Brain, Vol. 126, No. 1, 186-198,
January 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg019
Demyelination and axonal loss in multifocal motor neuropathy: distribution and relation to weakness
Departments of 1 Neurology and 2 Clinical Neurophysiology, Rudolf Magnus Institute for Neurosciences, University Medical Centre Utrecht, The Netherlands
Correspondence to: H. Franssen, MD, PhD, Department of Clinical Neurophysiology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands E-mail: h.franssen{at}neuro.azu.nl
Received July 5, 2002. Accepted July 5, 2002.
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Summary |
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Multifocal motor neuropathy (MMN) is characterized by a slowly progressive, asymmetric weakness of the limbs without sensory loss. The arms are usually affected to a greater extent than the legs, and distal muscles more than proximal muscles. The distribution of electrophysiological abnormalities and its correlation with weak muscle groups in MMN have not been investigated systematically. The aim of the present study was to assess whether electrophysiological abnormalities have a preferential or random distribution, whether electrophysiological abnormalities in a nerve correlate with weakness in the innervated muscles, and whether these results are relevant for the development of optimal electrodiagnostic protocols. We compared the pattern of weakness and electrophysiological abnormalities in 39 patients with a lower motoneuron syndrome and a positive response to intravenous immunoglobulins. All patients underwent an extensive standardized electrophysiological examination. Electrophysiological evidence of demyelination was found more often in the nerves of the arms and was distributed randomly over lower arm, upper arm and shoulder segments. Electrophysiological evidence of axonal loss presented more frequently in longer nerves, occurring most often in the leg nerves. For the arm nerves, it is possible that the length dependence of axonal loss is due to the random distribution of demyelinating lesions that lead to axonal degeneration. Weakness was associated with features of demyelination and axonal loss in the nerves of the arm, and with features of axonal loss in leg nerves. However, a substantial number (approximately one-third) of electrophysiological abnormalities were found in nerves innervating non-weakened muscles. These results imply that in MMN, conduction block is most likely to be found in long arm nerves innervating weakened muscles, but if conduction block cannot be detected in these nerves, the electrophysiological examination should be extended to other arm nerves including those innervating non-weakened muscles.
Keywords: multifocal motor neuropathy; neuropathy; weakness; demyelination; axonal degeneration
Abbreviations: CB= conduction block; 95 CI = 95% confidence interval; CMAP = compound muscle action potential; DML = distal motor latency; IVIg = intravenous immunoglobulins; MCV = motor conduction velocity; MMN = multifocal motor neuropathy; MRC = Medical Research Council; OR = odds ratio; P/D = proximal versus distal stimulation; TD = temporal dispersion
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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Multifocal motor neuropathy (MMN) is characterized by slowly progressive, asymmetric weakness of the limbs without sensory loss (Nobile-Orazio, 2001
). Differentiation from motoneuron disease has become increasingly important (Donaghy, 1999) as MMN has proved to be a treatable disorder (Kaji et al., 1992; Nobile-Orazio et al., 1993; Azulay et al., 1994, 1997; Comi et al., 1994; Bouche et al., 1995; Leger, 1995; Cappellari et al., 1996; Meucci et al., 1997; Carpo et al., 1998; Federico et al., 2000; Leger et al., 2001). The diagnosis of MMN is based on clinical, laboratory and electrophysiological characteristics (Parry and Sumner, 1992; Hughes, 2001; Nobile-Orazio, 2001).
Weakness in MMN has been attributed to the consequences of demyelination and axonal loss in peripheral nerves (Feasby et al., 1985; Katz et al., 1997). On electrophysiological examination, features of demyelination that can be observed in MMN include conduction block, increased temporal dispersion and severe conduction slowing. The features of axonal loss include needle electromyography abnormalities and decreased distal compound muscle action potentials, although the latter can also be caused by distal conduction block (Cappellari et al., 1996; Jaspert et al., 1996; Nobile-Orazio, 1996; Katz et al., 1997, 2002; Taylor et al., 2000; Van den Berg-Vos et al., 2000a). Conduction slowing compatible with demyelination and increased temporal dispersion are not assumed to give rise to weakness, whereas conduction block and axonal loss are (Feasby et al., 1985). This assumption has, however, not yet been proved in patients with MMN.
