Multifocal Motor Neuropathy With Conduction Blocks 

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

Overview

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), subcutaneous immunoglobulins (SCIG) or cyclophosphamide, even after many years of duration.[1, 2, 3]

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 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]

Epidemiology

Frequency

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

In Japan and Austria, the prevalence has been estimated at 0.29 and 0.65 cases per 100,000 population, respectively.[9, 10]

Mortality/Morbidity

Dexterity and walking ability are commonly affected to some extent, but most patients are able to maintain autonomy with indoor and outdoor activities.[11] Most patients maintain productive lives despite ongoing symptoms, and up to 94% remain employed.[1] However, gradual progression of symptoms may also lead to significant disability.[12]

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.

Demographics

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

The mean age of onset is 40 years. Eighty percent of patients are aged 20-50 years at presentation. Rarely, children as young as 6 years may be affected.[13]

 

Presentation

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. As with other neuromuscular disorders, patients also commonly complain of fatigue.

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

Definite MMN, as follows:[3, 14]

  • Weakness without objective sensory loss in the distribution of 2 or more nerves is present for more than 1 month

  • Definite motor conduction block is present in at least one motor nerve with normal sensory nerve conductions

  • Exclusion criteria not present

Probable MMN, as follows:

  • Weakness without objective sensory loss in the distribution of 2 or more nerves

  • The presence of probable motor conduction block in 2 or more motor nerve segments with normal sensory nerve conduction studies

  • Exclusion criteria not present

OR:

  • Weakness without objective sensory loss in the distribution of one nerve

  • The presence of probable motor conduction block in one motor nerve segments with normal sensory nerve conduction studies

  • Exclusion criteria are not present.

  • At least 2 supportive criteria met

Supportive criteria, as follows:

  • Elevated titers of serum IgM anti-GM1 antibodies

  • Increased cerebrospinal fluid (CSF) protein (< 1 g/L)

  • MRI shows increased signal on T2-weighted imaging of brachial plexus with diffuse nerve swelling

  • Objective clinical improvement following intravenous immunoglobulin (IVIG) treatment

Exclusion criteria, as follows:

  • Upper motor neuron signs, such as spasticity, clonus, extensor plantar response

  • Marked bulbar involvement

  • Sensory involvement more marked than minor vibration loss in the lower limbs

  • Diffuse symmetric weakness during initial weeks

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 are typically absent (particularly in affected limbs) or normal. However, brisk tendon reflexes were found in 9% of patients, even in the weakened limbs.

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. Weakness of respiratory muscles is very rare.[15] Weakness frequently worsens with exposure to cold.[16]

Muscles innervated by motor nerves with persistent conduction block are usually weak.

Muscle atrophy

Atrophy may be present in weak muscles, but it is usually 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

Sensory examination should be normal, and the sensory loss may be 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. Rarely, MMN may develop following treatment with tumor necrosis factor (TNF) – α antagonists.[4]

 

DDx

 

Workup

Laboratory 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).

Clinical features of MMN patients with high titers of anti-GM1 antibodies are typically indistinguishable from patients with negative titers.

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 some commercially available assays for anti-GM1 antibodies may have sensitivity that is as low as 20-30%.

The sensitivity of testing may be further increased by adding anti-GM1/galactocerebroside antibodies, although this test may still not be available through commercial laboratories.[17]

Other autoantibodies

Various studies showed elevated titers of other antibodies in MMN including NS6S, neurofascin-186, and gliomedin antibodies.[18, 19] Clinical significance of these antibodies is still not well understood, and these assays are not widely comercially available. 

Creatine kinase (CK)

CK is frequently elevated (< 3 times the upper limit of 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]; less than 1 g/L). 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 and nerve thickening of the nerve roots and proximal nerves of the arm, 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.

In patients with MMN, neuromuscular ultrasound frequently shows enlargement of multiple nerves including cervical spinal roots and proximal arm nerves (rarely in proximal legs).[20]  Certain features, such as increased regional variance and asymmetric enlargement may help distinguish MMN from other chronic immune-related neuropathies. Similarly, the degree of spinal root and distal upper extremity nerve enlargement may help to distinguish MMN from ALS.

Other Tests

Nerve conduction study (NCS) with needle electromyography (EMG) is essential in demonstrating the presence of multifocal motor involvement without significant sensory component.[14]  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 image below) 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. See the image below.

Nerve conduction studies demonstrating conduction Nerve conduction studies demonstrating conduction block with temporal dispersion after proximal stimulation.

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

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

Medication Summary

Multifocal motor neuropathy (MMN) is an immune-mediated disorder, and while multiple immunomodulatory and immunosuppressive treatments have been used, only intravenous immunoglobulin (IVIG),[21, 22, 23] subcutaneous immunoglobulin (SCIG)[24, 25] and cyclophosphamide have been consistently effective. Delay of treatment may result in increased weakness and disability. Anecdotal reports also indicate that rituximab,[26, 27, 28] interferon-beta, azathioprine and cyclosporine may be efficacious.[29, 30]

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

Most patients (~80-90%) improve with IVIG, but frequently long-term maintenance IVIG infusions are required to prevent worsening of symptoms.[23, 31] The pharmacokinetics of IVIG vary among individual patients and may influence the clinical response.[32] Subcutaneous immunoglobulin (SCIG) infusions may be used as an alternative to IVIG with similar efficacy and improved safety profile.[33]

Cyclophosphamide may be used in combination with plasmapheresis. Lack of benefit was reported for 1 patient who received high-dose cyclophosphamide treatment followed by autologous stem cell transplantation.[34]

Corticosteroids or plasmapheresis (without cyclophosphamide) is not effective, and in some cases, MMN may even worsen. Mycophenolate is ineffective as adjunct treatment with IVIG.[31]

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.

