Hemicrania.33) with its chronic. but may take up to two weeks to develop fully. In chronic migraine. Unilateral headache does not exclude the diagnosis. the PHs may be either episodic or chronic (39). a prompt response to indomethacin confirms the diagnosis (39).35).38). It is advisable to offer patients with unilateral chronic daily headache a therapeutic trial with indomethacin prior to other intervention (doses of up to 225 mg/day for three to four days).38). it does not usually have the morning and end-of-dosing-interval pattern of exacerbations typical of chronic migraine.35). unilateral attacks of pain with ipsilateral autonomic features (37. the patient may not remember how they began. melatonin. Two or More Headache Disorders Diagnosis is complicated when two or more headache disorders coexist or when patients classify their headache experience differently than the doctor. and also does not have the autonomic features. it is characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain that awakens the patient at a consistent time each night. In addition. caffeine. unilateral orbital and periorbital knife-like quality of cluster headaches. In hemicrania continua. Although pain fluctuates in hemicrania continua. If lithium is unsuccessful. Unlike cluster headache. unilateral pain is commonly mistaken for transformed migraine (34. Paroxysmal hemicrania (PH) is occasionally mistaken for cluster headache.When the Treatment of Headache Fails 513 Misdiagnosed Primary Headache Misdiagnosed primary headache disorders constitute a rare but important reason for intractability. a shorter attack duration (typically 2–30 minutes). Like cluster headache. Hypnic Headache. In transformed migraine. ergots. The patient may not be able to clearly report the onset or characteristics of the two disorders. REASON 2: IMPORTANT EXACERBATING FACTORS MAY HAVE BEEN MISSED Medication overuse (prescription or over-the-counter analgesics. Sometimes hormonal therapy improves headache control. butalbital. and triptans).4. When a new headache type emerges in a patient with an established headache disorder. psychosocial factors. may trigger headaches (49). especially red wine. caffeine overuse. Alcohol use. caution is advisable.46). The patient with migraine commencing after head injury may have components of the post-traumatic headache disorder. Stressful life events such as divorce. when compared with controls (48). we can often control headaches despite hormone therapy. Hormonal factors may trigger headaches and contribute to intractability (47). we begin by asking about factors the patient may have identified and then probe for common and uncommon exacerbating factors. Sleep apnea is common in middle-aged obese men .46). In the search for exacerbating factors. therefore. may be due to aseptic meningitis and intracerebral and subarachnoid hemorrhage. widowhood. Caffeine overuse (including the dietary intake) can be an important cause of intractability (3. Intractable bouts of headache in established migraine sufferers. education. and triptans produce increased headache frequency and significantly attenuate the effectiveness of both acute and preventive treatments. medication overuse and withdrawal is by far the most common cause of intractability (45. In headache subspecialty practices. including both prescription and over-the-counter medication. The treatment of medication overuse is described in detail in Chapter 27. Estrogen withdrawal and fluctuation leads to headache exacerbation during menses and during the perimenopausal period. Dietary or lifestyle factors may play a significant role in headache (17). Hormonal contraceptives and hormone replacement therapy have effects that vary widely from individual to individual. similar to but worse than their preexisting headache. However. dietary or lifestyle triggers. or the use of other medications that trigger headaches such as nitroglycerine may lead to intractability. they should probably be modified or even eliminated. especially those that are subject to modification or intervention. A superimposed infectious or metabolic process may not be recognized. A history of multiple partners should prompt a search for a potential infectious cause of the headache. Excessive use of agents that contain caffeine. and friendships. It may be difficult to distinguish an intracranial catastrophe from an unusually severe migraine. barbiturates. Patients are often embarrassed about medication misuse and fear that the physician will make harsh judgments. separation. Historical clues should be sought to determine the influence of hormones on patients who are taking them. Explore the patient’s marital and family status. outside interests. and problems with children are more likely to be associated with refractory headaches. opioids.514 Lipton and Bigal Diagnosis may be difficult if two or more disorders are present simultaneously (44). ergotamine. hormonal triggers. It is. important to specifically establish the patient’s pattern of medication use. Many patients do not consider over-the-counter medications as ‘‘real drugs’’ and will not report them unless specifically asked. occupation. If historical evidence suggests that exogenous hormones contributed to intractability. Occupational and environmental factors may cause or aggravate the headache. One important issue is the failure to use stratified care in selecting the initial therapy. including aspartame. Careful questioning about possible stressors may uncover a source of conflict or a psychological component to