Multifocal motor neuropathy without overt conduction block

One of the defining electrophysiological characteristics of multifocal motor neuropathy (MMN) is focal motor nerve conduction block. We have noted occasional patients with typical clinical features of MMN in whom there is no demonstrable conduction block. Upon review of 5 such cases, we conclude that otherwise typical MMN may present without overt conduction block. This subset of patients does not otherwise differ from patients with MMN in whom this hallmark electrodiagnostic feature is present. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 243–245, 1998.     

Multifocal motor neuropathy with conduction block misdiagnosed as multiple entrapment neuropathies

We describe a 58-year-old male with a few years history of multifocal weakness in the upper limbs with minimal to absent sensory complaints. He was diagnosed as having multiple compressive neuropathies, which required repeated decompressive surgeries. Electrodiagnostic studies prior to diagnosis were limited to a few nerves, evaluating only distal segments. Because of delay in making the diagnosis, his condition progressed, and possibly because of the unnecessary surgeries, he developed atrophy in some muscles, which resulted in significant motor disability. He was later diagnosed as having multifocal motor neuropathy with conduction block and has partially responded to intravenous immunoglobulin therapy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:813–815, 1998.     

Multifocal motor neuropathy with conduction block: a study of 24 patients.

Twenty four patients with pure motor neuropathy are reported. The chronic motor involvement associated with fasciculations and cramps, mainly in the arms, led, in most patients, to an initial diagnosis of motor neuron disease. In some patients (nine of 24), there was no appreciable muscle atrophy. Tendon reflexes were often absent or weak. The finding of persistent multifocal conduction block confined to motor nerve fibres raises questions about the nature and the importance of this syndrome. Segmental reduction of motor conduction velocity occurred at the site of the block, but significant slowing of motor nerve conduction was not found outside this site. The response to intravenous IVIg treatment seems to be correlated with the absence of amyotrophy. Patients with little or no amyotrophy had an initial and sustained response to IVIg, and did not develop amyotrophy during the follow up study. They could be considered to have a variant of chronic inflammatory demyelinating polyneuropathy. Patients with pronounced amyotrophy independent of the disease duration did not respond as well to IVIg treatment, suggesting the existence of a distinct entity. Among the patients treated about two thirds who had an initial good response to IVIg had high or significant antiganglioside GM1 (anti-GM1) antibody titres, but there was no correlation between the high titres before treatment and long lasting response to IVIg treatment.     

Multifocal motor neuropathy with conduction block: current issues in diagnosis and treatment

Multifocal motor neuropathy (MMN) with conduction block is an acquired, autoimmune-mediated neuropathy that is responsive to treatment. The clinical history is one of slowly, progressive distal weakness, which more commonly involves the upper extremities, and it affects mainly young adults. Physical examination reveals weakness without sensory loss in the distribution of individual nerves. Atrophy may be present, but hyperreflexia and spasticity are not seen. Electrophysiological studies reveal motor conduction blocks at sites not prone to compression with normal sensory responses. Immunoglobulin M anti-GM1 titers may be elevated. Treatment with human immunoglobulin or cyclophosphamide has been shown to improve strength in the majority of patients with MMN in the short term. However, motor strength and function may gradually decline over years in spite of long-term therapy.     

Multifocal motor neuropathy human sera block distal motor nerve conduction in mice

Multifocal motor neuropathy (MMN) is associated with serum autoantibodies to gangliosides, but their pathogenic role is uncertain. We have used a novel approach to study the effects of serum and plasma from 8 patients with this syndrome, 6 of whom were anti-GM1 positive. The nerve stimulus required to evoke muscle contraction and endplate potentials (EPPs) was measured in the mouse phrenic nerve—diaphragm preparation during 4 to 6 hours of direct application (plasma at 1:1 or serum 1:2 dilution) and following intraperitoneal injection of plasma (1 ml/day) for 1 to 5 days (“passive transfer”). Direct application of MMN serum or plasma produced a progressive increase in stimulus threshold, followed by complete block of nerve-evoked muscle contraction in 3 cases, and an associated decline to about 50% of the EPP amplitude followed by sudden loss of EPPs. These effects were complement independent. Even with complete block of nerve-evoked EPPs, miniature EPP (MEPP) frequency could be increased by raising external K⁺ to depolarize the nerve terminal directly. Passive transfer of 1 ml of MMN plasma (n = 5) for 3 days caused similar but less marked changes. These results demonstrate that serum factors in MMN can block nerve conduction at distal motor nerves.     

