Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 59, Num. 5, 2011, pp. 700-706

Neurology India, Vol. 59, No. 5, September-October, 2011, pp. 700-706

Topic of the Issue: Review Article

Multifocal motor neuropathy

Thy P Nguyen, Vinay Chaudhry

Johns Hopkins University School of Medicine, Baltimore, MD, USA
Correspondence Address: Vinay Chaudhry, Johns Hopkins University School of Medicine, JHOC 5072 A, 601 North Caroline Street, Baltimore, MD, USA, vchaudh@jhmi.edu

Date of Submission: 11-Oct-2011
Date of Decision: 11-Oct-2011
Date of Acceptance: 12-Oct-2011

Code Number: ni11214

PMID: 22019654

DOI: 10.4103/0028-3886.86544

Abstract

Keywords: Demyelinating, immune-mediated, motor neuropathy, multifocal, neuropathy

Introduction

All peripheral neuropathies can be characterized by their distribution (symmetrical, asymmetrical, distal or proximal), types of fibers affected (sensory, motor, autonomic), time course (acute, subacute, chronic; monophasic, recurrent, progressive), site of involvement (myelin or axon), etiopathogenesis, and response to treatment. Multifocal motor neuropathy (MMN) is a unique disorder that is Multifocal in distribution; involves only Motor Nerve fibers; has chronic, sometimes stepwise progressive course; is demyelinating with partial motor conduction block (PMCB); has immune-mediated pathogenesis; and responds exquisitely to intravenous immunoglobulin (IVIG) treatment. Over the past two decades, many advances have been made in characterizing and understanding this unique treatable disorder. This review aims at providing a concise overview of the clinical features, laboratory and electrophysiological features, management, and pathogenesis of MMN. References for this review were identified from PubMED searches between 1988 and 2011. The search terms "multifocal motor neuropathy" and "conduction block" were used. Additional references were obtained from reviewing primary sources from relevant articles. Papers/abstracts were selected if published in English and were relevant to the review topic.

Clinical Presentation

MMN is a rare disorder with a prevalence in the range of 1-2 per 100,000. ^[1] Most reported patients range in age from 20 to 70 years, with 80% of patients reporting onset from 20 to 50 years of age. Men are more often affected than women, with a 3:1 ratio. Patients present with multifocal weakness that can be localized to named nerve distributions. ^[2] Hence, patients may present with weakness in posterior interosseous nerve distribution with wrist or finger drop; median, ulnar and radial nerve distribution with dexterity problems or grip weakness; peroneal nerve distribution as foot drop; or musculocutaneous nerve distribution with biceps weakness. Presentation is markedly asymmetrical with distal upper > lower extremities more often affected than proximal muscles. ^[2] Because of this very focal/multifocal distribution, patients are often considered to have entrapment/compressive neuropathies and have often undergone decompressive surgeries before presentation to specialized clinics. Initial symptom onset to diagnosis may take several years; median duration of 4 years has been described. ^[2] Sensory complaints of numbness, tingling, or pain are distinctly absent, differentiating MMN from entrapment neuropathies. If sensory symptoms are reported, these are often mild. Remarkably, sensory examination in the above-named nerves is normal despite the severe motor dysfunction. Patients often note twitching or cramps in the affected muscles. Atrophy is not an early feature, although may become prominent later in the disease course. Facial, ocular, bulbar (lower cranial nerves), or respiratory involvement is extremely rare but has been reported. ^[3],[4] Similarly, autonomic features are not seen. Relatively preserved bulk in the face of severe weakness should be a clue to the possibility of this disorder. Myokymia is often found on examination. Muscle stretch reflexes are often noted to be asymmetrically absent or reduced even in regions without significant weakness.

Differential Diagnosis

As in the rest of neurology, differential diagnoses should start with anatomical localization. Since MMN is a pure motor disorder, all disorders localizable to the motor unit, viz. alpha motor neuron, nerve root, plexus, nerve, neuromuscular junction and muscle, should be considered.