the headache. excessive initial doses are used. Recent evidence demonstrates that acute migraine treatment works best if given early in the course . When patients report that acute treatment is unsuccessful. REASON 3: PHARMACOTHERAPY MAY BE INADEQUATE Inadequate pharmacotherapy may occur if inappropriate treatments are selected. Workers in munitions factories may develop nitroglycerine induced headaches (55). the duration of treatment is too short. Several common issues may lead to treatment failure in the acute management of migraine. or with early morning awakening.57). corrective strategies can be developed. especially in those with very frequent headaches. or the patient is noncompliant. may trigger headache (51. which can lead to intractability in some patients. A randomized trial supports the U.S. or other environmental contaminants may trigger headaches (54). combination treatment is required. It is important to determine the dosage and duration of treatment with prior therapies. Medications appropriate for the patient’s diagnosis or diagnoses should be carefully reviewed. including headache-related disability. solvents. Table 3 summarizes some of the medications that may cause headache. Taking certain medications may contribute to headache. Headache Consortium Guidelines in their recommendation for stratified care (56. it is important to understand what they mean: (i) Was there no response or was there an incomplete response to treatment? (ii) Did treatment response take too long? (iii) Did the headache respond well initially but then recur? (iv) Did the treatment cause too many side effects? By understanding the type of treatment failure. Some dietary factors. Environmental exposures to carbon monoxide. One strategy is to treat early during the attack (58). the patient fails to absorb the drug.52). final doses are inadequate. Depression or anxiety may present with difficulty in falling asleep or staying asleep. Vitamin A and D overuse may cause IIH (53).When the Treatment of Headache Fails Table 3 Selected Medications Reported to Cause Headaches Amantadine Calcium-channel blockers Caffeine Corticosteroids Cyclophosphamide Dipyridamole Estrogens Ethanol Hydralazine Indomethacin L-Dopa Monoamine oxidase inhibitors Nonsteroidal anti-inflammatory agents Nitrates Nicotinic acid Phenothiazines Ranitidine Sympathomimetic agents Tamoxifen Theophyllines (thioxanthines) Tetracyclines Trimethoprim 515 and may cause morning headache (50). That strategy is based on the selection of initial therapy based on patient characteristics at the time of presentation. Unanticipated side effects may lead patients to discontinue the treatment. nonoral therapy may also be needed (60). Compliance is improved if the patient can see that the degree of disability caused by the headache outweighs the disadvantages of prophylactic drugs. ergotamine. Unsuccessful treatment is often the result of incorrect dosing strategies. Caution is required to avoid the development of medication overuse. Another option is to change the route of administration. It is sometimes helpful to escalate the dose or to switch drugs. Aspirin plus metoclopramide. Once central sensitization develops. rizatriptan or eletriptan may be helpful. For example. It is best to start preventive agents at a low dose. If efficacy or speed of onset is the issue among the oral agents. and then gradually increase the dose until therapeutic effects. Short-acting propranolol given once a day may be ineffective. or the ceiling dose for the agent in question is reached. therefore. provide important. There are also common reasons for preventive treatment failure. early treatment is an important approach to making acute treatment more successful. treatment limiting side effects. a beta-blocker. Noncompliance with Treatment. Ideally after an explanation of the options. the patient’s motivation to treat may diminish between the attacks. Although monotherapy is usually recommended. particularly refractory chronic cluster headache. Preventive treatment is often ineffective if taken when the patient is overusing acute medications (‘‘rebounding’’). but the addition of an antiepileptic medication (divalproex sodium). may help control refractory headache. Further increases beyond the ceiling dose may be necessary if there is a partial response at the ceiling dose without side effects but the headaches remain disabling. When switching drugs. For the depressed or anxious migraine sufferer. Methysergide. and frovatriptan are important options. a monoamine oxidase inhibitor is sometimes the only effective treatment option. while pain is still mild. almotriptan. Because migraine attacks are episodic. . Treatment is often discontinued prematurely. Nasal sprays and injections. For the patient with truly refractory headache and refractory depression. Combining triptans with metoclopramide or nonsteroidal anti-inflammatory agents is sometimes helpful (61). For that reason. naratripan. Migraine-related gastric paresis may delay or prevent the absorption of oral medication. underutilized treatment alternatives. especially in the setting of comorbid illness.59). Selection of preventive medications has been reviewed elsewhere (62). Preventive medications must be given at an adequate dose for an adequate duration. or a calcium channel blocker may be useful. Patients may not understand that sustained treatment is necessary to achieve therapeutic success (63). Rational Polytherapy. At least several weeks are required to evaluate the success or failure of a treatment. treatment