Multifocal motor neuropathy
Multifocal motor neuropathy
It represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients.
One of the most important entities in the DDX of ALS.
Epidemiology:
Prevalence: estimated 1:100,000
It is rarer than ALS. It is estimated (Cornblath and Chaudary at John Hopkins) that for every 1 or 2 cases of MMN, there are 100 cases of ALS.
Male: female (2.7:1)
Age of onset: 20 to 70 years of age, although 20% of cases occur later (upto 80s).
Most patients are younger than 50 years (mean age of onset: 40).
TNF-alpha blocker reportedly causes MMNBC.
Clinical features:
The diagnosis of MMN requires motor nerve involvement in at least two nerves for more than 1 month. Anti-GM1 antibodies are seen in some but not all patients with MMN, and the absence of GM1 antibodies does not exclude the diagnosis. In patients with MMN, the presence of anti-GM1 antibodies ranges from 30% to 80%. Clinically, no sensory symptoms are present. Reflexes are often absent or diminished in the affected limb. Electrophysiology often demonstrates demyelinating features with conduction block in the motor nerves. However, if the conduction block is very proximal or distal, it may be more difficult to detect. If any signs of sensory loss, upper motor neuron dysfunction, bulbar involvement, or symmetric weakness are present, one should consider an alternative diagnosis.
Classically MMN presents as an asymmetrical upper limb, pure motor multiple mononeuropathy, with often prominent wasting despite a short history of weakness. There is progressive, asymmetric weakness, and wasting more distally than proximally, usually of one limb (usually begins in arms), before progressing to other limbs, slowly and step-wise in several years time.
The first symptom is most commonly distal upper limb weakness but with relative sparing of finger flexors. Involvement of the non-dominant upper limb is more frequently reported.
Foot drop is the first symptom in a third of patients. Many with initial lower limb involvement later develop upper limb symptoms.
Fasciculations and cramps are prominent and observed in up to 40% of patients, and in some cases may generate local muscle hypertrophy.
Aggravation of weakness by cold is common and reported in of cases in one study.
MSR (reflexes) are usually reduced in the affected limb, but may also be normal.
The presence of sensory symptoms, signs or neurophysiological abnormalities particularly at diagnosis or early in disease should raise significant diagnostic uncertainty and prompt further investigation including consideration of targeted nerve biopsy. However, in one case series, 22% had abnormal vibration sense in the distal lower limb, with these cases having had a longer median disease duration compared with those without sensory findings.
Involvement beyond the limbs is rare, with scattered reports of phrenic and cranial nerve involvement.
Diagnostic criteria for MMN were proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society and published in 2010
Presence of UMN should be considered a red-flag, and brings the diagnosis of MMN into question.
UMN signs such as spasticity, extensor plantar responses, hyperreflexia, clonus, or bulbar dysfunction (spastic dysarthria, dysphagia) if present will make the diagnosis of MMNCB doubtful.
Laboratory features:
Associated with IgM-GM1 antibodies and asialo-GM1 and GM2.
These antibodies are present in at least 40% of cases. Sensitivity is low and they are detectable in a proportion of neurologically normal, ALS and other neuropathy patients. However in the setting of high positive titres and when an immune-mediated motor neuropathy is suspected, specificity can exceed 90%. In MMN, these antibodies are likely produced by a limited number of B cell clones.
MRI of brachial plexus with and without contrast
MR neurography and neuromuscular U/S.
Diagnosis can be considered to be specific if high-titers of anti-GM1 ab, are present.
Clinical neurophysiology
Identification of motor conduction block (CB) is the key neurophysiological criterion in the diagnosis of MMN .
The two most commonly affected nerves are the median and ulnar nerves, in their forearm segments and not at typical compression sites.
The CB observed in MMN is unique in that it affects motor fibers exclusively with normal sensory conduction through the same segment in mixed nerves.
Additionally the block is focal and occurs abruptly and, at least in the earliest stages of the disease, motor conduction distal to the site of block may remain normal.
CB is very difficult to delineate reliably when the distal evoked CMAP amplitude is less than 1 mV.
Electromyography (EMG) almost always reveals significant chronic denervation and reinnervation of muscles supplied by nerves with CB, demonstrating that axonal degeneration is a significant feature of MMN even from the earliest onset of the disease.
There have been reports of MMN with typical clinical features but no CB identified.
A possible reason is very proximal or distal locations of CB where routine electrophysiology is unable to detect block.
Another possibility is conduction studies were performed only in clinically affected limbs while CB may be found also in nerves innervating muscles with normal strength.
DDx:
The differential diagnosis of progressive limb weakness and atrophy without sensory symptoms is mainly restricted to motor neuron disease, including amyotrophic lateral sclerosis and its lower motor neuron form, progressive muscular atrophy, bibrachial motor neuron disease, benign monomelic amyotrophy, CIDP, MADSAM and MMN, and HNPP. Other conditions to be considered include postpolio syndrome, lead- or dapsone-induced motor neuropathies, and hexosaminidase-A deficiency.
Multifocal neuropathies/multiple mononeuropathies DDx:
Peripheral nerve vasculitis: PAN, GPA, CSS (EGPA), MPA, SLE, RA, MCTD, nonsystemic vasculitic neuropathy, remote effects of cancer.
