AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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) or cyclophosphamide, even after many years of duration.

Pathophysiology

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 disimmune 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.

Titers of anti-GM1 antibodies are frequently elevated (>50%), but their role has not been established even though they remain a useful marker for the diagnosis of MMN. 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.

Frequency

United States

MMN is a rare disorder, and its lifetime prevalence is estimated to be 1 case in 100,000 population.

International

Reported prevalence of MMN in other countries is similar to that in the United States.

Mortality/Morbidity

Most patients maintain productive lives despite ongoing symptoms, and up to 94% remain employed.

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.
• Gradual progression of symptoms may lead to significant disability.

Race

No racial predilection exists.

Sex

MMN is more common in males (the male-to-female ratio is about 3:1).

Age

The mean age of onset is 40 years. Eighty percent of patients are aged 20-50 years at presentation.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

Typically, multifocal motor neuropathy (MMN) manifests with a slowly progressive, asymmetric, predominantly distal weakness developing over years. Weakness usually starts in a distribution of a single peripheral nerve with unilateral wrist drop, foot drop, or grip weakness. Initial involvement of the distal upper extremities is most common. Rarely, MMN may manifest with initial phrenic or cranial nerve involvement. Cramps and twitching are common, but muscle atrophy is minimal if present at all. Sensory symptoms are minimal or absent. Transient exacerbation may occur during pregnancy.

Electrodiagnostic evaluation may document the presence of asymptomatic conduction blocks in other clinically unaffected nerves, and it may document more extensive involvement in patients with relatively few symptoms. Positive serology for anti-GM1 antibodies is supportive of the diagnosis of MMN, particularly higher titers.

Clinical and electrodiagnostic criteria for the diagnosis of MMN include the following:

• Definite MMN
• • Weakness without objective sensory loss in the distribution of 2 or more nerves is present.
  • Definite conduction block is present in 2 or more motor nerves outside of common entrapment sites.
  • Sensory nerve conduction velocity is normal across the segments with demonstrated motor conduction block.
  • Results are normal for sensory nerve conduction studies on all tested nerves, with a minimum of 3 nerves tested.
  • Upper motor neuron signs, including spasticity, clonus, extensor plantar response, and pseudobulbar palsy are absent.
• Probable MMN
• • Weakness without objective sensory loss in the distribution of 2 or more nerves.
  • The presence of either (1) probable conduction block in 2 or more motor nerve segments that are not common entrapment sites or (2) definite conduction block in one motor nerve and probable conduction block in a different motor nerve segment (uncommon entrapment sites).
  • Sensory nerve conduction velocity is normal across the segments with demonstrated motor conduction block.
  • Results are normal for sensory nerve conduction studies on all tested nerves, with a minimum of 3 nerves tested.
  • Upper motor neuron signs, such as spasticity, clonus, extensor plantar response, and pseudobulbar palsy are absent.

Physical

On physical examination, the most remarkable finding is asymmetric weakness in the distribution of individual peripheral nerves that is out of proportion to muscle atrophy. Fasciculations may be present.

• Cranial nerves
• • Cranial nerves are rarely affected, but this may be an uncommon initial manifestation of MMN. Cranial nerve involvement may be limited to the twelfth cranial nerve.
  • Speech is normal.
• Deep tendon reflexes: Deep tendon reflexes may be absent (particularly in affected limbs) or normal. Early in the course, tendon reflexes may be brisk.
• Motor strength
• • Asymmetric weakness may occur in a nonmyotomal pattern, usually in the distribution of individual nerves. The upper limbs, particularly the hands, are more commonly involved than the lower limbs.
  • Muscles innervated by motor nerves with persistent conduction block are usually weak.
• Muscle atrophy: Atrophy may be present in weak muscles, but it is fairly mild. Late in the disease course atrophy may be more prevalent.
• Upper motor neuron signs: These signs are absent.
• Muscle tone: Tone is decreased or normal. No clonus, extensor plantar response, or pseudobulbar palsy is present. Pathologic reflexes (eg, Babinski, Hoffman) are not present.
• Sensory examination: Findings are normal, and the sensory loss is suggestive of Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]).
• Coordination: Coordination is normal.
• Gait: Gait is usually normal, unless more prominent involvement of lower extremity muscles occurs.
• Fasciculations and cramping: These are common and may occur outside of the distribution of clinically affected nerves.
• Other: No rash or gynecomastia is present.