is much less likely to work (24). Compliance may improve if the patient understands the need for long-term treatment and anticipates the process of dose adjustment (64). it is helpful to consider the difficulty the patient had with the original drug. Some patients may take appropriate doses of a drug but not achieve the necessary blood levels for response due to difficulty with absorption. alone or in combination with a calcium channel blocker. Noncompliance with prescribed preventive medication or misuse of acute treatment is common. if tolerability or headache recurrence are the problems. if one or two breakthrough headaches occur before an effective dose is established. antidepressants are usually a rational choice. rational combination therapy is sometimes necessary. and several triptans produce higher pain-free rates when given while pain is mild (58.516 Lipton and Bigal of the headache. When treatment trials are repeated. or when inpatient treatment is required but not offered. Side effects may be better tolerated if the patient knows that they may ameliorate over time (65). In intractable headache patients. stroke. Concomitant diseases occur together with chance frequency.67–69). Patients may not avoid known provoking factors. These disorders can impose therapeutic challenges and limit treatment options.When the Treatment of Headache Fails 517 the patient should suggest or opt for a prophylactic rather than have the decision imposed by the doctor. Occasional occipital nerve and facet joint blocks are useful. Modulating expectations can be difficult. vascular disease. Comorbid diseases occur in migraineurs with a greater frequency than would be expected by chance. Patients should not tolerate pain and disability needlessly. leading to poor headache control (65). REASON 5: OTHER REASONS FOR TREATMENT FAILURE Treatment may fail if the patient has unrealistic expectations. affective disorders. Noncompliance with nonpharmacologic treatment can render treatment unsuccessful. Migraine is comorbid with depression. and epilepsy (20. A restricted therapeutic armamentarium can severely . comorbid conditions that complicate therapy. common concomitant diseases that limit options in migraine treatment include asthma (beta blockers). The patient who has a chronic daily headache may complain a year later that he is no better because he is having two attacks per month that respond promptly to acute treatment. ulcers and gastritis (nonsteroidal anti-inflammatory drugs). Concomitant obesity may limit the utilization of many prophylactic drugs. If rebound headache was present during previous therapeutic trials. Patients with intractable headache disorder sometimes are relieved by the use of trigger point injections into tender areas using a combination of a local anesthetic and a depocorticosteroid. Cognitive training helps them decrease the stress they impose on themselves and may improve their headaches (64. and uncontrolled hypertension (triptans and ergot alkaloids). their expectations may escalate and they may forget how bad they were. Patients who are tense and anxious and have trouble coping with their daily existence can have trouble getting their headaches under control. But it may not be realistic to expect a treatment regimen to give perfect headache control with no side effects.65). it is useful to separate pain and ability to function. REASON 4: NONPHARMACOLOGIC TREATMENT MAY BE INADEQUATE Patients who are tense sometimes need physical medicine or behavioral interventions. it may be necessary to retry unsuccessful but incorrectly used treatments. generally when there are concomitant physical signs such as a sensory abnormality over the C2 distribution on the back of the head. As patients improve. anxiety. Patients with occipital tenderness and trigger points often do not get relief of their headache disorder until they have a nerve block or trigger point injection (66). behavioral strategies should focus on optimizing function. it is well worth explaining the reasons for returning to a previously used drug. Headache diaries can be used to remind patients about their previous headache pattern. Patients with comorbid or concomitant medical or neurologic illness are often more difficult to treat. If pain does not improve. Physical therapy is often a useful adjunct for these patients. Pascual J.518 Lipton and Bigal compromise treatment. Psychiatric problems often abate as headache comes under control. Headache 1982. Nurses. Berciano J. Headache characteristics in subarachnoid hemorrhage and benign thunderclap headache. In: Nappi G. more aggressive treatment interventions may be required (70). Inpatient level treatment should be reserved for people who require the intense interventions and around-the-clock monitoring that can only be provided in an inpatient setting. Chronic headache syndromes. U. 43:1678–1683. Combarros O. et al. 11. Reino AJ. headache subspecialty centers use a team approach to patient management. 4. Rehydration and careful monitoring are often required. Headaches in older people. Distribution of headache by diagnosis as the reason for neurologic consultation. Mathew NT. Celentano DD. Edmeads J. Posner JB. Rebollo M. Neurology 1998. Rinkel GJ. Bono G. Transformation of episodic migraine into daily headache: analysis of factors. Pituitary apoplexy presenting as a thunderclap headache. 7:387–412. Am J Prev Med 1991. New York: Raven Press. Neurology 1993. Linn FH. Stewart WF. and psychologists can help support and educate the patient. 