Clinical Neurophysiology 118 (2007) 124–130 www.elsevier.com/locate/clinph Multifocal motor neuropathy with conduction block: Distribution of demyelination and axonal degeneration Steve Vucic a, Kristin Black b, Peter Siao Tick Chong b, Didier Cros a b,* Institute of Neurological Sciences, Prince of Wales Hospital, Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Randwick, 2035, Sydney, Australia b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA Accepted 27 September 2006 Available online 13 November 2006 Abstract Objective: Multifocal motor neuropathy with conduction block (MMN) is an immune-mediated neuropathy, characterized by progressive muscle weakness. Although demyelination is regarded as the underlying pathophysiologic mechanism of MMN, recently, it was reported that different pathophysiologic mechanisms were responsible for disease in the upper and lower limbs. Specifically, demyelination in the upper limbs and axonal loss in the lower limbs. Consequently, the aim of the present study was to assess, through clinical neurophysiology studies, whether different pathophysiologic mechanisms were occurring in the upper and lower extremities. Furthermore, we wanted to investigate whether the presence of conduction block (CB) correlated with axonal degeneration (AD), and to determine the electrophysiological abnormalities that correlate with muscle weakness. Methods: We reviewed medical records of 18 patients with MMN for clinical features (using the Medical Research Council score and Guys Neurology Disability Scale) and neurophysiologic abnormalities (CB, AD prolongation of distal motor and F-wave latencies, and reduction of conduction velocity in the demyelinating range). Results: Electrophysiological abnormalities deemed specific of demyelination were non-significantly different in the upper and lower extremities. The presence of axonal degeneration correlated significantly with conduction block (odds ratio 10.4, 95% CI 4.2–25.6), and both parameters correlated with muscle weakness (P < 0.01). Conclusion: Our study suggests that the same pathophysiologic process occurs in the upper and lower extremity nerves. Moreover, one pathophysiologic process may be responsible for the development of CB and AD, and therefore muscle weakness. Significance: The present study has established that both AD and CB occur in MMN, irrespective of extremity, and both correlate with muscle weakness. Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Multifocal motor neuropathy; Weakness; Conduction block; Axonal degeneration 1. Introduction Multifocal motor neuropathy with conduction block (MMN) is a demyelinating neuropathy, characterized by Abbreviations: AD, Axonal degeneration; CB, Conduction block; CV, Conduction velocity; DML, Distal motor latency; GND, Guy’s Neurological Disability Scale; MRC, Medical Research Council; MMN, Multifocal motor neuropathy with conduction block. * Corresponding author. Tel.: +1 617 726 3642; fax: +1 617 726 2019. E-mail address:
[email protected] (D. Cros). slowly progressive, asymmetric weakness of the limbs without sensory loss (Nobile-Orazio, 2001). The pathophysiological mechanism of MMN is thought to be an immune-mediated attack on both the myelin sheath and the motor axon, resulting in demyelination and axonal loss (Kaji et al., 1993; Taylor et al., 2004). Supporting an immune-mediated mechanism are findings of elevated serum antibodies against GM1 ganglioside and response of MMN patients to immunomodulatory therapies (Azulay et al., 1994; Federico et al., 2000; Leger et al., 2001; Van den Berg et al., 1995). 1388-2457/$32.00 Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.09.020 . 2. above elbow. Assessment of disability Upper and lower limb disability was scored using the Guy’s Neurological Disability Scale (Sharrack and Hughes. The following nerves and nerve segments were studied. extensors.. on the Medical Research Council Scale [MRC]) in the territory of 2 or more motor nerves.1.S. no upper limb problem. was recently proposed as an alternative mechanism of CB (Taylor et al. 1. The muscles studied included: deltoid. 2. wrist flexors and extensors. Although the presence of conduction block has been pathologically linked to demyelination (Feasby et al. extensor indicis proprius. 