What is the pathophysiology of multifocal motor neuropathy (MMN) with conduction block?

Updated: Nov 12, 2018
  • Author: Sasa Zivkovic, MD, PhD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

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]


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