27:435–438. Polo JM. and manage patients. fellows. and pharmacologic and nonpharmacologic maintenance treatment can be started. Nigam MP. REFERENCES 1. Med Clin 1995. 6. Saper JR. 7:40–46. 22:66–68. CONCLUSIONS In this chapter. or is simply very difficult to treat. 65: 791–793. 7. Dodick DW. Wijdicks EF. 8. When outpatient treatment fails and patients have continuing and severe pain and disability. Isolated sphenoid sinus disease: an analysis of 132 cases. Headache and Depression: Serotonin Pathways as a Common Clue. Mathew NT. 50:510–511. We believe that the vast majority of refractory headache patients have a biologically determined problem that has been either misdiagnosed or mistreated. eds. Aggressive parenteral treatment to ‘‘break’’ the headache cycle and/or maintain the patient in reasonable comfort during detoxification (if necessary) represents the initial step. 3. Lawson W. Available inpatient programs provide an important option for carefully selected patients. 9. How are they different in this age-group? Postgrad Med 1997. 101:91–94. we have presented the five most common categories of treatment failure in the patients who consult in headache subspecialty centers based on the authors experience. Headache characteristics associated with physician consultation: a population-based survey. Patients with major comorbid psychiatric disorders may require ongoing care with a mental health professional appropriate to the disorder. Neurol Clin 1989. Sandrini G. Headaches in patients with brain tumours: a study of 111 patients. Chronic daily headache: clinical features and natural history. 5.S. Headache 1987. Forsyth PA. 107:1590–1595. Stubits E. answer questions. Leno C. . Saper JR. Attendant medical and psychological issues must be addressed. physician’s assistants. Linet MS. 2. 10. Inpatient care. Algra A. Laryngoscope 1997. 104:161–164. J Neurol Neurosurg Psychiatry 1998. which can help reduce the burden of caring for difficult patients. 1991:49–59. Persistence in treating these patients can be very rewarding. Ergotamine dependency—a review. 28. Campbell JK. New York: Oxford University Press. Silberstein SD. New York: Oxford University Press. Dalessio DJ. Silberstein SD. eds. Mathew NT. 51:245–249. Young WB. 35. Nasopharyngeal carcinoma. Cerebral venous thrombosis. Evers S. Dalessio DJ. eds. Neurology 1994. Martin TJ. Headache characteristics in hospitalized patients with Lyme disease. Patterson S. 1997:355–368. including transformed migraine. 85:987–996. Lipton RB. 16. Lipton RB. 4:65–70. 31. Lipton RB. 2001:475–493. Solomon S. Sundt T. Low cerebrospinal fluid pressure headache. 57:948–951. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Spierings EHL. Scelsa SN. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations. Cutrer MF. Solomon S. Lipton RB. Semin Neurol 1997. chronic tension-type headache. Graff-Radford S. Silberstein SD. Nahmias S. 36. New York: Raven Press. Med Clin North Am 1991. 29. Neurol Clin 1992. 123:1703–1709. et al. Evans RW. Neurology 1998. 22. Neurology 1994. Hemicrania continua: 10 new cases and a literature review. In: Goadsby P. In: Silberstein SD. 36:677–680. Migraine-epilepsy relationships: epidemiological and genetic aspects. 14. Chronic daily headache. and medication overuse. Wolff’s Headache and Other Head Pain. Soyka D. Mokri B. Lipton RB. Tfelt-Hansen P. Lipton RB. 1987:281–291. 34:1–7. et al. Lipton RB. eds. Yarnitsky D. Brain 2000. and prospective analyses. Sinus headache or migraine? Considerations in making a differential diagnosis. eds. Classification of daily and neardaily headaches: proposed revisions to the IHS criteria. Pseudotumor cerebri without papilledema. Cough. Posttraumatic headache. Andermann E. Marks DR. 33. 19. Schreiber CP. 25. cross-sectional. Boston: Butterworths. Silberstein SD.’’ Another headache absolutely responsive to indomethacin. 13. In: Andermann FA. Welch KMA. 10:87–111. Sjastaad O. Neurol Clin 1996. In: Silberstein SD. Newman LC. Cady RK. Peres MFP. Sands GH. Burstein R. 24. 30. The impact of HIV infection on primary headache. Headache 1995. Idiopathic intracranial hypertension without papilledema: a case-control study in a headache center. 44:1191–1197. Mokri B. Bousser MG. Silberstein S. 35:125–130. Reichelt D. Neurology 2002. 30:304–305. Practical evaluation and diagnosis of headache. Unexpected findings from retrospective. 7:307–312. Bajwa ZH. and Horner’s Syndrome. et al. Newman LC. Andermann FA. New York: Oxford University Press. Wang SJ. Headache 1990. 21. 44:2111–2114. 85:191–200. Frishberg BM. 20. Silberstein SD. exertion and other miscellaneous headaches. Migraine and Epilepsy. Lipton RB. 75:733–748.When the Treatment of Headache Fails 519 12. In: Olesen J. Lipton RB. Neurology 2001. 23. Headache 1994. Solomon S. . 27. The Headaches. 32. Hemicrania continua is not that rare. Houser W. Cardiac cephalgia: a treatable form of exertional headache. Ann Diagn Pathol 1999. Wolff’s Headache and Other Head Pain. In: Silberstein SD. 49:813–816. 1993:748. ‘‘Hemicrania Continua. Lowenkopf T. 26. Sander H. Herskovitz S. Cephalalgia 1984. Diagnostic testing for the evaluation of headaches. Lay CL. hemicrania. Wenig BM. Arch Neurol 1979. Pain 2000. 58(suppl 6):10–14. 34. 3:374–385. Wolff’s Headache and Other Head Pain. 2001:447–458. Edmeads JG. Dalessio DJ. Wibbeke B. Neurology 1997. 14:1–26. Lugaresi E. Rapoport AM. eds. 2001:247–282. Ocular causes of headache. Marcelis J. 17. Med Clin North Am 2001. eds. 15. Boston: Butterworth-Heinemann. Blue Books of Practical Neurology: Headache. 