1999). Weakness in MMN is said to follow a typical pattern. ankle dorsiflexors. 3. 1985. hip flexors and hip extensors. 1993). toe flexors. usually uses a wheelchair indoors. and it has been suggested that the mechanisms mediating CB result in secondary AD (Kiernan et al.. problems in one or both arms affecting some but not preventing any of the functions listed. Vucic et al. 2003. Kaji et al. and cervical root). using Oxford Synergy or Teca Mystro EMG machines (Oxford Instruments. with subsequent axonal degeneration (AD). flexor carpi radialis. and at the popliteal fossa).. 2003). unable to use either arm for any purposeful movements. The following muscle groups were assessed in the lower limbs bilaterally. one explanation is that different pathophysiological mechanisms were responsible for disease in the upper and lower limb nerves (Van Asseldonk et al. arm or ankle foot orthoses) to walk outdoors but walks independently indoors. the aim of the present study was to further investigate whether different pathophysiologic mechanisms were occurring in the upper and lower limb nerves and to determine whether axonal degeneration is associated with conduction block.. and abductors.. Although the mechanisms behind this pattern of weakness remain elusive. 4. Van den Berg-Vos et al. washing or brushing hair and eating. common peroneal nerve to the extensor digitorum brevis muscle (stimulation at the ankle. Near-nerve electrical cervical nerve root stimulation was performed using monopolar needle electrodes according to previously reported methods (Berger et al. 1987.2. or unilateral support to walk indoors. Assessment of muscle power Muscle strength was assessed with the MRC scale (Medical Research Council. Surface Ag/AgCl disk electrodes were used for recording the compound muscle action potentials (CMAP).. and cervical nerve roots). 1976). Taylor et al. thumb abductors.. 5. tying a bow in string. Disability of the upper limbs was scored as follows: 0. Old Woking. Axonal degeneration has been documented at sites of CB in MMN patients (Katz et al. Collision studies were used for determining the median nerve CMAP amplitude (Kimura. 2002). tibial nerve to the flexor hallucis brevis muscle (stimulation at the ankle and popliteal fossa). below elbow. 2. knee flexors and extensors. Nerve conduction studies Nerve conduction studies (NCS) were performed at the Massachusetts General Hospital Neurophysiology Laboratories. problems in one or both arms preventing three of the functions listed.. finger flexors. affecting all or preventing one or two of the functions listed. below the fibular head. not affecting functions such as doing zips or buttons. 2000). antibody-mediated attack against components of axolemma at the nodes of Ranvier. The temperature of extremities was maintained at 32 °C. plantar flexors.. Old Woking. deltoid. median nerve to the abductor pollicis brevis muscle (stimulation at the wrist. Patients We reviewed the clinical and electrophysiological records of 18 patients with MMN. 2004). 2001). and (ii) electrophysiological evidence of CB in two or more motor nerves at sites distinct from common entrapment.. above spiral grove. 4. 1997. above elbow. musculocutaneous nerve to biceps brachii muscle (stimulation at cervical nerve roots). 2006a). problems in one or both arms. 1. 2006). usually uses a wheelchair to travel outdoors or bilateral support to walk indoors. The following muscle groups were assessed in the upper limbs bilaterally. usually uses unilateral support (stick. problems in one or both arms. Surrey. usually uses bilateral support to walk outdoors. Vucic et al. walking is affected but patient is able to walk independently. Taylor et al. England).. 3. 2. Both conduction block and axonal degeneration were recently established as significant correlates of muscle weakness (Van Asseldonk et al. Needle electromyography (EMG) was performed using a disposable 20-gauge concentric needle electrode (Oxford Instruments.. triceps. Surrey. England). 2003). 2000. Disability of the lower limbs was scored as follows: 0.3. abductor pollicis bre- . / Clinical Neurophysiology 118 (2007) 124–130 125 The neurodiagnostic feature of MMN is the presence of conduction block (CB) in two or more motor nerves that are not at common sites of entrapment. 