Immune Globulin

Class Summary

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. Infusions are performed in an inpatient setting (hospital), in outpatient settings (infusion center or physician's office), or at home. Most patients improve with IVIG treatments (~80-90%), and dosing must be individualized based on patient's response.

Subcutaneous immunoglobulin (SCIG) therapy is used as an alternative to IVIG and can provide more treatment flexibility and autonomy for the patients. Infusion-related adverse effects are less common with SCIG than with IVIG, and SCIG may be given at home by the patient and his or her family. SCIG does require more frequent dosing (typically weekly). The optimal dosing of SCIG has not been established and various ratios of IVIG to SCIG have been used from 1:1 to 1:1.53, and others.[24]

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.

Immunoglobulin, intravenous (Gamimune, Gammar-P, Sandoglobulin, Gammagard Liquid and S/D, Gammunex, Carimune, Flebogamma, Gamaplex, Octigam, Privigen)

Intravenous immunoglobulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It down-regulates proinflammatory cytokines, including INF-gamma. It blocks Fc receptors on macrophages, suppresses inducer T and B cells and augments suppressor T cells, blocks complement cascade, and promotes remyelination. It may increase CSF IgG (10%).

After 3-7 years of treatment, IVIG may become less effective, possibly because of development of axonal degeneration.

In other patients, few doses of IVIG may induce prolonged remission.

Immune globulin, subcutaneous (Hizentra, Gammagard Liquid, and Gamunex-C )

Immune globulin subcutaneous is used to treat patients with primary immune deficiency. It has also been used in the treatment of autoimmune neuromuscular disorders. It supplies a wide spectrum of IgG antibodies against bacteria, viral, mycoplasma, and parasitic agents, as well as their antigenic toxins. It is also used in patients with poor venous access and those who want to be able to self-administer to increase independence in administration.

Immunomodulators

Class Summary

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

Rituximab (Rituxan)

Rituximab is a second-line agent that may be used for patients with MMN who do not respond to IVIG. Its efficacy is based on anecdotal reports. While most patients exhibiting a response to rituximab had positive anti-GM1 IgM antibodies, improvement was observed in seronegative patients as well.

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Immunosuppressive Agents

Class Summary

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.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

 

Follow-up

Further Outpatient Care

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

Further Inpatient Care

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

Inpatient & Outpatient Medications

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.[15]

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.[1]

Patient Education

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

 

Questions & Answers

Overview

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

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

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

What is the mortality and morbidity associated with multifocal motor neuropathy (MMN) with conduction block?

Which patient groups have the highest prevalence of multifocal motor neuropathy (MMN) with conduction block?

Presentation

Which clinical history findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

What are the clinical and electrodiagnostic criteria for definite multifocal motor neuropathy (MMN) with conduction block?

What are the clinical and electrodiagnostic criteria for probable multifocal motor neuropathy (MMN) with conduction block?

What are the supportive criteria for multifocal motor neuropathy (MMN) with conduction block?

What are the criteria for exclusion of multifocal motor neuropathy (MMN) with conduction block?

Which sensory exam findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

What is the most remarkable physical finding of multifocal motor neuropathy (MMN) with conduction block?

Which cranial nerve findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which deep tendon reflex findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which motor strength findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which muscle atrophy findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which upper motor neuron signs are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which muscle tone findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

How does multifocal motor neuropathy (MMN) with conduction block affect coordination and gait?

How are fasciculations and cramping characterized in multifocal motor neuropathy (MMN) with conduction block?

How prevalent is rash and gynecomastia in multifocal motor neuropathy (MMN) with conduction block?

What causes multifocal motor neuropathy (MMN) with conduction block?

DDX

What are the differential diagnoses for Multifocal Motor Neuropathy With Conduction Blocks?

Workup

What is the role of antibody testing in the workup of multifocal motor neuropathy (MMN) with conduction block?

Which creatine kinase (CK) findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Which CSF analysis results are characteristic of multifocal motor neuropathy (MMN) with conduction block?

What is the role of imaging studies in the workup of multifocal motor neuropathy (MMN) with conduction block?

What is the role of nerve conduction studies in the workup of multifocal motor neuropathy (MMN) with conduction block?

Which histologic findings are characteristic of multifocal motor neuropathy (MMN) with conduction block?

Treatment

How is multifocal motor neuropathy (MMN) with conduction block treated?

Which dietary modifications are used in the treatment of multifocal motor neuropathy (MMN) with conduction block?

Which activity modifications are used in the treatment of multifocal motor neuropathy (MMN) with conduction block?

Medications

What is the role of medications in the treatment of multifocal motor neuropathy (MMN) with conduction block?

Which medications in the drug class Immunosuppressive Agents are used in the treatment of Multifocal Motor Neuropathy With Conduction Blocks?

Which medications in the drug class Immunomodulators are used in the treatment of Multifocal Motor Neuropathy With Conduction Blocks?

Which medications in the drug class Immune Globulin are used in the treatment of Multifocal Motor Neuropathy With Conduction Blocks?

Follow-up

Which specialist consultations are beneficial to patients with multifocal motor neuropathy (MMN) with conduction block?

When is inpatient care indicated for multifocal motor neuropathy (MMN) with conduction block?

How are IVIG infusions administered for the treatment of multifocal motor neuropathy (MMN) with conduction block?

What are the possible complications of multifocal motor neuropathy (MMN) with conduction block treatment?

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