Weakness in MMN usually follows a typical pattern, being more prominent in distal than proximal muscles and more prominent in the arms than the legs (Katz et al., 1997; Taylor et al., 2000), but the mechanisms that lead to this distribution have not yet been elucidated. Explanations for the distribution of weakness in the arms include preferential location of demyelination in nerve segments of the lower arm, preferential location of demyelination in nerve fibres innervating lower arm muscles at the level of the proximal forearm or brachial plexus, or a random distribution of demyelination resulting in more damage to the longest arm nerves. Insight into these distributions may help to understand the pathophysiological mechanisms involved in MMN and in fibre length dependency of abnormalities in immune-mediated neuropathies.
Due to the multifocal nature of MMN, an extensive electrophysiological examination may be necessary to detect conduction block or other features of demyelination. Its detection in MMN depends on the criteria used for conduction block and the number of nerves investigated (Ellis et al., 1999; Van den Berg-Vos et al., 2000a). In our extensive electrodiagnostic protocol, we investigated a large number of nerves independently from the distribution of weakness, whereas other protocols depend on the investigation of nerves that innervate weak, non-atrophic muscles (Katz et al., 1997; Ellis et al., 1999; Taylor et al., 2000). The distribution of electrophysiological abnormalities and the correlation with weak muscle groups in MMN may, therefore, also have important implications for the way in which an electrodiagnostic investigation is conducted in a patient suspected of having MMN.
The aim of the present study was to assess: (i) whether electrophysiological abnormalities have a preferential or random distribution; (ii) whether electrophysiological abnormalities in a nerve correlate with weakness in the innervated muscles; and (iii) whether these results are relevant for the development of optimal electrodiagnostic protocols. For this purpose, we compared the pattern of weakness and electrophysiological abnormalities in 39 patients with MNN.
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Patients and methods |
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Patients
Thirty-nine patients were selected for this study from a group of patients with the clinical presentation of an asymmetric lower motoneuron syndrome on the basis of a favourable response to high-dose intravenous immunoglobulins (IVIg) (Van den Berg-Vos et al., 2000
a; Hughes, 2001). On follow-up, the response to treatment lasted at least 12 months. The clinical and laboratory features are summarized in Table 1. Sensory conduction studies were normal in all patients. The clinical and electrophysiological data were obtained before IVIg treatment was started. Muscle strength was assessed bilaterally by one investigator (R.M. Van den Berg-Vos), who was blinded to the results of electrophysiological studies. Medical Research Council (MRC) grading (Medical Research Council, 1976) was performed in thenar abductors, hypothenar abductors, wrist extensors, wrist flexors, elbow extensors, elbow flexors, arm abductors, ankle dorsiflexors, ankle plantarflexors, knee extensors, knee flexors and hip flexors. Weakness was defined as an MRC score <5. By summing all MRC grades, an MRC sumscore was calculated for each patient (maximum 120). Most patients were tested for serum IgM anti-GM1 antibodies (Van den Berg et al., 1992). MRI of the brachial plexus was performed according to a previously described protocol (Van Es et al., 1997). All participants gave informed consent to participate in the study, which was approved by the Medical Ethical Committee of the University Medical Centre, Utrecht.
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Electrophysiological studies
Nerve conduction was studied bilaterally by the same investigator (H. Franssen), who was blinded to the results of muscle strength measurement. A standardized protocol and surface electrodes were used (Van den Berg et al., 1998
). Motor nerve conduction was investigated up to Erb’s point in the median (recording m. abductor pollicis brevis and m. flexor carpi radialis), ulnar (recording m. abductor digiti V), radial (recording m. extensor carpi ulnaris), and musculo cutaneous (recording m. biceps brachii) nerves and up to the popliteal fossa in the deep peroneal (recording m. extensor digitorum brevis) and tibial (recording m. abductor hallucis) nerves. Antidromic sensory conduction was investigated in the median, ulnar, radial and sural nerves. In the case of motor conduction block in the ulnar or median nerve, sensory conduction was measured over the affected segment. F-waves were recorded after 20 distal stimuli to the median, ulnar, deep peroneal and tibial nerves. Prior to an investigation, the arms and legs were warmed in water at 37°C for at least 30 min; thereafter, they were kept warm by infrared heaters (Franssen and Wieneke, 1994).
