Multifocal Motor Neuropathy With Conduction Blocks

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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]}

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. 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]

MMN 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]}

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.

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]

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Sasa Zivkovic, MD, PhD Professor, Department of Neurology, Division of Neuromuscular Diseases, University of Pittsburgh School of Medicine

Sasa Zivkovic, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Peripheral Nerve Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals; Akcea Therapeutics.

Michael C Isfort, MD Resident Physician, Department of Neurology, University of Pittsburgh Medical Center

Michael C Isfort, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, Gold Humanism Honor Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals<br/>Received income in an amount equal to or greater than $250 from: Alnylam Pharmaceuticals; GLG.

Nicholas Lorenzo, MD, MHA, CPE Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Paul E Barkhaus, MD, FAAN, FAANEM Professor of Neurology and Physical Medicine and Rehabilitation, Chief, Neuromuscular and Autonomic Disorders Program, Director, ALS Program, Department of Neurology, Medical College of Wisconsin

Paul E Barkhaus, MD, FAAN, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Neurological Association

Disclosure: Nothing to disclose.

Multifocal Motor Neuropathy With Conduction Blocks

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