• Motor neuron localization: Patients with motor neuron disease are often sent to electrodiagnostic laboratories to rule out MMN, especially when there are no upper motor neuron findings. Earlier descriptions of MMN described this as a "reversible lower motor neuron syndrome" resembling lower motor neuron variant of amyotrophic lateral sclerosis. However, the relentlessly progressive weakness with atrophy, fasciculations, and the non-nerve distribution are features not seen in MMN. Nerve conduction and electromyography (EMG) findings (see below) of prominent diffuse denervation (fibrillation and positive sharp waves) and lack of demyelinating changes differentiate motor neuron disease from MMN. Other motor neuron diseases such as distal spinal muscular atrophy, monomelic amyotrophy (focal motor neuron disease or Hirayama disease), brachial amytrophic diplegia, cord tumors, syrinx, and poliomyelitis (as well as other infections such as enteroviruses, West Nile, HIV) may also be considered in the differential diagnosis. Once again, the distribution of weakness, time course, and relative minimal atrophy in the face of severe weakness (suggesting conduction block) are features that distinguish MMN from other lower motor neuron disorders.
• Radiculopathies: Cervical and lumbosacral radiculopathies from various causes including disk disease, stenosis, Lyme, and tumor infiltration need to be considered although the invariable radicular pain, the myotomal distribution, and imaging studies should easily differentiate this localization from MMN.
• Plexopathies: Brachial plexus involvement, for example, with thoracic outlet syndrome (from cervical rib, lymphoma, and other causes), inflammatory (brachial neuritis), or tumor (such as lymphoma) infiltration may masquerade as a differential diagnosis for MMN. Sensory symptoms are invariably noted, and clinical history and electrophysiological findings often are able to distinguish between plexopathy and MMN.
• Motor nerve: Other causes of multiple mononeuropathies include inherited neuropathies such as hereditary neuropathies with tendency to pressure palsies (HNPP), CMT-2D with GARS mutation, toxic neuropathy from lead, tumors along the course of the nerve (neurofibromatosis, perineuriomas, amyloidomas, and lymphomas) and entrapment neuropathies. Although vasculitic mononeuropathy multiplex may be considered, pain and acute/subacute onset are not seen with MMN. In this context, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM; also known as Lewis Sumner syndrome) and focal upper limb predominant multifocal chronic inflammatory demyelinating polyneuropathy (CIDP) should be mentioned, although given the sensory symptoms, these are considered more as variants of CIDP. ^[5] MMN is distinguishable by its pure motor focal or multifocal presentation and presence of conduction block.
• Neuromuscular junction: Although myasthenia gravis (MG) is distinguished by ocular, bulbar, and proximal muscle involvement, distal MG has been described in 5% of patients. ^[6] Patients may have foot drop, focal triceps or grip weakness, although often other distinguishing features of MG are present and conduction block is absent.
• Myopathy: Like MG, most myopathies' distribution is symmetrical and proximal. However, some myopathies may be distal and asymmetrical such as muscular dystrophies including Miyoshi, caveolinopathy, desminopathy, Laing distal myopathy, Welander distal myopathy, and myotonic muscular dystrophy. ^[7] Inclusion body myositis may also present mainly as grip weakness without the quadriceps involvement. Once again, the clinical phenotype and electrophysiology features should help separate from the myopathies.

Diagnostic Criteria

Many diagnostic criteria have been proposed [Table - 1] and [Table - 2]. ^{[8],[9],[10],[11]} Clinical criteria, such as Joint European Federation of Neurological Societies/Peripheral Nerve Society, usually incorporate the following features: weakness without sensory loss, slowly progressive or stepwise progressive course, asymmetric involvement of two or more motor nerves for more than 1 month and absence of upper motor neuron signs. Definite MMN requires more stringent criteria for conduction block than probable or possible MMN. ^[10],[11] The accepted use of clinical criteria may be advantageous because of homogeneity of MMN patient selection in trials and a common understanding of MMN in the literature. Additionally, clinical criteria may correlate well with treatment response. For clinical criteria proposed by Van den Berg-Vos, treatment response prognosis was 81% for definite MMN, 71% for probable MMN and 11% for possible MMN. ^[12]