18. Spontaneous internal carotid dissection. Disorders of the neck: cervicogenic headache. Disorders of the mouth and teeth. Ameri A. Scher AI. Chronic paroxysmal hemicrania: a disabling headache syndrome responding to indomethacin. Headache 1995. 49:914–918. 36:14–19. 49:1749–1751. Identification and treatment of sleep apnea in patients with chronic headache. Solomon S. In: Goadsby PJ. Neurology 1997. Saxena PR. Clin Ther 2000. The role of headache-related disability in migraine management: implications for headache treatment guidelines. et al. O’Quinn S. Cady RK. 40:792–797. 49. Headache Classification Committee of the International Headache Society. Stewart WF. 54:140–159. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. The hypnic (‘‘alarm clock’’) headache syndrome. Jones JM. 56. 50. 54:1553. 1997:243–254. 46. Newman LC. Gould JD. eds. Jensen R. Mosek AC. Cephalalgia 2001. Silberstein SD. 9:244–256. 42. Rasmussen BK. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. 40. 53:1114–1118. Lipton RB. Dodick DW. Treatment of mild headache in disabled migraine sufferers: results of the Spectrum Study. 48. Ferrari MD. Interrelations between migraine and tension-type headache in the general population. 57. 45. 51. 41:899–901. Characteristics of headache associated with acute carbon monoxide poisoning. Unilateral hypnic headache: a case study. Jacobson DM. Silberstein SD. 58. Lipton RB. Stewart WF. Gutterman D. Multispecialty consensus on diagnosis and treatment of headache. Hampson LA. Headache 2000. Headache 1990. Acta Neurol Scand 1976. Silberstein SD. Newman LC. 44. Cephalalgia 1996. Lipton RB. Price RW. 39. et al. 38. Goadsby PJ. Markley H. 8(suppl 7):1–96. The hypnic headache syndrome. Nicolodi M. London: Butterworth-Heinemann. et al. Lipton RB. 16:405. Dale I. Rapoport A. Berg R. 42:220–223. Hampson NB. Ann Neurol 1978. Wall M. Poceta JS. Classification and diagnostic criteria for headache disorders. Stressful life events and risk of chronic daily headache: results from the frequent headache epidemiology study [abstract]. Silberstein SD. Stang P. 43. 59. 52. 35:586–589. Cephalalgia 1988. Cady RK.520 Lipton and Bigal 37. 37:665–666. 18:52–56. Headache and female hormones: what you need to know. Hall C. Rosenberg J. Arch Neurol 1992. Roon KI. Lipton RB. Headache 1996. 358:1668–1675. Wine and migraine: compatibility or incompatibility? Drugs Exp Clin Res 1999. 41. Cephalalgia 1998. Neurology 2000. Lipton RB. Schroll M. Neurology 1999. Saper JR. Lipton RB. Analgesic rebound headache in clinical practice: data from a physician survey. 14:323–333. Headache 2001. Van Gelderen EM. Lancet 2001. Ergotamine tartrate dependency: features and possible mechanisms. Clin Neuropharmacol 1986. 60. A new (?) clinical headache entity ‘‘chronic paroxysmal hemicrania’’ 2. Curr Opin Neurol 2001. Posner JB. Lipton RB. Olesen J. 21:279. 55. Headache 2002. Gutterman DL. Sheftell R. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Cady R. . 53. Newman LC. Dalessio DJ. 56(suppl 1): 35–42. cranial neuralgias and facial pain. Sjastaad O. 47. Chewing gum headaches. Vance DA. Sicuteri F. 54. Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Paroxysmal hemicranias. Neurology 2001. Nitroglycerin-induced headache. Silberstein SD. Headache 1997. Campbell JK. Headache. Blumenthal HJ. 22:1035–1048. 3:183–184. 25:147–153. 40:1904–1905. 10:1831–1845. 64. Peterson EL. Neurol Rev 1995. Diener HC. Advances in pharmacological treatment of migraine. Lake AE. 66. Penzien DB. Limmroth V. Hauser WA. Davidoff RA. Appl Psychophysiol Biofeedback 2001. 2001:562–598. eds. 65. Davis GC. BMJ 1995. Kreeger C. 69. Behavioral management of headache. Learning from our treatment failures. Silberstein SD. .When the Treatment of Headache Fails 521 61. 34:387–393. Ottman R. Cephalalgia 2002. Dalessio DJ. Tehindrazanarivelo A. Joint 1994 Wolff Award Presentation. Saper JR. Exp Opin Invest Drugs 2001. 70. Madden SF. Wolff’s Headache and Other Head Pain. Migraine and major depression: a longitudinal study. 33:55–62. 310:830–833. 67. In: Silberstein SD. Lipton RB. Migraine: preventive treatment. New York: Oxford University Press. Breslau N. Trigger points and myofascial pain: toward understanding how they affect headaches. Case-control study of migraine and risk of ischaemic stroke in young women. 8:436–448. Holroyd KA. Comprehensive inpatient treatment for intractable migraine: a prospective long-term outcome study. Lipton RB. 62. Weeks R. Neurology 1994. Headache 1993. Comorbidity of migraine: the connection between migraine and epilepsy. 44(suppl 7):28–32. Tzourio C. 63. Holroyd KA. 26:319–323. Goadsby PJ. 3:15–16. The difficult headache patient calls for a multifaceted approach. Ehrenberg BL. Cephalalgia 1998. et al. Lipchik GL. 42: 491–512. Iglesias S. Headache 1994. 68. Schultz LR. . 52–53 Black box warning. 338. 196 Analgesics. 420 Blind spots. 315. See Blood–brain barrier BDNF. 274 Acute migraine therapy. 227. 227 subtypes. 275. 194 Blindness. 316–317 mechanism of action. cerebellar. unruptured. See also Migraine. clinical spectrum of. 451 Alpha antagonists. 386 APAP. 227 Acetaminophen. 383–385 antiepileptic drugs (AEDs). 119 Benign paroxysmal torticollis (BPT). 299 a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA). 199 Balance disorders. 315–316 Beta-blockers. 476 visual. 204 Acephalgic migraine. 75 Aura diagnosis.Index Abdominal pain. 481 Botox1. 196 Arteriovenous malformation (AVM). 163 Analysis of covariance (ANCOVA). 29 Amitriptyline. 343 Allodynia. 340 Alternating hemiplegia of childhood (AHC). 75. 198–199 BBB. 189 pathophysiology of. 119 American Migraine Study-1 (AMS-1). 