2000). being more prominent in nerves that innervate distal than proximal muscles and more prominent in the upper than lower limb nerves (Katz et al. antecubital fossa. triceps. and toe extensors. biceps brachii. walking is not affected. Consequently... Criteria for diagnosis of MMN included: (i) asymmetric limb weakness (grade 4 or less. with normal mixed and sensory nerve conduction studies (Olney et al. 1997. ulnar nerve to the abductor digiti minimi muscle (stimulation at the wrist. radial nerve to the extensor indicis proprius (stimulation at the forearm. and cervical nerve roots) and triceps muscles (stimulation at cervical nerve roots). 5.4. 2. 2003). Methods 2. 2. with normal sensory nerve conduction studies (Olney et al. trapezius. biceps. 8 ± 15..4 nerves examined per patient.2. Proximal . 3. SD) mg/dl 8:10 52.3 ± 8. 3. 2. and minimum F-wave response latency were classified as demyelinating (DM) if they satisfied the American Academy of Neurology diagnostic criteria for CIDP (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force.9 1. 1991). 8 in the musculocutaneous.1–24) 11 (73) 5 (28) 2 (11) Per patient (%) 12 (67) 11 (61) 8 (44) 6 (27) 6 (18) 2 (11) 1 (6) 12 (67) 4.5 (1549) 4. with definite CB being documented in 16% and probable CB in 5.1. 38 in the radial. followed by median and tibial nerves. and SNAP amplitude. The mean number of nerves clinically affected per patient was 3. and spinal accessory nerves (1). with a mean of 8. 30 tibial. lV. common peroneal (27). Conduction block was defined according to existing criteria (Olney et al. Cranial nerve abnormalities were not evident in any of the patients. DML. Results 3. In lower limbs. radial (16). and 1 spinal accessory.5. Tendon reflexes were reduced or absent in 67% of patients.3% of nerve segments (Table 2). ulnar and radial nerves to the axilla. A diagnosis of CB was made only when the distal CMAP amplitude exceeded 1 mV. A total of 151 nerves were assessed in 18 patients. ms. between distal and proximal sites of stimulation when studying the median. Atrophy of target muscles was noted in 67% of patients.6. 2006b). Specifically.3. CB was defined as >45% reduction in CMAP amplitude and area. A probability value <0. In the lower limbs definite CB was defined as >60% reduction in CMAP amplitude and >50% reduction in CMAP area for tibial and common peroneal nerves when stimulating to the knee and fibular head. Anti-GM1 antibodies were detected in 22% of patients. musculocutaneous (8). ulnar and radial nerves (Vucic et al. All data are expresses as means ± standard error of the mean (SEM). with <30% increase in CMAP duration.5 4 (22) 36. first dorsal interosseous.7 (26–59) 3. / Clinical Neurophysiology 118 (2007) 124–130 Table 1 Clinical and laboratory features of 18 patients with multifocal motor neuropathy with conduction block Clinical features Male: Female Current age mean (range) (years) Age at onset mean (range) (years) Disease duration before diagnosis (range) (years) Upper limb onset (n [%]) Lower limb onset (n [%]) Upper and lower limb onset (n [%]) Nerve territories clinically involved: Median Ulnar Common peroneal Radial Tibial Musculocutaneous Spinal accessory Muscle atrophy MRC: mean (sum score) Upper limb Lower limb GND: mean Upper limb Lower limb Laboratory features GM-1 antibodies (n [%]) CSF protein (mean.. The nerves assessed included median (35). motor nerve conduction velocity.7 Per nerve (%) 16/36 (44) 15/36 (42) 8/36 (22) 8/36 (22) 11/36 (31) 2/36 (6) 1/36 (3) vis. Conduction block Conduction block was documented in 21. with weakness in the median nerve territories being the most frequent. Neurophysiology The electrophysiological features are summarized in Tables 2–4.05 was deemed significant. Probable CB was defined as 40–49% reduction in amplitude and 30–39% reduction in area with minimal temporal dispersion (<30% increase) or >50% reduction in amplitude and >40% reduction in area with moderate temporal dispersion (30–61% increase) for median. 2003). No patient had signs of upper motor neuron dysfunction.6 (0. tibialis anterior.6 (1322) 1. minimum F-wave latency. with 61 segments examined in the ulnar nerve. 3. 