Electrophysiology

Electrodiagnostic studies are crucial for the diagnosis of MMN. The classical finding in MMN is well-localized, persistent, segmental PMCB detected outside the usual sites of entrapment. Proximal sites of stimulation, including Erb's point, should be included in the nerve conduction testing. ^[13],[14] The attached figure [Figure - 1] shows the presence of PMCB in the forearm segment of left median nerve in a 30-year-old woman who presented with 4-year history of left-hand weakness. Note the 68% drop in amplitude from wrist to elbow segment. Conduction velocity is reduced in this segment to 34 m/sec. Although there is no temporal dispersion in elbow stimulation, more proximal stimulation reveals an increase in duration by 70%.

Conduction block is the inability of an impulse to transmit through an axon. This can be detected on electrophysiologic studies by the decrement of compound muscle action potential (CMAP) amplitude/area from distal to proximal stimulations without a significant increase in CMAP duration. The appropriate criteria for conduction block continue to be debated. Previously, a reduction in CMAP amplitude/area of >50% from distal to proximal stimulation in the absence of abnormal temporal dispersion (>15% change in the negative peak duration) was accepted to avoid over-interpretation of physiologic temporal dispersion and phase cancellation based on computer simulation studies. ^[15] However, if nerve conduction studies are performed over short nerve segments, these criteria may be too stringent. Other authors propose accepted reduction in amplitude/area of CMAP for short nerve segments of >30%. ^[16] Diagnostic criteria published by European Federation of Neurological Societies/Peripheral Nerve Society/PNS incorporate these different parameters for definite, probable or possible conduction block [Table - 2]. ^[10] Interestingly, the electrophysiologic features of conduction block have been shown to improve with immunomodulatory treatment, suggesting a role in pathogenesis. ^[4],[17] In addition, other electrophysiological features of peripheral nerve demyelination may be found: reduced conduction velocity, especially segmentally across sites of PMCB; absent or prolonged F-wave responses; and prolonged distal motor latencies. Remarkably, sensory nerve conductions are normal, even in those mixed nerves where motor fibers are affected. Needle EMG should show reduced recruitment but minimal abnormal spontaneous activity in the affected nerve distribution. Myokymic potentials and/or fasciculation potentials can be seen. More widespread denervation, including paraspinal denervation, is not seen with MMN, and if present, should raise the possibility of motor neuron disease or multilevel radiculopathy.

Diagnosis of MMN patients can be challenging when conduction block is not present. Many authors have described MMN without conduction block responsive to immunomodulatory treatment. ^[18],[19] Multifocal acquired motor axonopathy (MAMA) has similar clinical features such as response to IVIG and anti-GM1 association. ^[20] Debate exists as to whether these patients had true conduction block that might be identified using more sensitive techniques such as root stimulation, triple stimulation and fatiguability testing. ^{[21],[22],[23]} This idea of proximal conduction block (which may be missed on routine testing) is corroborated by evidence of anti-GD1A antibodies in MAMA, as these antibodies tend to reside in proximal roots. ^[24] A very proximal or a very distal PMCB should be suspected in a patient with a typical phenotype under the following scenario: a very proximal PMCB may be present when CMAP amplitudes are preserved in a very weak muscle and a distal PMCB should be suspected in a weak muscle with preserve bulk that shows reduced CMAP amplitudes. In either case, multiple nerves should be tested at all available stimulation sites to look for PMCB.

