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- The diagnosis
of MMN is suspected in a patient presenting with gradual (or sometimes
abrupt) onset of slowly progressive asymmetrical weakness; normal
sensation, reduced or normal reflexes.
- Nerve conduction
studies are crucial in making a diagnosis. Multifocal demyelination
confined to motor nerves is present. Partial motor conduction block
is the hallmark of this disorder.
(see figure below)
- OTHER LABORATORY
FEATURES
- High titers of IgM antibody directed against GM1 and other gangliosides
are reported in 22% to 84% of patients. Although the presence of high
anti-GM1 antibody titers was emphasized in early reports, it is now
clear that this is neither important for diagnosis nor helpful in
predicting response to therapy. The presence of high titers of these
antibodies in a patient with multifocal lower motor neuron weakness,
however, should mandate a careful electrophysiological evaluation.
- An elevated serum
CK level is frequently found, probably secondary to the myokymia and
cramps in the muscles.
- MRI scans of
the affected regions may show hypertrophic nerve segments.
- Cerebrospinal
fluid is usually normal or may reveal a slight elevation in total
protein content.
- PATHOLOGY:
Frequent, albeit mild, morphological abnormalities are seen in sensory
fibers in patients with multifocal motor neuropathy. Increased numbers
of large-caliber axons with thinly myelinated fibers, sometimes associated
with minor onion bulbs, are reported in sural nerve biopsies. Unlike
chronic imflammatory demyelinating polyneuropathy, multifocal motor
neuropathy is not marked by epineural and endonuclear mononuclear
cell infiltrates or endoneurial and subperineurial edema. Two reports
of motor or mixed nerve biopsy have confirmed the findings of noninflammatory
demyelination and remyelination.
PATHOGENIC
MECHANISM
- Multifocal motor
neuropathy is now widely accepted to have an immune-mediated pathogenesis
based on (a) the presence of demyelinating features like those seen
with immune-mediated chronic inflammatory demyelinating polyneuropathy;
(b) elevated serum antibodies to GM1 ganglioside, a potential autoantigen
on the nodes of Ranvier and the surface of motor neurons; and (c)
clinical improvement observed with immunomodulation.
- Why motor fibers
of a mixed nerve are selectively affected is unknown. Possible hypotheses
include: the distribution of the demyelination may be determined by
fascicular arrangement within the nerve trunk, and demyelinative lesions
may be restricted to the "motor fascicles" and, therefore, result
in pure motor symptoms; the potential target antigen for this immune
disorder may be different for myelin in motor axons than in sensory
axons; the underlying pathologic process in multifocal motor neuropathy
may affect the sensory and motor fibers equally, but cause conduction
failure only in the motor fibers because of a greater safety factor
of conduction in the sensory fibers.
- The pathogenic
role of anti-glycolipid antibodies in the serum of multifocal motor
neuropathy patients remains speculative. Some studies correlated clinical
improvement with reduction in titers of the antibodies, thus suggesting
that these antibodies are pathogenic, but this has not been true in
other studies. Immunoglobulin deposits have been found at the nodes
of Ranvier in biopsied nerve from a patient with MMN and in rat sciatic
nerve treated with anti-GM1 antibody. Sera from patients with multifocal
motor neuropathy has induced block of conduction when injected into
rat sciatic or tibial nerve in vivo or in a mouse phrenic nerve preparation
in vitro. These results, however, were not confirmed by Harvey et
al. using purified anti-GM1 antibodies. Experimentally, anti-GM1 antisera
produced in rabbits immunized with GM1 ganglioside increased K+ current
and blocked Na+ channel current in isolated rat myelinated nerve fibers.
This could not by confirmed by Hirota et al. At this time, anti-GM1
antibodies can at best be considered a marker of the disease.
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