60 in the median. The electrophysiological parameters of CV. 27 in the common peroneal. A total of 225 nerve segments were assessed in the 151 nerves. ulnar (34). definite partial CB was defined as >50% reduction in CMAP amplitude and >40% reduction in CMAP area when studying the median and ulnar nerves to the axilla. Sensory examination was normal in all the patients. Disease onset was most frequently noted in the unilateral upper limb. m/s (CV). distal motor latency (DML). vastus lateralis. Electrophysiological criteria and analysis The following electrophysiological parameters were assessed: conduction block (CB). and medial gastrocnemius muscles.3% nerve segments. Clinical features The clinical features of all 18 MMN patients are summarized in Table 1. For cervical nerve root stimulation. probable conduction block was defined as >50% reduction in CMAP amplitude and >40% reduction in area with minimal temporal dispersion (<30%) or >60% reduction in amplitude and >50% reduction in area with moderate temporal dispersion (31–60% increase) for tibial and common peroneal nerves.126 S. Pearson Chisquare (v2) testing was used to determine the electrophysiological correlates of muscle weakness. respectively. Vucic et al. tibial (30).1 ± 12 (27–78) 43. ms. Conduction block was most frequently documented in tibial nerves. 4) 21/30 (70) 12/27 (44. There was no significant difference in the frequency of CBs between upper and lower limb nerves (upper limb. was documented in 13. followed by common peroneal and tibial nerves.30 0.7–9. below elbow (BE). Further. needle EMG testing revealed reduced recruitment and a reduced distal CMAP amplitude.5) 10/30 (33) 0 (0) Reduced DCMAP N (%) 4/36 (11) 4/34 (12) 4/16 (25%) DML N (%) 7/36 (19.5) Lower limb N (%) 11/57 10/58 29/69 11/62 (19) (17. distal segment. Although the presence of CB was significantly associated with muscle weakness (Table 4). prolonged distal motor latency. In the upper limbs.75 0. accessory nerve and was diagnosed retrospectively after IVIg treatment.6%. the tibial nerve was stimulated at the ankle (A) and knee (K).4–6. were significantly associated with muscle weakness *. / Clinical Neurophysiology 118 (2007) 124–130 Table 2 Electrophysiological abnormalities in 18 patients with multifocal motor neuropathy with conduction block Nerve Median Ulnar Radial Nerve segment W-E E-R W-BE AE-R F-E E-SG SG-R EP-R MM-PF A-FH CB N (%) 9/60 (15) 8/60 (13. lower limb.9 Odds ratio 95% Confidence interval 1. the median nerve was stimulated at the wrist (W). above elbow (AE).4) 5/30 (16.4) 1/38 (2. Table 3 Comparing electrophysiological abnormalities in the upper and lower extremities Electrophysiological parameter Conduction block Reduced DCMAP EMG changes of AD Demyelinating electrophysiological parameters Upper limb N (%) 38/168 (23) 13/93 (14) 52/131 (40) 11/88 (12. positive sharp waves.2) (42) (17.1* 4. and cervical nerve root (R). 19%.6) 6/27 (22. spiral groove (SG).3 0.4) 3/34 (8. In one patient. and cervical nerve root (R).6) 10/61 (16.1–0. reduced conduction velocity. as revealed by cervical nerve stimulation.2% of nerve segments tested.4.5 1. in 6% of nerve segments there was no accompanying muscle weakness. including distal compound muscle action potential (CMAP) amplitude.0 0. The denominator for other electrophysiological parameters.8) 0 (0) CV N (%) 6 (17) 4/34 (12) 0 (0) 127 F-waves N (%) 0 (0) 16/34 (47) 0 (0) Musculocutaneous Tibial Common peroneal 2/8 (25) 5/30 (16. 9%. and F-wave latency is the total number of nerves studied.72 0. while the musculocutaneous nerve was stimulated at Erb’s point (EP) and cervical nerve root (R).0* 0. Further conduction block was significantly associated with weakness *.3) 4/61 (6.9 1. In the lower limbs. 23%. Evidence of ongoing axonal degeneration (fibrillation potentials and positive sharp waves) together with denervation-reinnervation changes were noted in all target muscles innervated by nerves with a low distal CMAP amplitude.S. Distal CMAP amplitude Distal CMAP amplitude was reduced in 16% of nerves and was most frequency documented with radial nerve stimulation. The denominator for conduction block (CB) is the number of nerve segments studied for the particular nerve. Vucic et al.9 0.6–11.6) 1/38 (2. presenting with weakness and atrophy of the left trapezius muscle.30).5%.30 Changes of axonal degeneration (AD) include fibrillation potentials.6) 3/38 (7. expressed as a percentage of the lower limit of normal.4) In the upper limbs. Table 3).2–1.8 0. P = 0. 