262 Bipolar disorder. 104–108 Almotriptan. 341–342. 321. 405 523 . 324. 317–319 tricyclic. 381 Antiepileptic drugs (AEDs). 386–387 Biofeedback training. 318. 193 Aura-like symptoms. 7 symptoms. 295. 322 serotonin. acetaminophen Aphasic aura. 274. 320 Amnesia. 337–340 Anticonvulsants. 320 Antiemetics. 341 Ataxia. 332 Aneurysm. 182 effect of. 340–341 Antagonists calcium-channel. 385 clinical trials.340. 198 ATP1A2 gene. 503 Angiotensin-converting enzyme inhibitors. mimicking Aspirin. 99. 208 Basilar-type migraine. 450 Age headache prevalence and. 331 Antidepressants. 319 mechanism of action. 133. 447 Adenosine receptors. preventable. See Aspirin. 7 meaning of. 512 Blood–brain barrier (BBB). transient global. 118–120 Atrial natriuretic peptide (ANP) gene expression. 69–73 prolonged. 138. 8 b-Adrenergic blockers clinical use of. See Brain-derived neurotrophic factor Benign familial infantile convulsions (BFIC). 106–107 in migraine. 416 Acetylsalicylic acid (ASA). 157 Agency for Healthcare Policy and Research (AHCPR). 325. 331 Antihistamines. 204 Benign paroxysmal vertigo. 37–38 demographic factors associated with. 318–319 Butterbur (Petasites hybridus).524 Botulinum toxin. 139 Cerebral thrombosis. 454. 477 effective drugs for. 448–449. 481. 102. 366–367 Comorbid pain. 40 overuse. 234 Cerebral venous thrombosis (CVT). 383. 107. 325. symptomatic. 84–85. 41–42 Compliance/noncompliance to treatment. 7. 135. 7. 432 history of. 341–342. 75 Cyclic vomiting syndrome (CVS). 123 Cyclical vomiting (CV). 478 Clusterin. 344. 160. 452 Calcium channel blockers. 323 Diltiazem. 139. 387. 1. See Calcitonin gene–related peptide CH. 434 Depression. 475 Chronic tension-type headache (CTTH). clinical spectrum of. 209 Carbamazepine. 323. 516 as treatment agent. 339. 421 Calcitonin gene–related peptide (CGRP). 431 early stage of TM. 324 pharmacology of. 141 C-fibers. 431. 228. mimicking Divalproex sodium. 483 refractory. 281 Distal internal carotid artery dissection. 316 Continuum theory. 400–401. 104 Cyclic adenosine monophosphate (cAMP). 14–15. 289. See Chronic daily headaches Cerebral ischemia. 326 Cardiac cephalalgia. 483–484 treatment for. 467 type A. 114–117 Caffeine consumption of. 460 Cluster headache (CH). 502 Caffeine-withdrawal headache. 439 treatment of. 330. 279. 518 Contingent negative variation (CNV). 504 acute (symptomatic) therapy of. effect on sleep. 204 Cyclooxygenase (COX). 313. transient. 369 Index Chronic paroxysmal hemicrania (CPH). 276 Dihydroergocryptine (DEK). 416. 38–40 epidemiology of. 69–70. 514 imaging. 405–408 use of. 498 Cranial neuralgias. 400. 16 Cranial or cervical vascular disorders. 75 Coenzyme Q. 275–276 Disability assessment. See also Headache: secondary CSD. 478 classification. 398 CACNA1A gene mutations. 209 Chlorpromazine. 89. 101. 249 Strategies of Care (DISC) study. 123. 11 clinical features of. hemiplegia of. 16–18. 405 Chronic migraine (CM). 181 Cortical spreading depression (CSD). 220. 324 Dihydroergotamine (DHE). 460 classification. 322 Capsaicin. 475 receptor antagonists. 88 Brain-derived neurotrophic factor (BDNF). 5. 313–314 Corticosteroids. 501 mechanism of action. 380–381. 207 Brain abscess. 431. 85. 479 Dihydropyridines. See Benign paroxysmal torticollis BPV of childhood. 386. 480 Cough headache. See Cortical spreading depression Cutaneous allodynia. 421. 38 risk factors. 514 CDH. 322 types of. 408 See also Botox1 BPT. 123. 318 Cyclic guanosine monophosphate (cGMP). 182. 516 Diclofenac. 344–345. 12. 499 Childhood. See also Migraine. 475 differential diagnosis of. See Cluster headache Chiari malformation. 465 Convergence hypothesis. 482 . 420 Chronic daily headache (CDH). 483 Car (motion) sickness. 100. 277 Cyproheptadine. 451 CGRP. 501 Dipyrone. 61–63 525 Head tilt. 146. 84–86 Health Maintenance Organization (HMO). trigger factor for BPV. 147. 395 intensity of. 137 Flunarizine. 209 Hepatotoxicity. 486 Ergot alkaloids. 215 Headache impact test (HIT-6).Index Dopamine receptor antagonists/ phenothiazines. 289–290. 208 Feverfew (Tanacetum parthenium). 290–292 Ergotamine tartrate (ET). 460 visual loss and. 513–514 types of. 501. 431. 113 ICHD-2 classification. 194 Dyskinesia. oral triptans. 208 Headache anatomy of. 419 vs. 7. 82–83. 197 Fatigue. 516 Horner syndrome. 13. 480 Ethmoid pressure. 419–420 Dorsal horn. and reasons for treatment failure. 12–14 progression. 74 Hypertension. 330 HMO. 379–381 Ergotamine. 515 Hemiplegia. 453 Greater occipital nerve (GON). 13. retinal migraine and. 76–77. See Health Maintenance Organization Homeostasis. 114. causes of. 399 prevention of. 242–244 diaries. 189. 176. 104 Episodic paroxysmal hemicrania (EPH). 519 disorders. 380. 253 triggers. 70 Gamma-knife radiosurgery. 1. 480 HC. 67 Exclusion. 208 Dysphasia. 324. 512 Glutamate receptors. 326. sensitization of. manifestation of. 515 . 451 Glyceryl trinitrate (GTN). 387 Frovatriptan. 299–300 Gabapentin. 226 Hypertensive headaches. 2–4 inpatient. 261–262 primary. 487. 14–16 temporal profile of. 100–102 Dosing strategies. 138 diagnosis algorithm. 252–253 causes of. 298–299 Epilepsy. 14. 420 Dysarthria. 483 Galanin. See Episodic ataxia type 2 Electroencephalogram (EEG). 107. See Aura EA-2. 477. 218 Hemicrania continua (HC). 518 Droperidol. 151. paroxysmal. 231–232 Eletriptan. See also Headache: secondary Hormonal therapy. anatomy of. 383 Hyperandrogenism. 512 treatment plan. See Familial hemiplegic migraine First-line migraine therapy. 15. 193. valproate. 12. 75 Gamma-aminobutyric acid (GABA). 8. 8 Exertional headache. disorders of. 303. 367–369 FHM. 227. of childhood. 