For each compound muscle action potential (CMAP), we measured the latency, amplitude, area and duration of the negative part. The following variables were studied: (i) distal amplitude (mV), which is the CMAP amplitude on stimulation of the most distal site of the nerve; (ii) amplitude reduction or area reduction (%) on proximal versus distal stimulation (P/D) (Van den Berg-Vos et al., 2000b) calculated as (distal CMAP – proximal CMAP x 100)/(distal CMAP); (iii) duration prolongation P/D (%) calculated as (proximal CMAP – distal CMAP x 100)/(distal CMAP); (iv) motor conduction velocity (MCV); (v) distal motor latency (DML); (vi) shortest F–M latency.
Conduction abnormalities were categorized into: (i) definite conduction block (CB) (area reduction P/D = 50% in a long segment, which is lower arm, upper arm, shoulder or lower leg, or amplitude reduction P/D = 30% over 2.5 cm) (Rhee et al., 1990; Franssen et al., 1997; Van den Berg-Vos et al., 2000a); (ii) probable CB (amplitude reduction P/D = 30% in a long segment of an arm nerve) (Albers et al., 1985; Oh et al., 1994); (iii) increased temporal dispersion (TD) (duration prolongation P/D = 30% in a long segment) (Lange et al., 1992; Oh et al., 1994); (iv) conduction slowing compatible with demyelination (MCV decreased below 75% of the lower limit of normal; DML or shortest F–M latency increased above 130% of the upper limit of normal) (Franssen et al., 1997; Van den Berg-Vos et al., 2000a); (v) F-wave absence; (vi) decreased distal CMAP (distal CMAP amplitude decreased below the lower limit of normal).
The distal CMAP amplitude had to be at least 1.0 mV to score CB and increased TD, and at least 0.5 mV to score conduction slowing compatible with demyelination and F-wave absence. Reference values for DML compatible with demyelination in the median nerve with recording from the m. flexor carpi radialis, radial and musculocutaneous nerves were not available. Features of demyelination at entrapment sites, which are the elbow segment of the ulnar nerve and the fibular head segment of the peroneal nerve, were not analysed and did not contribute to the diagnosis of MMN. Responses were only scored if supramaximal stimulation was possible (which is at least 20% above the strength yielding a maximal CMAP; for Erb’s point at least 30%). In the case of CB, we ensured that the proximal CMAP did not increase after setting the stimulator at maximal output. If necessary, a collision technique was used to detect effects of co-stimulation (Kimura, 1989; Van den Berg et al., 1997).
For each nerve the presence of a conduction abnormality was correlated with the presence of weakness (MRC <5), either in the muscle group innervated by the same nerve (leg nerves) or in the muscle from which the CMAP was recorded (arm nerves). This resulted in the following correlations: median nerve (recording from m. abductor pollicis brevis) with thenar abductors, ulnar nerve with hypothenar abductors, radial nerve with wrist extensors, median nerve (recording from m. flexor carpi radialis) with wrist flexors, musculocutaneous nerve with elbow flexors, deep peroneal nerve with ankle dorsiflexors, and tibial nerve with ankle plantarflexors.
Statistical analysis
Statistical significance for the distributions of weakness and electrophysiological abnormalities was calculated using a 
2 test. A P value <0.05 was considered significant. Relations between weakness and electrophysiological abnormalities in one or more segments of the innervating nerve were analysed by stepwise forward logistic regression—a tool also used to analyse relations between CB and other electrophysiological abnormalities in the same nerve. Relations were expressed by odds ratios (OR) and their 95% confidence interval (95 CI).
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Results |
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Distribution of weakness
The distribution of weakness (MRC <5) is shown in Table 2 and Fig. 1. Patients showed weakness in two to 15 muscle groups, always including the distal arm muscles. When all muscle groups were included in a
2 test, unilateral weakness was found more often than bilateral weakness (P < 0.01). Weakness was found significantly more often in distal than in proximal muscle groups and significantly more often in arms than in legs (all P < 0.01).