3.7) Pvalue 0.2 Reduced distal compound muscle action potential amplitude (DCMAP) along with electromyography (EMG) changes of axonal degeneration (AD) including the presence of fibrillation potentials/positive sharp waves and the presence of motor unit potentials of increased duration. the radial nerve was stimulated in the forearm (F). amplitude. the finding of muscle atrophy strongly correlated with neurogenic findings (low distal CMAP amplitude.6 1.2–0.5) 0 (0) 6/30 (20) 2/27 (7. was 68 ± 3. ongoing and denervation-reinnervation changes) on electrophysiological testing (P < 0. while the common peroneal nerve was stimulated at the ankle (A) and fibular head (FH). denervetaion-reinnervation changes and/or reduced distal compound muscle action potential (DCMAP) amplitude Demyelinating parameters deemed specific for a demyelinating neuropathy include. and cervical nerve root (R).2 mg/kg for 5 consecutive days). there was no significant difference between the frequency of CBs between proximal (nerve root-elbow) and distal (wrist-elbow) segments (proximal segment. The mean distal CMAP amplitude. One third of these asymptomatic CBs were detected in the proximal nerve segments with cervical nerve root stimulation.0001). Further. without evidence of ongoing or denervation-reinnervation changes. The ulnar nerve was stimulated at the wrist (W).9) 1/8 (12. 12.9–4.7) 5/27 (18. CB was documented in the distal segments of the spinal . elbow (E). distal motor latency (DML).1 0. along with normalization of the distal CMAP Table 4 Correlation between weakness and electrophysiological abnormalities Electrophysiological abnormality Conduction block Reduced DCMAP EMG changes of AD Conduction velocity Distal motor latency F-wave latency Fibrillation potentials Odds ratio 3.4 0. Upon treatment with one course of IVIg (0.3* 4. In one patient. and polyphasia with or without reduced recruitment and increased firing. there was complete resolution of weakness and wasting. CB. elbow (E). and prolonged minimum F-wave latency in the demyelinating range (see Section 2). Recently it was proposed that different pathophysiologic processes were responsible for disease in the upper and lower limbs of MMN patients. As for the CB findings. 2006) has been borne out in the present study. nerve excitability studies have shown that upper limb nerves exhibit more prominent K+ conductances predisposing the nerve to hyperpolarizing conduction block (Kuwabara et al. These findings were attributed to differences in ion channel distribution between the upper and lower limb nerves. 2003). Specifically. The present study did not find any significant difference between upper and lower limb nerves with regard to the frequency of demyelinating parameters including CB. lowering the safety factor for transmission in an already compromised demyelinated axon.128 S. may result in conduction block (Kaji. being most frequently documented in the ulnar nerve (Table 2). 1997. and hence muscle weakness. Further. Discussion In this series of 18 MMN patients. the CV was reduced in the demyelinating range including. 1998). expressed as a percent of the upper limit of normal.. 1994. 3. 3. In addition to providing an explanation for the link between demyelination and axonal degeneration in MMN. expressed as a percentage of the lower limit of normal was 96. 2003. we find no significant difference between the upper and lower limb nerves for the presence of electrophysiological parameters deemed specific of primary demyelination and axonal degeneration. Katz et al. suggesting that one pathophysiologic process may be responsible for the development of both electrophysiological findings. and late responses deemed specific of primary demyelination (Table 3). Conduction velocity was reduced in 14% of nerves and was most frequently documented in the common peroneal nerve (Table 2).. Van Asseldonk et al. Chaudhry et al. resulting in CB. and common peroneal (n = 1). activation of the electrogenic Na+/K+ pump by intra-axonal Na+ accumulation would increase the membrane threshold (Vagg et al... Given that there were no significant differences in the frequency of CB between upper and lower limb nerves. suggesting that one pathophysiological process is underlying the development of both conduction block and axonal degeneration. As such. suggesting that one pathophysiologic process may be responsible for the development of CB and AD. DML was prolonged in the demyelinating range. Blockage of voltage gated Na+ channels. Further. 