16 Familial hemiplegic migraine (FHM). 421 Fluid-attenuated inversion recovery sequence. 476 5-HT1F receptor. 330 Hyperemia. 83 calendars. 376 Hyperalgesia. 416 Hypnic headache (HH). 444 secondary. 228 Giant cell arteritis. 99 Hyperammonemia. 449–450 5-Hydroxytryptamine (5-HT1). 86 peripheral connections. treatment. 499 Facial pain. 150. 393. diagnosis of. 13. 253 genetic studies on. 249 Headache physiology central connections. 414 classification by frequency and duration. 148 common location of. 1. 113–114. 266–267 Hemianopsia. See also Headache: secondary Head pain. 116 Episodic migraine (EM). 46–47 Hypertensive encephalopathy. 473. 12–13. 5. 342–344. See Hemicrania continua Head and/or neck trauma. 388. 485 Gender bias. 4. 196 medication-overuse. 205 Episodic ataxia type 2 (EA-2). 216 Generalized tonic/clonic (GTC). 517 overuse. 224. 46. 120–121 genetic epidemiology. 413 Migraine-associated stroke (MAS). 332 International Classification of Headache Disorders (ICHD). 313–314 retinal. 114 Lysine clonixinate. 65 Migraine. association of. 336 Naratriptan. 198 MRM. 431. 336–337 Lanepitant (substance P antagonist). 220. 313 complications of. 250 treatment of. origin. 342 Lithium carbonate. 141 Ibuprofen. spontaneous intracranial. 459 International Classification of Headache Disorders. 486. 278. Second Edition (ICHD)-2. 486 Nausea. 164. 232–236 tiggers. 235 Migralepsy. 82. 75 MCA. 338–339. 342 Leukotriene receptor antagonist (montelukast). 189. 29. 481 Lumbar puncture. 417–422 headache causing. See International Headache Society Classification ICHD-2. 66 Meningismus. 135 Mood disorders. 215 Monocular visual scintillations. 277 Magnesium. 121–123 ICHD-2 classification of. 275 Methysergide. 460 Melatonin. 499 Lymphocytic pleocytosis. 420 Lamotrigine. 178–180 comorbidity. 230 Migrainous infarction. 23 epilepsy and. 481. 147. Second Edition Idiopathic intracranial hypertension (IIH). 483. 228–232 Minocycline. 1. See International Classification of Headache Disorders. evidence. role in. 192. 276 ICHD. 448 Migraine-abortive therapy. 83. See Middle cerebral artery MCP. 295 Nasal congestion. medications for treatment of. 24 pain. episodic disruption of. 321 Monocular visual loss (MVL). 205 aura. 396 Monoamine-reuptake inhibitors. 230 family and twin studies in. 9 diagnosis of. 31 preventive therapy. 295. 393–395. 5–7. principles. 370 Maintenance prophylaxis. 174. 439 Medication overuse headache (MOH). 505 Inpatient headache treatment. 321–322. See Matrix metalloproteinases Monoamine oxidase inhibitors (MAOIs). 137. 403–404 Intent-to-treat (ITT) population. 499 Menstrually related migraine (MRM). 100 precursors of. 199. 277–278 NDPH. 5 incidence of. 262–266. 399. definition. 8–9 sensitization in. See New daily-persistent headache Neck pain. 177 epidemiology of. 5–9. 315 Migraine-triggered seizure. 227 Migraine-preventive agents. 434 clinical phases of. 313 basilar-type. 405. 182. 481 Metoclopramide (MCP). 207 Motor weakness. 174 Nervous system function. 160 Middle cerebral artery (MCA). 106 stroke. 451 Ketorolac. 514 Indomethacin. 8 chronification. 102 Mitral valve prolapse (MVP).526 Hyporcretin neurons. 148. 63. 189 Index MIDAS questionnaire. 25. 173 sensory processing by. 498 Meninges. 123 Hypotension. 376. See Menstrually related migraine Mydriasis. 448 acute confusional. See Metoclopramide Medications classes of. 204 prevalence of. 100 Kainate (KA). 481 Matrix metalloproteinases (MMP). 499. 274. 420 . 234 MMP. 515 L-type calcium channels. 39 Occipital cortex excitability. 478 P/Q calciumchannel. 279–280. 321 NOS. See also Headache: secondary Nortriptyline. gastric. 69–70. 450 Nonsteroidal anti-inflammatory drugs (NSAIDs). 341. 9. 479 Oligohidrosis. 141 Psychiatric disorders. 66 Rapid eye movement (REM) sleep. 16. 72 PS. 23 Prochlorperazine. 479–480 Propranolol. 505 New-onset headache. 250–251 Preventive prescription drugs. 17. definition of. combinations of. 405 Relaxation training. 518 Paresthesias. 364–366 Rizatriptan (maxalt). 76 Occipital nerve stimulation. See Monocular visual scintillations Paroxysmal dyskinesia. premonitory Prophylactic therapy. flaccid. 117 Neurotrophins. 292–293 Obesity. 13–14. See Nonsteroidal antiinflammatory drugs Numbers needed to harm (NNH). 344 PH. 273. 277 and triptans. 301–302. 216 Oral contraceptive (OCP). 344. general care during. 499 Neuroleptics. 312 Primary stabbing headache (PSH). 376 Riboflavin. 486 OCP. 11–12. 515 facial. 234–235 Orgasmic headaches. See also Corticosteroids Pregnancy and lactation. 84–85 Positive predictive value (PPV). 196 Paresis. 15. 344 Petasites. 318 New daily-persistent headache (NDPH). 425 Red flag features. 419 Oxygen inhalation. 466 Retinal migraine. 316 Prostaglandin E2 (PGE2). spreading depression of. 135 Nitric oxide synthase (NOS). 376 Optic nerve ischemia. See Symptoms. 278 Nonvascular intracranial disorders. 8–9. 203 Petadolex1. 486. 50–52. 292–293 Numbers needed to treat (NNT). 420 Prodrome. 399 Pituitary apoplexy. 453. 515 Patent foramen ovale (PFO). 450 Opioids. 101 Prostaglandins. 336 Opioid receptor–like (ORL)-1 receptor. 276. See Oral contraceptive Octreotide. See also Headache: secondary Pyrrolizidines alkaloids (PA). 370 Queckenstedt’s maneuver. 114. 431. secondary amines. 339 Plasma protein extravasation. 208 Paroxysmal hemicrania (PH). 192 527 Paresthesias. 74 Protein extravasation (PPE). 216–217 IHS criteria for diagnosis of. acute severe. 69. 452–453 NMDA. 454 Pain abdominal. 512 Pizotifen. 234–235 Patient health questionnaire (PHQ). 138 Paralysis. See Neuromuscular junction Nociceptin/orphanin FQ (N/OFQ). 