Review
Multifocal motor neuropathy

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Abstract

Multifocal motor neuropathy (MMN) was first described in 1988 as a purely motor neuropathy affecting multiple motor nerves. The diagnosis was based entirely on demonstrating electrophysiological evidence of a conduction block (CB) that selectively affected motor axons, with sparing of sensory axons even through the site of motor CB. Subsequently, a similar disorder was reported but with absence of demonstrable CB on routine nerve conduction studies and there is still some debate as to whether MMN without CB is related to MMN. MMN is thought to be an inflammatory neuropathy related to an immune attack on motor nerves. The conventional hypothesis is that the primary pathology is segmental demyelination, but recent research raises the possibility of a primary axonopathy. Anti-GM1 antibodies can be found in some patients but it is unclear whether these antibodies are pathogenic. Intravenous immunoglobulin is the mainstay of treatment but other immunosuppressive treatments can also be effective.

Introduction

In 1985, at the annual meeting of the American Academy of Electrodiagnostic Medicine, Parry and Clark presented an account of three patients with a pure motor neuropathy affecting upper limb nerves. All had been diagnosed with motor neuron disease but none had bulbar or upper motor neuron features and electrophysiological testing showed that they had severe conduction block (CB) confined to motor axons. Sensory nerve conduction studies in affected nerves were completely normal. In 1988 they published a full account of these patients and added two further patients. The clinical picture was of a multifocal motor neuropathy (MMN); motor deficits were in the distribution of individual peripheral nerves, not within a spinal segmental pattern as would be expected in a motor neuron disease. Evanescent paresthesias occurred in one patient but none had persistent sensory symptoms such as numbness, tingling or pain and the sensory examination was normal in all.1 The diagnosis was based on electrophysiological testing which showed CB purely affecting the motor axons; sensory nerve conduction studies done through the site of motor CB were normal. In 1986, Roth and Magistris described a further patient with identical clinical and electrophysiological features. It is likely that, prior to these reports, many such patients were classified as having a benign form of amyotrophic lateral sclerosis (ALS) lacking overt upper motor neuron findings and with respiratory and swallowing functions spared. Therefore, unlike with ALS, these patients did not die from their disease. One could speculate that the lack of prior appreciation that MMN was a disorder distinct from ALS was probably because of the failure to recognize that weakness in MMN was in the distribution of individual peripheral nerves rather than in a segmental distribution (as in ALS). It is also likely that the motor CB that may have been seen in these patients was dismissed as being related to technical factors such as suboptimal nerve stimulation, and anomalous innvervation. Lastly, some of the difficulties in diagnosis may be because MMN is a relatively rare disorder compared to ALS, with an incidence of 1 to 3 per 100,000. Nevertheless, the initial recognition of this disorder has over the last two decades facilitated research that has led to better understanding of its pathogenesis, which, in turn, has led to various efficacious treatment strategies.

A decade after the initial description of MMN, a similar disorder but without evidence of CB on routine nerve conduction studies was described.2 Several reports have suggested subsequently that MMN without conduction block (MMNWOCB) is probably the same disease as MMN, and that the inability to demonstrate CB is related to its location (for example very proximal at the nerve root level) and/or to the lack of sensitivity of routine nerve conduction studies in detecting CB, rather than to its absence.[3], [4] The presence of anti-GM1 antibodies in some patients with MMNWOCB and response to treatments that are also effective in MMN further suggests that these diseases may be related and have pathogenetic similarities with differences only in the electrophysiological phenotype.[4], [5], [6]

Section snippets

Pathology and pathophysiology

In view of the characteristic electrophysiological findings of localized motor CB without significant immediate distal axonal degeneration, focal segmental demyelination as the underlying pathological basis was thought to be the most likely. Patches of demyelination (thinly myelinated axons), along with onion bulb formation related to repeated demyelination and remyelination, were seen in ulnar nerve biopsy at the site of motor CB in one patient.7 Similar findings along with endoneurial edema

Clinical features

MMN typically presents with progressive asymmetric distal limb weakness in the distribution of individual peripheral nerves[1], [4], [6], [19], [20] (Table 1). When the neuropathy becomes confluent, it can be difficult to differentiate it from weakness in a segmental distribution such as is seen in motor neuron disorders. The consensus diagnostic criteria require weakness in the distribution of two or more named nerves without objective sensory loss or upper motor neuron signs.21 However, motor

Motor nerve conduction

Electrophysiology is of primary importance in the diagnosis of MMN since motor CB on nerve conduction studies was the initial defining characteristic of the disorder (Fig. 3). The electrophysiological hallmark of MMN is the presence of purely motor CB at non-entrapment sites in two or more named nerves, with normal sensory responses (Fig. 4, Fig. 5) even across the sites of motor CB.[1], [21] MMNWOCB is much more challenging to diagnose and requires an intimate knowledge of myotomes and

Treatment and prognosis

MMN and MMNWOCB are immune mediated neuropathies that respond to immunomodulatory treatments. Unlike some immune mediated disorders, spontaneous improvement has not been described, and is unlikely in our opinion, although the disease can progress very slowly.27 Immunomodulatory treatments tend to be expensive and have potential adverse effects. Therefore, if the disability related to the neuropathy is mild and does not affect activities of daily living and vocational functions in a meaningful

Controversies and future directions

MMN was initially described as a demyelinating neuropathy with CB that was thought to be related to focal segmental demyelination.1 That CB in MMN can remain localized for a long time with minimal distal axonal degeneration would also support this hypothesis. Doubts were cast on this idea when, in one study, pathological findings at the site of CB showed signs of axonal degeneration rather than demyelination.11 It was later proposed that the primary site of pathology may be the axolemma at the

Conflict of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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