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Frequency of electrophysiological abnormalities
Examples of recordings are shown in Fig. 2. The electrophysiological abnormalities in each of the 39 patients are presented in Tables 3 and 4. Definite CB was found in 30 patients, probable CB in 37 patients, increased TD in 33 patients, MCV compatible with demyelination in 25 patients, DML compatible with demyelination in 15 patients, F–M latency compatible with demyelination in 24 patients, F-wave absence in 18 patients and decreased distal CMAP in 27 patients. Definite CB was found in 65 segments, probable CB in 133 segments, increased TD in 137 segments and MCV compatible with demyelination in 78 segments. DML compatible with demyelination was found in 24 nerves, F–M latency compatible with demyelination in 42 nerves and F-wave absence in 26 nerves. Electrophysiological abnormalities other than a decreased distal CMAP were found in 220 nerves. A decreased distal CMAP was found in 94 nerves, of which 34 also showed other abnormalities. Electro physiological abnormalities at entrapment sites were found unilaterally in the elbow segments of the ulnar nerve in nine patients. They consisted of increased TD and MCV compatible with demyelination. CB was not found at entrapment sites. No evidence of demyelination was found in the fibular head segments of the deep peroneal nerve.
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Electrophysiological abnormalities in arm versus leg nerves
To determine whether electrophysiological abnormalities were preferentially located in arm nerves, we compared the number of abnormalities in lower arm segments (median nerve with recording from m. abductor pollicis brevis and ulnar nerve) with the number of abnormalities in lower leg segments (deep peroneal and tibial nerve) (Table 5). Upper limb segments were not included, as these cannot be investigated in the legs. MCV, DML and F–M latency compatible with demyelination were found significantly more often in lower arm than in lower leg segments (P < 0.05). Definite CB and increased TD were also found more often in lower arm than in lower leg segments, but the difference was not significant. A decreased distal CMAP was found more often in leg than in arm nerves, but the difference was again not significant.
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Electrophysiological abnormalities in long versus short nerves
To determine whether the number of electrophysiological features of demyelination depends on nerve length, we compared (Fig. 1A–D) the number of nerves with at least one segment with definite CB, probable CB, increased TD or MCV compatible with demyelination in: (i) long (median nerve with recording from m. abductor pollicis brevis and ulnar nerve); (ii) intermediate (median nerve with recording from m. flexor carpi radialis and radial nerve); (iii) short (musculocutaneus nerve) arm nerves. Leg nerves were not included as features of demyelination can only be assessed in the lower leg. The frequency of definite CB, probable CB, increased TD or MCV compatible with demyelination increased significantly with nerve length (P < 0.05).
The number of shoulder segments with electrophysiological features of demyelination did not differ significantly among the different arm nerves indicating that shoulder segments of long arm nerves were not more susceptible to demyelination than those of shorter arm nerves.
Comparison of the number of decreased distal CMAPs in leg nerves (peroneal and tibial), which are the longest nerves, and in long, intermediate and short arm nerves showed that the number of nerves with a decreased distal CMAP increased significantly with nerve length (P < 0.05) (Fig. 1E).
Electrophysiological abnormalities in distal versus proximal nerve segments
We also investigated whether there is a preferential distal localization of electrophysiological abnormalities by comparing the distribution of features of demyelination in arm nerves with more than one segment (median nerve with recording from m. abductor pollicis brevis and from m. flexor carpi radialis, ulnar and radial nerves) with a random distribution. For each type of electrophysiological abnormality, the cumulated number for each segment (lower arm, upper arm or shoulder) was expressed as a fraction of the total number of the segment under investigation. Subsequently, these fractions were corrected for the average length of that segment and finally expressed as a percentage of the cumulated fractions of all three segments. The distributions of definite CB, probable CB and MCV compatible with demyelination did not differ significantly from random (2 test). This can also be deduced from Fig. 3, which shows that these distributions appeared to be similar in lower arm, upper arm and shoulder nerve segments. Only the distribution of increased TD was significantly different from random; this could be attributed to a disproportionately high number of lower arm segments with increased TD.