Causes

MMN is an autoimmune peripheral neuropathy without a known cause.

DIFFERENTIALS

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• Multimedia
• References

Other Problems to be Considered

Lewis-Sumner syndrome (MADSAM)
Mononeuritis multiplex
Hereditary motor sensory neuropathy type 2
Hereditary neuropathy with liability to pressure palsies (HNPP)
Lead neuropathy
Porphyric neuropathy
Progressive muscular atrophy
Spinal muscular atrophy (adult onset)

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Anti-GM1 antibodies
• • Most studies report elevated titers of anti-GM1 antibodies in 50% of patients with multifocal motor neuropathy (MMN), but values and sensitivity depend on the methodology. Very high titers of anti-GM1 antibodies (>1:6400) have 80% specificity for MMN, but only 20-30% of patients with MMN have titers of 1:1800 and higher. Lower titers (1:400-800) are less specific and can be found with other neuropathies and amyotrophic lateral sclerosis (ALS).
  • The variable sensitivity of different methods of measuring anti-GM1 antibodies is well described. The highest yields and sensitivity of up to approximately 90% have been reported with covalent enzyme-linked immunosorbent assay (ELISA) methodology, while most commercially available assays for anti-GM1 antibodies may have sensitivity that is as low as 20-30%.
• Creatine kinase (CK): CK is frequently elevated (<3 times the reference range).
• Cerebrospinal fluid (CSF) analysis: Findings are usually normal or reveal a mildly elevated protein content (not as much as in chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]). Cell count is normal.

Imaging Studies

• Neuroimaging studies are not routinely performed in patients with suspected MMN.
• Magnetic resonance imaging (MRI) of the brachial plexus may show an increased signal intensity on the T2-weighted images, usually without contrast enhancement. The differential diagnosis of MRI findings includes radiation-related nerve injury and trauma, while tumors are usually associated with contrast enhancement.
• Similar findings were reported with cranial nerve involvement.

Other Tests

• Nerve conduction study (NCS) with needle electromyography (EMG) is essential in demonstrating the presence of multifocal motor involvement without significant sensory component. When MMN is defined clinically, some patients may not have demonstrable conduction block on conventional NCS.
• • NCS of motor nerves shows multifocal conduction block. Other signs of demyelination may be present, including decreased velocities, prolonged terminal latencies, temporal dispersion, and delayed (or absent) F waves. Sensory NCS findings are normal, even across the same segments with demonstrated motor conduction block. Additionally, electrodiagnostic evidence of axonal degeneration has been demonstrated in at least one nerve from as many as 50% of patients.
  • Conduction block (see Media file 1) is indicative of focal demyelination and has been variably defined as a 15-50% reduction of the compound muscle action potential (CMAP) at proximal compared to distal sites of stimulation. Testing of multiple segments in several nerves may be required to demonstrate conduction block, and spinal root needle stimulation may be helpful to demonstrate proximal conduction block. The site of the conduction block should not be at a common nerve entrapment site.
  • Unlike ALS, needle EMG in MMN does not reveal the presence of widespread fibrillations, even though fasciculations and myokymia may be observed. Recruitment may be decreased as a result of conduction block, without significant changes in motor unit potential morphology.

Histologic Findings

Nerve biopsy is not routinely performed in the evaluation of patients with suspected MMN.

Sural nerve biopsy findings may be normal, but findings may also show mild demyelination and poor remyelination in the absence of significant inflammation. Evidence of axonal injury with regeneration may also be present.

The relevance of morphologic abnormalities in sensory nerves in a predominantly motor neuropathy such as MMN is uncertain.

Biopsy of motor nerves is not routinely performed in clinical practice, but several reported cases document demyelination and remyelination in MMN.

TREATMENT

Section 6 of 11  

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Medical Care

Multifocal motor neuropathy (MMN) is associated with slowly progressive weakness, but most patients are able to remain productive and employed. However, gradual progression may lead to significant disability. Physical and occupational therapy may be helpful in individual cases.

Diet

No specific diet is indicated for patients with MMN.

Activity

The level of activity depends on the extent of patient symptoms and disability.