Multifocal motor neuropathy: pathologic alterations at the site of conduction block

The pathologic changes of nerves in multifocal motor neuropathy (MMN), a rare neuropathy with selective focal conduction block of motor fibers in mixed nerves, remain essentially unstudied. Fascicular nerve biopsy of 8 forearm or arm nerves in 7 patients with typical MMN was undertaken for diagnostic reasons at the site of the conduction block. Abnormalities were seen in 7 of 8 nerves, including a varying degree of multifocal fiber degeneration and loss, an altered fiber size distribution with fewer large fibers, an increased frequency of remyelinated fiber profiles, and frequent and prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in 2 nerves. We did not observe overt segmental demyelination or onion bulb formation. We hypothesize that an antibody-mediated attack directed against components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination and remyelination, and axonal degeneration and regeneration. Alternatively, the antibody attack could be directed at components of paranodal myelin. We favor the first hypothesis because in nerves studied by us, axonal pathological alteration predominated over myelin pathology. Irrespective of which mechanism is involved, we conclude that the unequivocal multifocal fiber degeneration and loss and regenerative clusters at sites of conduction block explains the observed clinical muscle weakness and atrophy and alterations of motor unit potentials. The occurrence of conduction block and multifocal fiber degeneration and regeneration at the same sites suggests that the processes of conduction block and fiber degeneration and regeneration are linked. Finding discrete multifocal fiber degeneration may also provide an explanation for why the functional abnormalities remain unchanged over long periods of time at discrete proximal to distal levels of nerve and may emphasize a need for early intervention (assuming that efficacious treatment is available).     

Multifocal motor neuropathy with conduction block: Distribution of demyelination and axonal degeneration.

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.     

Multifocal motor neuropathy with persistent conduction blocks: 18 years on

Multifocal motor neuropathy with persistent conduction blocks was firstly reported in 1986 and outlined from the group of purely motor diseases of the peripheral nervous system. The main criterion is the presence of conduction blocks located only on the motor nerves; additionally 30 percent of patients have IgM subclass serum antibodies directed against GM1 ganglioside. The clinical picture is a multifocal, asymmetrical, neuropathy, starting and predominant in the upper limbs, occurring in males aged 50 years and more, and having a progressive course. There is no biological sign besides elevated anti-GM1 antibodies. CSF analysis discloses mild increased protein count. The course is unpredictable, the neuropathy may be strictly limited to one or two motor nerves, or spread to other motor nerves in the four limbs. There is no involvement of the sensory and the cranial nerves, no involvement of the autonomic and the central nervous system. The pathophysiology is unknown, animal models do not allow to confirm the role of humoral immunity, and the role of anti-GM1 antibodies is controversial. Randomized controlled trials have assessed the efficacy of intravenous immunoglobulins which dramatically improve strength in 70-80 percent of patients in the short term, but remain unable to prevent motor deterioration in most patients, together with the occurrence of new conduction blocks. Corticosteroids and plasma exchanges do not improve the patients and may be followed by transient worsening. Long-term efficacy of immunosuppressive agents is not known.     

Multifocal motor neuropathy with conduction block with sensory fibre involvement in a diabetic patient. Case report

Multifocal motor neuropathy with conduction block (MMNcb) is a relatively rare disease characterized clinically by asymmetric limb weakness with spared sensation and electrophysiologically by persistent focal motor conduction block. We present the case of a 40-year-old male patient with six-year history of progressive, asymmetric weakness of upper and lower extremities without sensory symptoms. Electroneurography revealed definite or probable motor conduction block in several nerves. However, features of axonal lesion of sensory fibres were also found. Laboratory studies were unremarkable apart from an abnormal glucose tolerance test, and type 2 diabetes was diagnosed. In the presented case the differential diagnosis should take into consideration MMNcb with coexisting diabetic sensory polyneuropathy and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM).     

Activity-dependent conduction block in multifocal motor neuropathy

Previous studies suggested that activity-dependent conduction block (CB) contributes to weakness in multifocal motor neuropathy (MMN). Obtaining more robust evidence for activity-dependent CB is important because it may be a novel target for treatment strategies. We performed nerve conduction studies in 22 nerve segments of 19 MMN patients, before and immediately after 60 seconds of maximal voluntary contraction (MVC) of the relevant muscle. We employed supramaximal electrical stimulation, excluded nerves with marked axonal loss, and adopted criteria for activity-dependent CB. Per segment, the segmental area ratio [area proximal compound muscle action potential (CMAP)/area distal CMAP] was calculated and, per nerve, total area ratio (area CMAP at Erb's point/area distal CMAP) was obtained. MVC induced no changes in mean area ratios and induced no activity-dependent CB. In segments with CB before MVC, the MVC induced increased duration prolongation. In MMN, MVC induced temporal dispersion but no activity-dependent CB.     

