Interpretation Guide to Eccrine sweat glands are innervated by long, thinly myelinated and unmyelinated C fibers of the sympathetic nervous system that are prone to early damage in many neuropathic processes, including dysautonomia. Small fiber neuropathy (SFN) may be the first manifestation of systemic disease and can predict progression to a more diffuse neuropathy, making this early diagnosis important for the treatment of patients. SUDOSCAN results will enable you to perform an objective assessment of small and peripheral sympathetic nerve fiber function. This will help you to identify the etiology of the disease, keeping in mind that about 33% of small fiber neuropathies remain idiopathic despite appropriate diagnostic evaluation. Objective evaluation of the disease with regular interval retesting can increase patient compliance and can be particularly important in the treatment of neuropathic pain, if present. The results of SUDOSCAN tests are provided as hand and foot Electrochemical Skin Conductances (ESC) that indicate sweat dysfunction and are a marker of small fiber peripheral neuropathy. ESC are expressed in microSiemens (μS), ranging from 0 to 100. In general, ESC in the ‘green’ zone are healthy, ESC in the ‘yellow’ zone indicate moderate dysfunction, and ESC in the ‘orange-‐red’ zone correspond to severe dysfunction. The two main points to consider for correct interpretation of SUDOSCAN results are: § Asymmetry. If greater than 20% it suggests damage limited to a single side. This is only valid when the contralateral ESC scores are in the ‘green’ zone. If the contralateral ESC is itself in the ‘yellow’ or ‘red’ zone, then bilateral dysfunction exists. § Location of disturbances (hands or feet) to evaluate length dependency of the damage. In the diagnostic strategy the following questions should also be answered: § What: Are there other signs or symptoms of autonomic dysfunction? Are sensory or motor nerves (large fibers) involved? § When: If symptoms are present, how long have they been present and was their onset acute or chronic? § Context: What are the patient’s medical history, current or past medications, family history (hereditary diseases)? Interpretation guide to SUDOSCAN 1 Causes of SUDOSCAN disturbances validated by Suggested evaluation clinical studies* 1 Diabetes or glucose intolerance Fasting glucose, 2-‐hour oral glucose tolerance test ; due to high rate of coexistance, Vit B12, thyroid, Vit D, and lipid levels should also be measured Diabetic peripheral neuropathy Clinical neurological examination, other assessments 2 based on NE exam and usual diabetes care 3,4 Diabetic nephropathy Medical history, renal function testing Peripheral and cardiac autonomic neuropathy Heart rate variability, Ewing tests, appropriate specialist 5 referral Familial Amyloid Polyneuropathy Medical and family history, genetic testing, appropriate 6 specialist referral Fabry disease (analysis ongoing) *classified according to frequency of occurrence; potential causes are not mutually exclusive Possible causes of SUDOSCAN disturbances, Suggested evaluation not currently validated by research 8-‐10 Connective tissue diseases, autoimmune See details for specific diagnostic testing in references diseases, hereditary conditions (Fabry, HSAN, Tangier’s, vasculitis) Hyperlipidemia Fasting lipid panel Chronic alcohol abuse, history of alcoholism Medical history, clinical examination, liver function tests Pharmacological toxins (statins, anti-‐ Medical history including current and/or past medications retrovirals), chemotherapy Environmental Toxins, Infections (HIV, Toxin exposure history, specialized toxicological and infectious 8-‐10 Hepatitis C, Lyme disease) disease studies Hypothyroidism Medical history, clinical examination, TSH and free T4 levels Potential unverified causes of asymmetry in Suggested evaluation SUDOSCAN results Nerve entrapment: spinal or peripheral Medical history, physical and neurological examination, (carpal tunnel, tarsal tunnel) unilateral extremity weakness Peripheral Artery Disease (PAD) Ankle brachial index, arterial Duplex ultrasound, angiography Extremity Trauma/Injury Medical history (comminuted fracture), imaging study Dorsal root ganglion, sympathetic ganglion Neurological examination, appropriate referral, imaging study chain disease Complex Regional Sympathetic Dystrophy Medical history, physical examination, imaging study Interpretation guide to SUDOSCAN 2 Effect on SUDOSCAN Potential confounding factors to Examples and Comments SUDOSCAN results, not fully validated by research ELEVATE SUDOSCAN Angiotensin-‐converting enzyme (ACE) May falsely elevate SUDOSCAN SCORES Inhibitors and angiotensin II receptor scores blockers (ARB) DECREASE SUDOSCAN Medications with anti-‐cholinergic Tricyclic antidepressants, SCORES effects antihistamines, antimuscarinics, anti-‐Parkinson agents, ranitidine, 11 muscle relaxants may decrease ESC Beta-‐blockers Propranolol, labetalol, timolol may decrease ESC scores Second and Third degree burns (of Medical history, clinical the palms or soles), palmoplantar examination keratodermas Acute Alcohol Intake Heavy alcohol ingestion within the last 24 hours may lower ESC scores REFERENCES [1] Schwarz P, Brunswick P, Calvet JH. EZSCAN a new tool to detect diabetes risk. British Journal of Diabetes & Vascular diseases. 