438 Periodic lateralized epileptiform discharges (PLED). See Periodic syndromes Pseudomigraine. 219. 387–388. 150. use of. 489 Probable migraine (PM). 450. 114 Pseudotumor cerebri (PTC). 500 Over-the-counter (OTC) users. 209 Papilledema. See Paroxysmal hemicrania Phenobarbital taper. 414 Regional cerebral blood flow (rCBF). See also Nitric oxide synthase NSAIDs. 379 . 278–279 Neuromuscular junction (NMJ). 232 Periodic syndromes (PS). 204 chronic unilateral. 179. 218 Retrochiasmatic lesions. 101 NMJ. 278–279. 163 Periaqueductal gray (PAG) matter. 476 Raskin IV protocol. 297–298. 214 Retinal neurons. 197 Paraphasia. 480. 173 migrating limb. See N-methyl-D-aspartate receptor N-methyl-D-aspartate receptor (NMDA). 158 Prednisone. 183 location of. 88. 467 efficacy of. 279. 218 Reye’s syndrome.Index Neuroimaging. 331 Syndrome. 500-501 Shared gene hypothesis. 330 . 71. 480 Treatments. 482–483 Toxoplasmosis. 461 ICHD-2 classification of. 502 Timed-released dihydroergotamine (TR-DHE). acute. 381–382 Thioctic acid (a-lipoic acid). 343 TCAs. 135. 504 pathophysiology of. 317–318 pharmacology of. 223–226. nonspecific vs. 159 Tension-type headache (TTH). 117 Single-nucleotide polymorphisms (SNPs). 330–336. 383. 12. 514 Transformed migraine (TM). 278 oral. 149. 290. 451 Trigeminal pain. 194 Sensory modulation. 193. 513–514 Triptans. See Trigeminal ganglion Therapy cognitive-behavior. 16 Trigeminal nucleus caudalis (TNC) neurons. 101 Index [Tension-type headache (TTH)] sex and age distribution of. 320 principles of. 473–475 Trigeminal ganglion (TG). 102. 377. 231 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome. 183 treatment. 216 Seizures. 326–330. 417 medications. 396 Sexual activity associated primary headaches. 133. 147. 317. 300–301 and NSAIDS. 196. 88 Serotonergic axon. 139. 512 Sumatriptan. 462–463 clinical presentation of. See Transformed migraine TNC. 123. 376. 292–295. 519 Triggers. 231 Trigger point injections. 149. 179. risk of. 431 Single-fiber electromyography (SFEMG). 88 Trigeminal receptor targets. See Tricyclic antidepressants Test–retest reliability. 302 TTH. 174 Sleep apnea. 396 Sensory aura. 199 Tonabersat. 146. 104.528 Rofecoxib. 499. 465 severity of. 1. 99. 488–489 Silberstein and Lipton (S-L) criteria. 463 Valproate. 17. headache. 116 Sinus headaches. 431. 513 Speech disturbances. 84. 440–441 Transitional prophylaxis. 448 Trigemino vascular system. 262 preventive. See Spinocerebellar ataxia type 6 Scotoma. 216 SAH. 448–449 Serotoninergic syndrome. 196 Spinocerebellar ataxia type 6 (SCA6). 83 Topiramate. 473. 103 use of. post-feverfew. 461 treatment of. 10 TG. 460 episodic. 302–303 Triptan-nonresponder. 199 Selective serotonin reuptake inhibitors (SSRIs). ICHD-2 classification of. 1. specific. obstructive. 475. 302. 421 hepatotoxicity. 181 Sinusitis. See Tension-type headache Tunnel vision. 295. See Trigeminal nucleus caudalis Todd phenomenon. See Subarachnoid hemorrhage SCA. 318 Serotonin (5-HT) receptor. 280–281 Tricyclic antidepressants (TCAs). 235 Thunderclap headache (TCH). 451–452 Trigeminal neuralgia. 293 meta-analysis. 459 history of. diagnosis of. 10 psychological aspects of. 319 TM. 61. 116 Sporadic hemiplegic migraine. 439 treatment of. 425 Subarachnoid hemorrhage (SAH). 466–467 types of. 459 characteristics of. 432–434. 321. 120 Status migrainosus. 462 epidemiological of. 277 Rostral ventral medulla (RVM). 478 Superior sagittal sinus (SSS). 385. 320 Trigeminal autonomic cephalalgias (TACs). combinations of. 367 Thrombotic or thromboembolic stroke. 413. 114. 13. medications with. 198. relationship. 137 Zolmitriptan (zomig). 83. 193 Visual loss and headache. 498 Vanilloid type 1 (VR1) receptors. 379. diffuse. 87 Verapamil. 326–330 Valsalva maneuver. 478 nasal spray. 481 529 Vertigo. 215 Xanthochromia. 475 Vasoconstrictive properties. 324–325. 85. 220 Vasopasm. 503 Ventroposteromedial (VPM). 451 Vasoactive intestinal polypeptide (VIP). 204 Visual aura. 295–297.Index Valproic acid. 479 . 148. . New York. neuroepidemiology. He completed a neurology residency and clinical neurophysiology fellowship at the Albert Einstein College of Medicine. as well as an additional fellowship in neuroepidemiology at the Sergievsky Center of Columbia University College of Physicians and Surgeons. New York. New York. He is an Associate Editor of the journals Cephalalgia and Headache. Dr. New York. New York. among other journals. and Abstract Editor of the journal Headache. He is an Associate Editor of the Journal of Headache and Pain. New York. Bigal is currently on the Scientific and Education Committees of the American Headache Society. New York. and Director of The Montefiore Headache Center. New York. Stamford. as well as in the Scientific Committee of the International Headache Society. and The New England Center for Headache. Dr. New York. MARCELO E. Connecticut. Contributing Editor of the journal Headache Currents. Bigal has published over 100 original articles and reviews in indexed medical journals. The Montefiore Headache Center. Lipton is past president of the American Headache Society and has published over 400 original articles and reviews in the fields of headache. and Director of Research.About the Editors RICHARD B. Dr. Albert Einstein College of Medicine. and serves on the editorial board of Neurology. Albert Einstein College of Medicine. BIGAL is Assistant Professor of Neurology. and health services research. New York. New York. LIPTON is Professor and Vice Chair of Neurology and Professor of Epidemiology and Population Health. New York. .