Practice Essentials
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.
Signs and symptoms
Typically, multifocal motor neuropathy (MMN) manifests with a slowly progressive, asymmetric, predominantly distal weakness developing over years. Weakness usually starts in a distribution of a single peripheral nerve with unilateral wrist drop, foot drop, or grip weakness. Initial involvement of the distal upper extremities is most common.
Diagnosis
Nerve conduction study (NCS) with needle electromyography (EMG) is essential in demonstrating the presence of multifocal motor involvement without significant sensory component. [14] When MMN is defined clinically, some patients may not have demonstrable conduction block on conventional NCS.
Management
MMN is an immune-mediated disorder, and while multiple immunomodulatory and immunosuppressive treatments have been used, only intravenous immunoglobulin (IVIG), [21, 22, 23] subcutaneous immunoglobulin (SCIG) [24, 25] and cyclophosphamide have been consistently effective. Delay of treatment may result in increased weakness and disability. Anecdotal reports also indicate that rituximab, [26, 27, 28] interferon-beta, azathioprine and cyclosporine may be efficacious. [29, 30]
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), subcutaneous immunoglobulins (SCIG) or cyclophosphamide, even after many years of duration. [1, 2, 3]
Pathophysiology
The complete cascade of events leading to motor nerve dysfunction and weakness in multifocal motor neuropathy (MMN) with conduction block 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. Similarly even anti-GM1-negative patients may exhibit distinct autoantibody-mediated pathology, possiby to the same or similar epitopes. [5] Experimental study results suggest that autoantibodies bound to gangliosides may activate the complement cascade pathway leading to the dysfunction of sodium channels and altered calcium homeostasis in peripheral motor nerve fibers. [5, 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]
Epidemiology
Frequency
Multifocal motor neuropathy (MMN) with conduction block is a rare disorder, and its lifetime prevalence is estimated to be less than 1 case in 100,000 population.
In Japan and Austria, the prevalence has been estimated at 0.29 and 0.65 cases per 100,000 population, respectively. [9, 10]
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. [11] 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. [12]
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. [13]
Prognosis
Prognosis is usually good, and 70-80% of multifocal motor neuropathy (MMN) with conduction block patients respond to treatment. Even in patients who do not respond to therapy, weakness is only slowly progressive and up to 94% of patients remain employed. [1]
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Nerve conduction studies demonstrating conduction block with temporal dispersion after proximal stimulation.
