Multifocal Motor Neuropathy With Conduction Blocks

Updated: Sep 27, 2016
  • Author: Sasa Zivkovic, MD, PhD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Overview

Background

Multifocal motor neuropathy (MMN) with conduction block is an acquired immune-mediated demyelinating neuropathy with slowly progressive weakness, fasciculations, and cramping, without significant sensory involvement.

Clinically, it may resemble amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron involvement, but muscle atrophy and more rapid progression are lacking. Duration of disease prior to diagnosis ranges from several months to more than 15 years.

Unlike ALS, MMN usually responds to treatment with intravenous immunoglobulin (IVIG) or cyclophosphamide, even after many years of duration. [1, 2, 3]

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Pathophysiology

The complete cascade of events leading to motor nerve dysfunction and weakness in MMN is not fully understood, but it appears to be related to dysimmune events. Histopathologic and electrodiagnostic studies demonstrate the presence of both demyelinating and axonal injury. Motor nerves are primarily affected, although mild demyelination has been demonstrated in sensory nerves as well. Efficacy of immunomodulatory and immunosuppressive treatment further supports the immune nature of MMN. Rare cases of MMN have been reported following treatment with tumor necrosis factor (TNF)-α antagonists. [4]

Titers of anti-GM1 antibodies are frequently elevated (>50%), but their role is still not well understood, even though they remain a useful marker for the diagnosis of MMN. Pathogenicity of anti-GM1 antibodies has been demonstrated in a stem cell derived model, and toxicity of GM1 antibodies was alleviated with IVIG treatment. [5] Experimental study results suggest that autoantibodies bound to gangliosides may activate the complement cascade pathway leading to the dysfunction of sodium channel function in peripheral motor nerve fibers. [6] The benefit of treatment with IVIG may be at least partly attributed to the blockade of complement pathway activation. [7]

While fluctuations in anti-GM1 titers do not correlate with clinical symptoms in most patients treated with IVIG, titers may decrease after treatment with cyclophosphamide and rituximab, correlating with improved strength. Selective involvement of motor nerves with high titers of anti-GM1 antibodies is somewhat surprising because antibodies bind both to ventral and dorsal spinal roots. Binding has also been shown to occur at the nodes of Ranvier, at compact or outer myelin of Schwann cells, and at the motor end plate of the neuromuscular junction.

Histopathologic studies of fascicular nerve biopsies showed multifocal fiber degeneration and loss with frequent regenerating nerve clusters and without significant segmental demyelination or onion bulb formation. The presence of multifocal fiber loss would explain persisting functional abnormalities and would support a need for early treatment. [8]

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Epidemiology

Frequency

United States

MMN is a rare disorder, and its lifetime prevalence is estimated to be 1 case in 100,000 population.

International

In southeast United Kingdom, the prevalence has been estimated at 0.53 case per 100,000 population, with a peak onset at age 50-59 years. [9]

Mortality/Morbidity

Dexterity and walking ability are commonly affected to some extent, but most patients are able to maintain autonomy with indoor and outdoor activities. [10] Most patients maintain productive lives despite ongoing symptoms, and up to 94% remain employed. [1] However, gradual progression of symptoms may also lead to significant disability. [11]

Fatal outcomes have been reported only rarely, and at least some case reports describe patients with other entities, including motor neuron disease.

Rarely, multifocal motor neuropathy may be associated with a B-cell lymphoma producing monoclonal antibodies against GM1 and GD1b myelin glycolipids.

Demographics

MMN is more common in males (the male-to-female ratio is about 3:1).

The mean age of onset is 40 years. Eighty percent of patients are aged 20-50 years at presentation. Rarely, children as young as 6 years may be affected. [12]

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