Multifocal motor neuropathy

PURPOSE OF THIS REVIEW: To conduct a critical review of recent studies on the clinical and therapeutic aspects of multifocal motor neuropathy, and to analyse their implications for patient management. RECENT FINDINGS: Recent studies have contributed to defining the specific position of multifocal motor neuropathy within the spectrum of chronic immune-mediated polyneuropathies. One study compared features of this condition with multifocal acquired demyelinating sensory and motor neuropathy, while others have focused on pathological alterations at the site of conduction blocks. A further study described six new cases of multifocal acquired motor neuropathy, which should be considered as a variant of multifocal motor neuropathy. Several Cochrane reviews and review articles have shown evidence of the efficacy of intravenous immunoglobulins in the treatment of multifocal motor neuropathy. The issue of long-term intravenous immunoglobulins in multifocal motor neuropathy, however, has yielded controversial results. Two studies have shown progressive motor deterioration in most patients, correlated with electrophysiological signs indicative of axonal degeneration, while a third study found signs of sustained clinical and electrophysiological improvement after a mean follow up of 7.25 years. SUMMARY: Multifocal motor neuropathy is a distinct clinical entity that differs from chronic inflammatory demyelinating polyradiculoneuropathy and multifocal acquired demyelinating sensory and motor neuropathy, although they share some electrophysiological characteristics. Although the aetiology remains unsolved, frequent association with high-titer antibodies against ganglioside GM1, together with an often positive response to intravenous immunoglobulins further support an autoimmune mechanism. New therapeutic strategies are required, however, that focus on the effects and the costs of treatment over long-term follow up.     

Multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a recently identified peripheral nerve disorder characterized by progressive, predominantly distal, asymmetric limb weakness mostly affecting upper limbs, minimal or no sensory impairment, and by the presence on nerve conduction studies of multifocal persistent partial conduction blocks on motor but not sensory nerves. The etiopathogenesis of MMN is not known, but there is some evidence, based mostly on the clinical improvement after immunological therapies, that the disease has an immunological basis. Antibodies, mostly IgM, to the gangliosides GM1, and though less frequently, GM2 and GD1a, are frequently detected in patients' sera, helping in the diagnosis of this disease. Even if there is some experimental evidence that these antibodies may be pathogenic in vitro, their role in the neuropathy remains to be established. Patients with MMN do not usually respond to steroids or plasma exchange, which may occasionally worsen the symptoms, while the efficacy of cyclophosphamide is limited by its relevant side effects. More than 80% of MMN patients rapidly improve with high dose intravenous immunoglobulin therapy (IVIg). The effect of this therapy is, however, transient and improvement has to be maintained with periodic infusions. A positive response to interferon-beta has been recently reported in a minority of patients, some of whom were resistant to IVIg. Even if many progresses have been made on the diagnosis and therapy of MMN, there are still several issues on the nosological position, etiopathogenesis and long-term treatment of this neuropathy that need to be clarified.     

Multifocal motor neuropathy

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.     

Multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterised by slowly progressive, asymmetrical weakness of limbs without sensory loss. The clinical presentation of MMN mimics that of lower-motor-neuron disease, but in nerve-conduction studies of patients with MMN motor-conduction block has been found. By contrast with chronic inflammatory demyelinating polyneuropathy, treatment with prednisolone and plasma exchange is generally ineffective in MMN and even associated with clinical worsening in some patients. Of the immunosuppressants, cyclophosphamide has been reported as effective but only anecdotally. Various open trials and four placebo-controlled trials have shown that treatment with high-dose intravenous immunoglobulin leads to improvement of muscle strength in patients with MMN. Although clinical, pathological, imaging, immunological, and electrophysiological studies have improved our understanding of MMN over the past 15 years, further research is needed to elucidate pathogenetic disease mechanisms in the disorder.     

Multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a unique disorder characterized by slowly progressive, asymmetric, distal and upper limb predominant weakness without significant sensory abnormalities. Electrophysiology is crucial to the diagnosis, revealing the hallmark partial conduction block. MMN is considered immune mediated due to the association with anti-GM1 antibodies and the response to immunomodulatory treatment. It is paramount to recognize MMN from other motor neuronopathies or peripheral neuropathies as it is treatable. Advances in pathogenesis, clinical features, electrophysiology, diagnostic studies and treatment are reviewed. References for this review were identified from literature search on Pubmed limited to dates from 1988 to 2011. Papers were selected if relevant to the review topic and published in English.     

Multifocal motor neuropathy

We present a review of the literature on multifocal motor neuropathy (MMN), a rare neurological disorder which has features in common with both chronic inflammatory demyelinating neuropathy and lower motor neuron disease. Clinically, MMN is characterised by slowly progressive asymmetrical limb weakness, usually most prominent in the forearms. Weakness may be associated with muscle wasting, fasciculations and decreased tendon reflexes. Serum anti-GM1 ganglioside antibody titres may be increased. The diagnostic hallmark of MMN is the electrophysiological demonstration of persistent localised motor conduction blocks, with otherwise normal or near-normal motor and sensory conduction velocities. The pathogenesis of MMN has not been elucidated completely. There is, however, substantial evidence for an autoimmune mechanism. Based on the possible involvement of the immune system in the pathogenesis of MMN the therapeutic efficacy of several immunomodulatory drugs has been tested. Treatment of MMN patients with human immunoglobulin or cyclophosphamide is usually followed by a marked improvement of strength. The finding that MMN is a potentially treatable disorder underscores the importance of distinguishing MMN from lower motor neuron disease, for which no effective therapy is currently available. Received: 14 October 1996 Accepted: 28 October 1996