Laboratory Testing

Twenty to 85% of MMN patients are seropositive for IgM anti-GM1 antibody. ^{[25],[26],[27],[28]} Variability in detection methodology plays a partial role in explaining this wide sensitivity range. ^[29] Additionally, anti-GM1 antibodies have been found in patients with other motor neuronopathies and neuropathies. Proposed guidelines currently do not incorporate anti-GM1 seropositivity as core diagnostic criteria. ^[8],[10] However, the presence of anti-GM1 antibodies in the appropriate clinical context is recognized to support the diagnosis of MMN. The role of anti-GM1 in prognostication and as a biomarker has also been explored, with conflicting results. Some authors report that anti-GM1 seropositivity suggests a more severe natural history. ^[30] Others suggest that anti-GM1 titers prognosticate responsiveness to immunomodulatory treatment. ^[12] However, patients without anti-GM1 also respond to IVIG. ^[31],[32] Additionally, anti-GM1 as a biomarker has not borne out. Many studies have demonstrated that anti-GM1 titers do not decline with immunomodulatory treatment. ^{[33],[34],[35]}

Other laboratory studies may include a normal to moderately high creatine kinase level. In general, immunofixation with electrophoresis is normal. Cerebrospinal fluid protein measurements are normal in two-thirds of patients and marginally increased (up to 0.8 g/l) in up to one-third of patients. ^[36]

Nerve Biopsy

Pathology has not played a large role in the diagnosis of MMN, partially due to feasibility of motor nerve biopsy. Pathologic studies reported in the literature are somewhat disparate. Taylor et al. described a series of fascicular motor nerve biopsies at the site of conduction block, which showed varying degrees of multifocal fiber degeneration and loss, altered fiber size distribution with fewer large fibers, increased frequency of remyelinated fibers and frequent/prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in two nerves. However, neither segmental demyelination nor onion bulb formation was observed. The authors hypothesized that the antibody-mediated attack directed against components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination/remyelination, and axonal degeneration/regeneration. ^[37] On the other hand, other studied motor nerves revealed patches of thinly myelinated fibers with onion bulb formation or the presence of inflammation and active segmental demyelination/remyelination. ^[14],[38] An explanation for the variability in pathologic findings may be that the nerves were biopsied at different stages in the disease process. Perhaps inflammation, demyelination, and remyelination are the key findings early in the disease process. A second stage may then be present with primarily axonal changes. ^[37] In the evaluation of sensory nerves, one study did show evidence of regenerating clusters in 5 of 12 superficial radial nerve biopsies, one with axonal loss. Also, demyelination and remyelination changes were present in 2 of 12 superficial radial nerve biopsies. ^[32] Other authors have reported similar findings with mild involvement of sensory nerves. Corse et al. found rare active demyelination in 3 of 10 sural nerves studied with increased number large-caliber fiber axons showing thinly myelinated fibers, rare regenerative clusters in 4 of 10 nerves and minor onion bulbs on electron microscopy. ^[39] Overall, these mild changes support the clinical feature that sensory involvement is not prominent in MMN.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brachial plexus may help distinguish MMN from motor neuron disorders. In MMN, there is increased T2 signal intensity asymmetrically and evidence of nerve swelling in 40-50% of patients. This is similar to findings in CIDP, which are present symmetrically. However, patients with lower motor neuron disorders do not have these findings. ^[40] MR neurography (MRN) is a relatively new imaging technique that is highly sensitive in detecting lesions in the peripheral nerves. MRN has been used to directly image the peripheral nervous system due to the improved signal to noise ratio from dedicated surface coils, which allows higher resolution scanning. The peripheral nerves are isointense on T1-weighted spin echo and slightly hyperintense on fat-saturated T2-weighted fast spin echo due to the presence of endoneurial fluid. Peripheral nerves can be easily distinguished from the surrounding tissue because muscle is very hypointense on T2-weighted scans, the inversion recovery technique suppresses the adipose in the neck, and vessels usually contain signal void. Peripheral nerve disorders from various etiologies, including trauma, compression, and inflammation, usually result in T2 hyperintensity with increased nerve/muscle signal intensity ratio due to increased water content in the nerves. As with conventional MRI, the T1-weighted sequence is useful for evaluating anatomy and the T2-weighted sequence for demonstrating pathology. Role of musculoskeletal ultrasound in the evaluation of inflammatory nerve lesions, especially in proximal lesions, is still in investigational phase.