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These results indicate that the higher frequency of features of demyelination in longer arm nerves can be explained by the fact that, due to the random distribution, longer arm nerves are more often affected than shorter arm nerves.
Relation between weakness and electrophysiological abnormalities
Both muscle strength and conduction studies of the innervating nerve were determined in 546 muscles (14 nerves for each of the 39 patients), of which 226 (41%) were weakened. Each type of electrophysiological abnormality was found more often in nerves innervating weakened muscles than in nerves innervating non-weakened muscles (Table 6). However, a substantial number (approximately one-third) of electrophysiological abnormalities were found in nerves innervating non-weakened muscles.
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Logistic regression analysis of all nerves, of all arm nerves and of long arm nerves (median nerve with recording from the m. abductor pollicis brevis and ulnar nerve) showed a significant relationship with weakness for a decreased distal CMAP, MCV compatible with demyelination and the presence of CB (Table 7). Logistic regression analysis of leg nerves showed a significant relation with weakness for a decreased distal CMAP.
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We determined whether CB was related to other electrophysiological abnormalities in the same nerve. Logistic regression analysis showed that CB in nerves innervating weakened muscles was significantly related to MCV compatible with demyelination (OR 9.4, 95 CI 3.9–22.5) and increased TD (OR 10.2, 95 CI 4.5–22.7), but not to a decreased distal CMAP (OR 0.2, 95 CI 0.1–0.5). This indicates that the various features of demyelination are mutually related.
Comparison of electrophysiological protocols
In the present study, all patients underwent an extensive standardized bilateral electrophysiological protocol in a large number of nerves. Using this protocol, all 39 patients were found to have CB or other features of demyelination; in 30 of 39 patients at least one segment with definite CB was found, and in 9 other patients at least one segment with probable CB (Table 8). We investigated how these numbers would change if a lower number of nerves had been examined in a bilateral standard protocol, or if the electrophysiological studies had been limited to all or a proportion of those nerves that innervate weakened muscles. Of the 30 patients with definite CB, investigation of the arm nerves revealed definite CB in 29 patients; in only one patient was additional investigation of the leg nerves required to reveal definite CB. Among the arm nerves, most abnormalities were found in the median nerve with recording from the m. abductor pollicis brevis and in the ulnar nerve. Protocols consisting of a bilateral standard investigation revealed 
10% more patients with definite CB, and 5% more with definite or probable CB compared with protocols limited to nerves innervating weakened muscles.
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Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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In the present study of 39 clinically and electrophysiologically well-defined patients with MMN, all of whom responded to IVIg therapy, we compared the pattern of weakness and electrophysiological abnormalities to identify a possible preferential localization of features of demyelination or axonal loss, and their relationship to weak muscle groups. This may have implications for developing electrodiagnostic protocols for MMN and other immune-mediated polyneuropathies. The weakness in our population was more pronounced in the arms than in the legs, and more in distal than in proximal muscles; this is similar to other reports on MMN (Katz et al., 1997
; Taylor et al., 2000). Electrophysiological evidence of demyelination was found most often in long arm nerves. For the arm nerves, this phenomenon can be explained by the random distribution of demyelination between lower arm, upper arm and shoulder segments. It is not known if this random distribution also holds true for the most proximal arm nerve segments since we did not perform cervical root stimulation (Menkes et al., 1998; Kaji et al., 2000). Electrophysiological evidence of axonal loss presented more often in longer nerves and was found most frequently in the legs. Weakness was significantly associated with decreased distal CMAPs, MCV compatible with demyelination and CB. All types of electrophysiological abnormalities were found more often in nerves innervating weakened muscles than in nerves innervating non-weakened muscles, but a substantial number (approximately one-third) of electrophysiological abnormalities were found in nerves innervating non-weakened muscles. For electrodiagnostic examination of patients with lower motoneuron syndromes, these results imply that CB or other electrophysiological features of demyelination are most likely to be found in long arm nerves (median and ulnar nerves) innervating weakened muscles. If CB cannot be detected there, the electrophysiological examination should be extended to other nerves of the arms and legs including those innervating non-weakened muscles.
