Cyclophosphamide is the
only immunosuppressive
medication that has been
reported to induce long-term
benefit in many patients (50% to
80%) with MMN. Unfortunately,
its toxicity, especially the
increased risk of neoplasia with
high cumulative life-time doses
(>75 g), requires a careful
analysis of the risk:benefit
ratio in each patient.
Therapeutic regimens should
utilize doses of
cyclophosphamide that are high
enough to reduce anti-GM1
antibody titers by 60%, or more.
We originally used an initial
dose of 3 g/M2 over 8 days
followed by chronic oral
medication (100-150 - mg/day for
6 to 12 months). More recent
experience suggests that 6
monthly treatments with
intravenous cyclophosphamide
(1g/M2), each preceded by two
plasma exchanges, is equally
effective, has fewer adverse
effects and utilizes a 50% to
70% lower cumulative dose of
drug. This regimen produces a
sustained reduction in titers of
serum anti-GM1 antibodies in
approximately 60% to 80% of
patients. Most patients in whom
antibody titers are reduced show
functional benefit. Remission
usually persists for 1-3 years;
after which, antibody titers
often rise and weakness recurs.
Retreatment may then be
necessary.
Deciding whether to treat
patients with D-LMN syndromes
without electrodiagnostic
evidence of demyelination may be
difficult. High titers of serum
IgM anti-GM1 antibodies are a
useful indicator that a D-LMN
syndrome may be immune- mediated
and treatable. Evidence of
demyelination on sural nerve
biopsy may also be helpful in
this regard. Measurable
improvement in strength after
treatment with HIG may provide
support for further
immunotherapy, with agents such
as cyclophosphamide or further
periodic HIG infusions.
2. Differential Diagnosis of Motor Neuropathies
The differential diagnosis of motor neuropathies includes motor neuron disorders, hereditary and acquired, on one hand, and demyelinating neuropathies, on the other.Motor neuropathies and motor neuron disorders. Some motor neuropathies have been classified as ALS variants, with predominantly LMN signs and axonal changes on electrodiagnostic studies. Certain features can aid in the differentiation between motor neuropathies and ALS. Patients with motor neuropathies may have preserved reflexes in weak muscles, but overt spasticity and bulbar features are conspicuously lacking. This is in contrast to patients with ALS who often have prominent upper motor neuron and bulbar findings. The prolonged course that is often noted in patients with motor neuropathies also helps to differentiate their syndromes from typical ALS. Acquired motor neuropathies most often produce asymmetric weakness. This pattern is usually clinically distinct from the proximal symmetric weakness that characterizes most of the hereditary spinal muscular atrophies.
Several lower motor neuron syndromes have been described that are of uncertain etiology and could be disorders of the motor axon or cell body. A majority of patients with D-LMN syndromes have neither evidence of peripheral nerve demyelination nor serum anti-ganglioside antibodies. These patients tend to have more rapidly progressive weakness than is typical for the immune-mediated motor neuropathies. In contrast to typical ALS, many D-LMN patients never develop bulbar dysfunction. There are no reports of response to immunosuppressive treatment in D-LMN patients with neither demyelination nor serum autoantibodies. Some patients develop progressive asymmetric lower motor syndromes with predominant early weakness in proximal musculature (P-LMN syndromes). Characteristic features include late-age onset, male predominance (85%) and initial signs of weakness in the upper extremities (80%). Progression is slow. Weakness is often confined to one or two extremities for 3 to 5 years. Electrodiagnostic studies show only evidence of axonal loss. Some patients with P-LMN syndromes (30%) have selective serum antibody binding to GA1 ganglioside. However, there is no evidence that P-LMN syndromes respond to immunosuppressive treatment.
Monomelic amyotrophy, a syndrome that affects mainly young (15 to 25 years) males (80%), presents with weakness of the distal musculature of one upper extremity that progresses for 1 to 2 years and then remains stable. Occasional patients develop weakness in the opposite limb, mild sensory symptoms or tremor. Electrodiagnostic studies show denervation in the affected limb. There are no associated serum antibodies.
Rare patients
with
paraneoplastic LMN syndromes
have been reported. The best
described of these is a subacute
motor neuronopathy associated
with lymphomas, such as
Hodgkin’s disease. Progressive,
asymmetric weakness develops,
most severely in the legs, at
times when the neoplasm is in
remission or during irradiation.
The weakness is rarely severe,
and often stabilizes or improves
over a period of months to
years. Pathological studies show
a loss of motor neurons in the
ventral horn of the spinal cord
and some involvement of sensory
tracts. LMN involvement has also
been described as an occasional
part of the paraneoplastic
encephalomyelitis and sensory
ganglionopathy syndromes that
occur in association with anti-Hu
antibodies. There is no clear
evidence that there is an
increased incidence of
paraneoplastic "typical" ALS
syndromes, with upper and lower
motor neuron involvement. A few
patients with ALS-like syndromes
and neoplasms, including renal
cell, lung and lymphoma, have
been reported to improve or
stabilize after treatment of the
cancer.
Immune demyelinating
Neuropathies. Although
MMN and CIDP are both
demyelinating neuropathies, the
differences in their clinical,
electrophysiological and
immunologic features are more
prominent than their
similarities. MMN commonly
presents with distal asymmetric
weakness while in CIDP, proximal
symmetric weakness is a more
common finding. The remitting
and relapsing course that may
occur in CIDP is uncommon in the
motor neuropathies. Patients
with MMN rarely have significant
sensory symptoms while in CIDP,
sensory signs are the rule.
Electrophysiological testing may
show conduction block in both
conditions. However, other
features of demyelination such
as prolonged distal latencies
and slowed conduction velocities
are more prominent in CIDP.
Abnormalities in sensory nerve
conduction studies are usually
seen in CIDP, but not in MMN,
unless complicated by another
disease process. The spinal
fluid examination shows markedly
increased protein concentration
in the majority of cases of CIDP
while this change is rare in
patients with MMN. High titer
anti-GM1 antibodies as well as
more specific patterns of
autoantibody reactivity (see
above) are common in MMN. In
CIDP anti-GM1 antibodies are
unusual. Serum autoantibody
binding to tubulin is more
common. Finally, differences in
the frequency of therapeutic
response to prednisone and
plasma exchange (common in CIDP,
but rare in motor neuropathies)
define a practical difference in
the management of the two
disorders.