MEDICATION

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Multifocal motor neuropathy (MMN) is an immune-mediated disorder, and while multiple immunomodulatory and immunosuppressive treatments have been used, only intravenous immunoglobulin (IVIG) and cyclophosphamide have been consistently effective. Anecdotal reports also indicate that rituximab, interferon-beta, azathioprine, and cyclosporine may be efficacious.

The presence of conduction blocks or elevated titers of anti-GM1 antibodies are not reliable predictors of response to treatment with IVIG.

Cyclophosphamide may be used in combination with plasmapheresis.

Corticosteroids or plasmapheresis (without cyclophosphamide) is not effective, and in some cases, MMN may even worsen. Mycophenolate is ineffective as adjunct treatment with IVIG.

Recent reports describe effective treatment with cyclosporine and rituximab in a small number of patients, but additional data are needed before these would be recommended for treatment of MMN.

Other treatments used with variable success include interferon-beta and azathioprine.

Drug Category: Immunoglobulins

IVIG infusions are the mainstay of MMN treatment. Patients are initially treated with IVIG (2 g/kg) over 2-5 days, followed by maintenance infusions. The frequency of maintenance treatments depends on patients' symptoms, and it is usually every 4-8 weeks. Maintenance dose is determined by patient's response and typically ranges from 1-2 g/kg per treatment.

Long-term IVIG treatment improves muscle strength and functional disability, but the responsiveness may decrease over time.

If IVIG is not (sufficiently) effective, then alternative treatments (eg, cyclophosphamide, rituximab, cyclosporin) should be considered.

Drug Category: Immunosuppressive agents

Cyclophosphamide is primarily used in patients with severe symptoms that do not respond to IVIG infusions and may be combined with plasmapheresis. Use of cyclophosphamide induced remission in 50-80% patients, but it is not routinely administered because of potential adverse effects. Oral cyclophosphamide is not as effective as intravenous therapy, and has the potential for more frequent dose-limiting adverse effects, so intravenous infusions are preferred.

The use of cyclophosphamide should be limited to more severely affected patients given the potential adverse effects.

Drug Category: Immunomodulators

These agents are used to modify the activity of the immune system.

FOLLOW-UP

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Further Inpatient Care

Most patients are treated as outpatients, although they may have to be admitted with severe exacerbations.

Further Outpatient Care

Outpatient care consists of clinic visits to neurologists, physiatrists, and occupational and physical therapists.

In/Out Patient Meds

IVIG infusions are usually administered on an outpatient basis in the physician's office or at home.

Complications

• Most complications are related to treatment. IVIG can lead to aseptic meningitis, thromboembolic events, and kidney failure; cyclophosphamide can lead to myelosuppression, hemorrhagic cystitis, and bladder carcinoma.
• Rarely, patients develop phrenic nerve involvement leading to respiratory insufficiency.

Prognosis

Prognosis is usually good, and 70-80% of patients respond to treatment. Even in patients who do not respond to therapy, weakness is only slowly progressive and up to 94% of patients remain employed.

Patient Education

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Multifocal motor neuropathy (MMN) with conduction block is uncommon, and most patients require referral to a neurologist who specializes in neuromuscular disorders.
• Considering whether patients with MMN may actually have ALS with predominantly lower motor neuron involvement is important because prognosis and treatment are significantly different.
• • On examination, confirm the absence of upper motor neuron signs in MMN. Signs of more severe muscle atrophy may point towards the diagnosis of ALS.
  • Electrodiagnostic studies are helpful to distinguish MMN from ALS with predominant lower motor neuron involvement. The presence of ongoing denervation on EMG findings is more suggestive of a motor neuron disorder.
• Conversely, MMN should be considered in the differential diagnosis of patients with lower motor neuron disorders.
• Proximal conduction blocks may be difficult to demonstrate using conventional electrodiagnostic studies.
• MMN should be distinguished from Lewis-Sumner syndrome (MADSAM), as the latter may respond to steroids and plasma exchange, while these treatments may worsen or are ineffective in MMN.
• Use of cyclophosphamide should be reserved for more severely affected patients and close monitoring for potential adverse events is warranted.

MULTIMEDIA

Section 10 of 11  

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• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Nerve conduction studies demonstrating conduction block with temporal dispersion after proximal stimulation.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

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• Van den Berg-Vos RM, Franssen H, Wokke JH, Van den Berg LH. Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment. Brain. Aug 2002;125(Pt 8):1875-86. [Medline].
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Article Last Updated: Jan 25, 2008