Pathogenesis

MMN is likely immune mediated based on association with anti-GM1 antibodies and response to immunomodulatory treatment. ^[41] After two decades, the role of anti-GM1 in the development of MMN remains unclear. Ligand binding studies have shown that anti-GM1 antibodies are concentrated in paranodal Schwann cell areas, setting a basis for propensity of conduction block in MMN. ^[29] Additionally, passive transfer of human sera with anti-GM1 antibodies led to conduction block in some animal nerves. ^[42],[43] However, transfer of human sera without anti-GM1 antibodies also led to conduction block, implicating involvement of other soluble factors. ^[42] Additionally, anti-GM1 is found in abundance in dorsal root ganglion (DRG) cells, but is characterized clinically by lack of sensory symptoms. ^[29]

Treatment

IVIG is the only evidence-based treatment for MMN. ^{[17],[31],[34],[35],[44],[45],[46],[47],[48],[49]} Sixty to 80% of MMN patients reportedly respond to IVIG. ^[2],[50] Many patients require long-term maintenance IVIG treatment lasting several years, at varying intervals as short as every week. ^{[17],[45],[51],[52]} Interest in increasing ease of administration has led to subcutaneous immunoglobulin and home-based IVIG, which seems to be as safe and effective as traditional IVIG. ^{[53],[54],[55]} "Smooth transition protocols" detailing conversion to subcutaneous immunoglobulins have also been reported. ^[56]

MMN response to IVIG is dose dependent, with increasing doses effective early in the disease course. ^[46,51] With time, IVIG may become less effective. Some studies have shown a decrease in the efficacy of treatment after 6-8 years, which corresponds electrophysiologically with reduced CMAP amplitudes distally, suggesting Wallerian degeneration and axonal loss from the site of initial Conduction block. ^[51] This less treatment-responsive secondary axonal loss stage underlies the importance of early diagnosis and treatment in MMN. This also may shape future therapeutic trials of MMN as interventions studied late in the disease course may seem less efficacious due to the natural history.

Unlike CIDP, treatment for MMN with steroids and plasma exchange is ineffective, perhaps even exacerbating some cases. ^{[41],[47],[57],[58],[59],[60],[61],[62]} In a randomized controlled trial, mycophenolate mofetil, although well tolerated, was not effective in reducing IVIG dosage. ^[33] Rituximab, a monoclonal anti-CD20 chimeric antibody, was also ineffective in reducing IVIG dose. ^[63],[64] Anecdotal reports and case series of cyclophosphamide suggest benefit, but effectiveness needs to be studied in a randomized controlled fashion. Additionally, toxicity profile may limit use in some patients. ^{[31],[41],[65]} Two case series suggest that interferon beta 1a may be beneficial, but also require further study. ^{[59, 66, 67]} Limited studies on cyclosporine and azathioprine have been reported with beneficial response. ^{[32],[59],[68],[69]} A recent unblinded study showed safety and tolerability of eculizimab, a monoclonal complement inhibitor. ^[70]

Future Studies

In the two decades since MMN was coined by Pestronk et al., there continues to be a multi-tiered need for research. First, elucidation of MMN pathogenetic mechanisms would guide future trials. Further understanding of the natural history of MMN would allow for optimally timed therapeutic interventions. Validation of prognostic clinical factors would identify patients who may require more aggressive therapies. The past two decades of literature on treatment have shown that anecdotal reports are limited by publication bias. There is a need for randomized controlled trials of treatment and particularly for two subpopulations of MMN patients. Eleven to 20% of patients with MMN do not respond to initial treatment with IVIG and could be targeted for trials with other modalities. ^[52],[59] Additionally, 68% of patients require maintenance IVIG for several years, at times at frequent and large doses. These patients could be targeted for adjunctive medications that decrease dose and frequency. ^[52],[59]

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