A decreased distal CMAP can be the result of CB distal to the most distal stimulation site or axonal loss (Albers et al., 1985; Cappellari et al., 1996). In the present study, 156 lower arm and 156 lower leg segments were investigated. CB was found in 50 lower arm segments and a decreased distal CMAP in 29. CB was found in seven lower leg segments and a decreased distal CMAP in 42. As CB was shown to be randomly distributed over arm nerve segments and as the lower arm and lower leg segments are 4x longer than the segments distal to the most distal stimulation sites, a decreased distal CMAP is more likely to be caused by axonal loss than by distal CB. In a follow-up study of MMN patients, we showed that a decrease in distal CMAP over time occurred more often than development of CB in lower arm or lower leg segments. This indicated that the decrease in distal CMAP was more likely due to axonal degeneration (Van den Berg-Vos et al., 2002). Finally, in five patients with MMN with a decreased distal CMAP amplitude of the median nerve, we stimulated the recurrent branch to the abductor pollicis brevis muscle distal to the wrist but found no evidence of CB (H. Franssen, unpublished observation). For these reasons, we have considered a decreased distal CMAP to most likely be the result of axonal loss.
In MMN, most evidence points to an association of CB with demyelination on the basis of pathophysiological studies (Feasby et al., 1985; Auer et al., 1989; Kaji et al., 1993; Corbo et al., 1997; Parry et al., 1997; Steck et al., 1998), increased signal intensity on MRI (Van Es et al., 1997; this study) and the correlation between CB and MCV compatible with demyelination (Feasby et al., 1985; Kaji et al., 1993; this study). Alternatively, it has been suggested that CB is the result of blocking of nodal sodium channels (Santoro et al., 1992); however, up until now no evidence has been obtained for this mechanism (Kaji et al., 1993). For these reasons, we have considered CB to be the result of demyelination.
All types of electrophysiological abnormality were found most often in nerves innervating weakened muscles, but also in nerves innervating muscles in which weakness was not found according to the MRC grading. Relations with weakness were found for axonal loss, MCV compatible with demyelination and CB. Because CB and MCV compatible with demyelination were related to each other, and as it is unlikely that weakness is caused by decreased MCV, weakness is most probably caused by CB or axonal loss. This had been suggested previously but not statistically proven (Feasby et al., 1985). It is in concordance with the finding that weakness occurred more often in nerves with CB than in nerves with increased TD (Katz et al., 1997). The predominant distal localization of weakness can be explained by the random distribution of demyelination in arm nerve segments, leading to more sites with CB in longer arm nerves, and the nerve length dependence of axonal loss in arm and leg nerves. Whether this axonal loss is secondary to demyelination or whether it occurs independently of demyelination is at present unclear. Excitability measurements distal to the site of CB in patients with MMN have revealed evidence of axonal hyperpolarization, thought to be secondary to intra-axonal accumulation of Na+ ions at the site of CB due to reduced Na+/K+ pump activity (Kiernan et al., 2002). The Na+ accumulation could in turn lead to intra-axonal Ca+ accumulation due to reversal of the Na+/Ca+ pump and, consequently, to axonal degeneration. Such a depolarizing block deteriorates with cooling due to further impairment of the Na+/K+ pump (Kaji and Kojima, 1997). This is in contrast to a demyelinative block, which improves with cooling due to the longer opening time of nodal voltage gated Na+ channels (Rasminsky, 1973). However, in a previous study we found that cooling improves CB, as is consistent with a demyelinative rather than a depolarising block (Franssen et al., 1997). Nevertheless, it is possible that, by an unknown mechanism, the length dependence of axonal loss is due to the random distribution of demyelinating lesions that lead to axonal degeneration. Relations between immune-mediated demyelination and axonal loss were also suggested for chronic inflammatory demyelinating polyneuropathy and Guillain–Barré syndrome, but the exact mechanisms are still not known (Hahn, 1998; Dalakas, 1999; Smith and Hall, 2001).