1998). based on findings that electrophysiological parameters of demyelination were significantly more common in the upper limb nerves (Van Asseldonk et al. Other electrophysiological parameters Distal motor latency was prolonged in 12% of nerves and was most frequently documented with tibial and median nerve stimulation (Table 2). 2003). Tibial nerve H reflexes were prolonged or absent in 47% nerves. suggesting that the same pathophysiologic process occurred in the upper and lower limbs. along with denervation-reinnervation changes were significantly associated with muscle weakness (Table 4). In 8.. 2006).8%. there was no significant difference between upper and lower limb nerves with regards to abnormalities of CV. Indirect support for this mechanism is provided by nerve excitability studies showing the presence of axonal hyperpolarization distal to sites of CB that results from overactivity of the Na+/K+ pump secondary to longitudinal diffusion of intra-axonal Na+ ions from sites of CB (Kiernan et al. ulnar (n = 4). was present in both upper and lower limb nerves of MMN patients.5 ± 0. The previous finding that conduction block and axonal degeneration correlate with weakness (Feasby et al. including prolongation of DML and late responses.. Findings of reduced distal CMAP amplitude. and reduction of conduction velocity were compared between the upper and lower limb nerves. and common peroneal (n = 1). The mean CV. / Clinical Neurophysiology 118 (2007) 124–130 amplitude and needle EMG findings. 2003).. was 119 ± 0. ulnar (n = 2). features of AD were significantly associated with CB (OR 10.6). Further.. 1991). 2003). tibial (n = 2). by perhaps anti-GM1 antibodies. Late responses (F-wave) were absent or prolonged in 33% of nerves. providing further evidence that a uniform pathophysiological process. Conduction block without accompanying muscle weakness. as documented in 6% of nerves segments assessed in the present study. the development of secondary AD may have obscured the presence of demyelinating features in the lower limbs. A potential explanation by which CB leads to axonal degeneration may be secondary to intra-axonal Na+ ion accumulation at sites of CB resulting in reverse Na+/Ca+ activity and accumulation of intraaxonal Ca++ (Stys et al. One possible explanation for this discrepancy may be shorter disease duration in the present series. both electrophysiological findings (AD and CB) were independently associated with each other (Van Asseldonk et al. the frequency of other electrophysiological parameters deemed specific for demyelination. The frequency of changes deemed specific for AD (distal CMAP amplitude and denervation-reinnervation changes) was not significantly different between upper and lower limb nerves (Table 3). by assessing patients at a later stage in the disease process. has been previously reported in MMN . 2000). In 5% of nerves. namely demyelination.1%.6 versus 11 years (Van Asseldonk et al.. DML. membrane hyperpolarization secondary to Na+/ K+ pump overactivity (Vagg et al. Specifically. suggesting that the findings were secondary to distal CB.5. 4. 95% CI 4. Vucic et al. 2002). tibial (n = 4).2–25. The mean prolonged DML. median (n = 4). will further reduce the safety factor for transmission and contribute to CB (Kaji. In one tibial nerve..0% of nerves the F-wave latencies were prolonged in the demyelinating range including. median (n = 2). and with each other.. conduction block and axonal degeneration were significantly associated with muscle weakness. 1985.4.. 63:129–37. The prevalence of antiGM1 antibodies in MMN ranges from 22–85% (NobileOrazio. Dyck PJ. Mult Scler 1999. Cornblath DR. Stys PK. Lin CS. Kaji R. Muscle Nerve 1998. Consensus criteria for the diagnosis of multifocal motor neuropathy. Bouche P. 2006b). Electrophysiologic findings in multifocal motor neuropathy. Kimura J. Ross MH.17:198–205. The pathological basis of conduction block in human neuropathies. Campellone Jr JV. Firing properties of single human motor units during locomotion. 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