2011;11(4):204-‐9. [2] Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a Noninvasive Tool for Detecting Diabetic Small Fiber Neuropathy and Autonomic Dysfunction. Diabetes Technol Ther. 2013;15(11). [3] Ozaki R, Cheung KK, Wu E, Kong A, Yang X, Lau E, Brunswick P, Calvet JH, Deslypere JP, Chan JCN. A new tool to detect kidney disease in Chinese type 2 diabetes patients—comparison of EZSCAN with standard screening methods. Diabetes tech & ther. 2011;13(9):937-‐43. [4] Freedman BI, Bowden DW, Smith SC, Xu J, Divers, J. Relationships between electrochemical skin conductance and kidney disease in type 2 diabetes. In Press. [5] Yajnik CS, Kantikar V, Pande A, Deslypere JP, Dupin J, Calvet JH, Bauduceau B. Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-‐invasive quick and simple assessment of sudomotor function. Diabetes Metab. 2013 Apr;39(2):126-‐31. [6] Adams D, Cauquil C, Mincheva Z, Theaudin M, Beaudonnet G, Labeyrie C, Depuydt S, Iliescu I, Lacroix C, Grisoni ML. Sudomotor function assessment by SUDOSCAN in FAP patients: the NNERF experience. Poster presentation. Peripheral Nerve Society. Saint-‐Malo, France, June 2013. [8] Burns TM, Mauermann ML. The evaluation of polyneuropathies. Neurology. 2011 Feb 15;76(7 Suppl 2):S6-‐13. [9] Freeman R. Autonomic peripheral neuropathy. Lancet 2005;365:1259-‐1270. [10] Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med. 2009 May;76(5):297-‐305. [11] Pharmacist’s Letter/Prescriber’s Letter – Document #271206. Therapeutic Research Center. December 2011. Available at www.pharmacistletter.com. Interpretation guide to SUDOSCAN 3 Case Studies Illustrating Various Scenarios of Abnormal SUDOSCAN results Peripheral autonomic Case 1 and small fiber dysfunction Background 33 year-‐old African American female, BMI 32, consults her primary care physician for burning in her feet in the evening after working at the pizza parlor all day. SUDOSCAN report > Feet Mean ESC: 26 μS, 10% asymmetry > Hands Mean ESC: 72 μS, 1% asymmetry Discussion Results are suggestive of a peripheral autonomic and small fiber dysfunction. From the brief history, the most likely clinical suspicion should be dysglycemia, whether metabolic syndrome, impaired glucose tolerance, or diabetes. An appropriate work-‐up and intervention should be conducted; SUDOSCAN should be repeated in 3 months or as medically necessary after treatment is instituted. If low feet scores persist, consider screening for cardiac autonomic neuropathy risk. Interpretation guide to SUDOSCAN 4 Effect of Case 2 alcohol Background 55 year-‐old Caucasian male with past medical history of mild hypertension, BMI 29; he is asymptomatic. SUDOSCAN report At t=0 > Feet Mean ESC: 38 μS, 19% asymmetry > Hands Mean ESC: 56 μS, 5% asymmetry After 48 hours > Feet Mean ESC: 87 μS, 3% asymmetry > Hands Mean ESC: 88 μS, 0% asymmetry Discussion The patient was a physician attending a medical conference and was scanned following ingestion of a large amount of alcohol earlier in the day. He was obviously impaired at time of testing. Alcohol may result in a chronic neuropathy, but may also impair SUDOSCAN scores following moderate consumption. Repeat testing after 48 hours of sobriety showed completely normal SUDOSCAN results. Interpretation guide to SUDOSCAN 5 Effect of Case 3 medication Background 55 year-‐old female treated with amitriptyline for depression with insomnia. No other significant past medical history. SUDOSCAN report § SUDOSCAN score while on amitriptyline > Feet ESC 8 μS, Hands ESC 22 μS § SUDOSCAN report 24 hours after stopping amitriptyline > Feet ESC 38 μS , Hands ESC 56 μS § SUDOSCAN report 48 hours after stopping amitiriptyline > Feet ESC 60 μS , Hands ESC 46 μS Discussion Amitriptyline, a tricyclic antidepressant, has significant anti-‐cholinergic effects. This is most likely the reason for this patient’s dramatically low ESC scores, considering she has no known neuropathy and sympathetic nerve endings on sweat glands predominantly release acetylcholine as a neurotransmitter. ESC scores eventually returned to normal after removal of amitryptiline. Interpretation guide to SUDOSCAN 6 Effect of ethnicity and Case 4 nerve entrapment Background 45 year-‐old right-‐handed African American female with tingling and numbness in her right hand. Diagnosed 2 years ago with Type 2 DM; treated with Metformin BID with HbA1c stable at 7.0%; BMI 30. She is employed as a receptionist/administrative assistant at your colleague’s family practice clinic. SUDOSCAN report > Feet Mean ESC 69 μS, 0% asymmetry > Hands Mean ESC 63 μS, 29% asymmetry > Left hand ESC is 73 μS and right hand ESC is 52 μS Discussion Several factors may be contributing to a peripheral autonomic neuropathy in this patient. Being African American, her scores may be normal though lower than a similar Caucasian patient. On this scan, her feet scores appear in the green zone and are considered normal for her racial background. This is reassuring in a diabetic patient with reasonable control of her diabetes. Losing some weight may help improve this score further. Her hand symptoms and SUDOSCAN suggest RIGHT hand dysfunction; clinical neurological examination will most likely expose a carpal tunnel syndrome, which is more common among diabetics than the general population. Appropriate treatment should be instituted and a follow-‐up SUDOSCAN may be used to follow therapeutic effectiveness. Interpretation guide to SUDOSCAN 7