Other immune mediated neuropathies: MADSAM, CIDP (asymmetric), MMN, sensory perineuritis, lumbosacral/brachial plexus neuritis, post-surgical neuritis.
Granulomatous infiltration: Sarcoid, lymphomatoid granulomatosis
Infectious Neuropathies; Leprosy, HZV, lyme disease, HIV, CMV, hepatitis B and C
Compression neuropathy: Primary compression neuropathies, secondary compression neuropathies (superimposed on generalized peripheral nerve disease; e.g. diabetes mellitus, and carpal/cubital tunnel syndrome.
HNPP
Others: DM, amyloidosis, neoplastic infiltration (lymphoma and leukemia), peripheral nerve tumors (neurofibromatosis), atherosclerotic vascular disease (monomelic neuropathy secondary to acute large artery occlusion of AV shunts/fistulas)
Drug induced (e.g., interferon-alpha, leukotriene receptor antagonist, TNF-alpha inhibitors, leflunomide, amphetamine, sulfonamides.)
Tx:
Response to IVIg or cyclophosphamide. Weakness recurs after discontinuation of treatment.
Treatment with IVIG, although highly expensive, is the preferred treatment. IVIG (0.4 g/kg body weight per day for 5 consecutive days) has been reported to benefit 70% of patients.
In a patient with a typical syndrome of MMN and high anti-GM1-abs, a trial of IVIG is appropriate even if conduction block is not found on NCS.
If CB is demonstrated on NCS, treat the patient with IVIG. The presence or absence of GM1 in this context is unimportant.
Continue maintenance infusions (1 g/kg once every 2-4 weeks) for at least 3 months in patients who have a functionally meaningful response.
Lack of response to IVIG over 3 monthly course is considered failed treatment.
Corticosteroids may worsen the disease.
Most patients with MMN respond to treatment with IV immunoglobulin.
Corticosteroids, plasmapheresis, and most immunosuppressants are ineffective
Rituximab and cyclophosphamide may be effective in some patients.
Rituximab can be given at 375 mg/m2 weekly for 1 month or 750 mg/m2 (upto 1 gm) and repeated after 1 or 2 weeks.
Cyclophosphamide is reserved for patients who fail IVIG and rituximab.
Cyclophosphamide is given at 300 mg/m2 over a 8 day period, with subsequent reduced maintenance dose.
SE: alopecia, nausea, vomiting, hemorrhagic cystitis, and bone marrow suppression.
Anti-GM1 antibody titer reduction of 60% or more, suggests response
Cyclophosphamide with IVIG may sometimes prolong the interval between IVIG infusions.
When given this way, start cyclophosphamide IV pulsed dose of 0.5 g/m2 and gradually increase to 0.75 g/m2 if tolerated and then to 1 g/m2.
Treat patients with Mesna and well hydrate to avoid hemorrhagic cystitis.
Nausea can be managed with ondansetron or granisetron.
Diagnostic criteria for MMN were proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society and published in 2010 .
Clinical Vignette: MMNCB
A 52-year-old man developed gradually progressive painless bilateral grip weakness over 4 months. Examination demonstrated weakness of the abductor pollicis brevis, flexor pollicis longus, interossei, and shoulder abductors bilaterally. He also had reduced sensation in his fingertips bilaterally and absent reflexes in his upper and lower extremities, although his lower extremities had normal strength. Electrodiagnostic testing demonstrated prolonged motor distal latencies, slowed conduction velocities, and conduction block in both median nerves, as well as demyelinating changes in both ulnar nerves and slowed conduction velocities in the fibular and tibial motor nerves that met the criteria for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Sensory nerve action potentials were absent in both upper extremities. CSF studies demonstrated albuminocytologic dissociation with no nucleated cells and a protein level of 110 mg/dL. MRI of the cervical spine was unremarkable. Anti-GM1 antibodies were negative. He started treatment with a loading dose of 2 g/kg intravenous immunoglobulin (IVIg), given over a period of 4 to 5 days, and subsequent doses every 4 weeks of 1 g/kg, given over a period of 1 to 3 days. Comparison of baseline grip strength dynamometry and the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and Inflammatory Neuropathy Cause and Treatment (INCAT) scores to measures after treatment after two cycles of maintenance treatment demonstrated improvement, as well as improvement on a strength-testing examination. He continued IVIg 1 g/kg with successful tapering to a 6-week dosing interval.
COMMENT: This case highlights the overlap between the clinical presentation of multifocal motor neuropathy (MMN) and the multifocal variant of CIDP. The important features to note are that multiple motor and sensory nerves are involved, and on electrodiagnostic testing, both sensory and motor nerves are affected with demyelinating changes that meet the criteria for diagnosis of CIDP. GM1 antibodies can be, but are not always, present in MMN. Additional supportive diagnostic testing is helpful in complex cases. This is important because treatment can have ramifications as MMN does not respond to steroid treatment and the multifocal variant of CIDP typically does. Finally, using outcome measures such as grip strength in this case in addition to clinical examination every 3 months can help guide treatment decisions for reducing the dose or increasing the interval of treatment.