Electrophysiological investigation can be of crucial importance in differentiating MMN from lower motoneuron disease. It remains controversial whether the detection of CB or other features of demyelination is necessary for the diagnosis of MMN. Previous studies concluded that diagnostic criteria for MMN requiring CB may lead to under-diagnosis of this potentially treatable neuropathy (Cappellari et al., 1997; Katz et al., 1997). On the other hand, we have previously shown that the presence of CB is highly predictive of a beneficial response to IVIg in patients with lower motoneuron syndromes (Van den Berg-Vos et al., 2000a). Comparison of different studies is difficult as the presence of CB in MMN may depend strongly on the criteria used for CB and the number of nerves investigated. In the present study, we showed that extensive bilateral electrophysiological examination, including arm and leg nerves innervating non-weakened muscles, may improve the diagnostic yield of CB and other features of demyelination. Recently, Katz et al. (2002) described three patients with a lower motoneuron syndrome without CB or other features of demyelination who responded to IVIg treatment. They suggested that these patients suffered from an immune mediated motor neuropathy with axonal features that was distinct from MMN or other motoneuron disorders. However, based on the results of our study, MMN cannot be excluded in these patients, as the electrophysiological protocol was restricted; in some patients, only two limbs were investigated. Alternatively, the patients of Katz et al. (2002) might suffer from progressive spinal muscular atrophy as follow-up was only 5 months whereas our patients showed a positive response for at least 12 months. We have previously described five patients with a lower motoneuron syndrome without CB or other features of demyelination, according to our protocol, who did not respond to IVIg with the exception of one patient who responded for 6 months but deteriorated thereafter (Van den Berg et al., 1997). This issue can only be solved if the response to IVIg is investigated in a large group of patients with a lower motoneuron syndrome without evidence of CB or other features of demyelination according to an extensive electrodiagnostic protocol. The detection of CB in such future studies might be further improved by fatiguability testing (Kaji et al., 2000) or root stimulation (Menkes et al., 1998; Kaji et al., 2000), both of which were shown to reveal CB in nerves in which CB was not found on conventional nerve conduction studies.
The question arises why demyelination is found predominantly in arm nerves and axonal loss predominantly in leg nerves. A possible factor is that demyelination in leg nerves cannot be detected because of the relative inaccessibility of proximal leg nerve segments to electrophysiological investigation. Although it has been shown that lumbar root stimulation can detect proximal demyelination in MMN (Menkes et al., 1998), this cannot explain the total absence in our study of MCV compatible with demyelination in lower leg segments including those with normal distal CMAPs. The absence of F-waves, as was found in a number of leg nerves in this study, cannot be interpreted as proximal demyelination because it was also found in patients with motoneuron disease (Peioglou-Harmoussi et al., 1987). Together with the predominance of weakness in arm nerves, these findings point to different pathophysiological mechanisms for arm and leg nerves; these might be related to differences in ion channel distributions. This is supported by the finding that in normal subjects accommodation to sub-threshold depolarizing currents was greater for median than for deep peroneal nerve motor fibres, suggesting that median nerve motor fibres express more outward rectifying slow K+ channels than deep peroneal nerve motor axons; inward rectification was not different between these nerves (Kuwabara et al., 2000). As demyelination exposes paranodal or internodal K+ channels, demyelination in an arm nerve as compared with that in a leg nerve might lead to a greater outward K+ current, more hyperpolarization and, consequently, a greater susceptibility to CB (Kaji et al., 2000).
In conclusion, this study shows that, in MMN, the distribution of demyelination is random in arm nerves and that the distribution of axonal loss is nerve length-dependent. For the arm nerves, it is possible that the length dependence of axonal loss is due to the random distribution of demyelinating lesions that lead to axonal degeneration. In combination with the correlation of features of demyelination and axonal loss with weakness, these distributions can explain the typical pattern of weakness in MMN. These results have implications for the way in which the electrophysiological examination is conducted in a patient suspected of MMN. In addition, they may help to understand the pathophysiological mechanisms involved in MMN and in fibre length dependency of abnormalities in immune-mediated neuropathies.
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Acknowledgements |
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This study was supported by a grant from the Princess Beatrix Fund. The research of Dr Van den Berg was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.
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References |
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