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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Multifocal Motor Neuropathy

Authors

Sajid Hameed1; Marco Cascella2.

Affiliations
1 Aga Khan University Hospital
2 Istituto Nazionale Tumori - IRCCS - Fondazione Pascale, Via Mariano Semmola 80100, Napoli. Italy

Last Update: July 4, 2022.

Continuing Education Activity

Multifocal motor neuropathy (MMN), also called multifocal motor neuropathy with conductio
block (MMNCB), is a rare, acquired, motor neuropathy characterized by progressive asymmet
weakness without sensory problems. It typically involves upper limbs more than the lower lim
Electrodiagnostic studies often reveal an asymmetric motor neuropathy with characteristic
conduction block. Serum IgM anti-ganglioside antibodies (anti-GM1) are present in the majori
the patients. These patients often have a favorable response to intravenous immunoglobulin (
This activity reviews the diagnosis and management of multifocal motor neuropathy with
conduction blocks and highlights the role of the healthcare team in improving care for patien
with this condition.

Objectives:

Outline the typical presentation of a patient with multifocal motor neuropathy.

Explain the common physical exam findings associated with multifocal motor neuropath

Describe the typical electrodiagnostic study findings associated with multifocal motor
neuropathy.

Review the importance of improving care coordination amongst interdisciplinary team

members to improve outcomes for patients affected by multifocal motor neuropathy.

Access free multiple choice questions on this topic.

Introduction
Multifocal motor neuropathy (MMN), also called multifocal motor neuropathy with conductio
block (MMNCB), is a rare, acquired, motor neuropathy characterized by progressive asymmet
weakness without sensory problems. The syndrome has a fairly recent nosographic location,
was described in 1986.[1][2] It typically involves upper limbs more than the lower limbs.
[3] Electrodiagnostic studies often reveal an asymmetric motor neuropathy with characteristi
conduction block. Serum IgM anti-ganglioside antibodies (anti-GM1) are present in the majori
the patients.

The syndrome is not included among neuropathies with severe clinical commitment and poor
prognosis. In some cases, the symptoms are so mild that patients do not require any treatmen
However, most patients may develop a progressive worsening of strength, especially in the ha
and arms, which can induce difficulties to perform even simple daily tasks such as writing,
washing, or dressing. However, these patients may benefit from drug treatments as they often
a favorable response to intravenous immunoglobulin (IVIG).[4]

Etiology
Multifocal motor neuropathy is considered immune-mediated motor neuropathy. A high
prevalence of serum IgM anti-GM1 antibodies in these patients and a favorable response to IV
support this consideration. The abundance of GM1 in the myelin of motor nerves as compared
sensory nerves can explain the characteristic motor involvement in MMN.

Earlier it was believed that the conduction block seen on electrophysiological studies in MMN
due to severe focal demyelination, but increasing evidence suggests that anti-GM1 antibodies
sodium and potassium channel dysfunction at or around the node of Ranvier of myelinated m
axons that play an important part in the conduction block. Hence the term ‘nodo-paranodopa
also sometimes used.[5] Complement activation probably plays a fundamental role in the
pathogenesis of the disease.[6]

Epidemiology
Multifocal motor neuropathy is a rare condition with an estimated worldwide prevalence of l
than 1 per 100,000 people. The reported prevalence of MMN is 0.65 in Austria [7] and 0.29 in J
per 100,000 people.[8] It is 2.7 times more common in men as compared to women.[3] Further
the disease is diagnosed, especially in adults in their third to fifth decades, although it is also
reported in children as young as 6 years of age and in the elderly.[9]

Pathophysiology
Anti-GM1 antibodies are proposed to play a major role in the pathophysiology of MMNCB. GM
present in greater concentration in peripheral motor nerves as compared to the sensory nerv
Even in peripheral motor nerves, the greater concentration of GM1 is present around the nod
Ranvier. Although the exact function of GM1 is unknown, they are considered to stabilize and
cluster the ion channels around the nodes of Ranvier that are important for the propagation o
action potential. The disruption of these ion-channels resulting in decreased action potential
propagation manifests as conduction block and decreased conduction velocity on the
electrophysiologic studies.

Anti-GM1 antibodies, although common, are not present in all cases of MMNCB. In the absenc
anti-GM1 antibodies, the pathophysiology of motor nerve dysfunction is controversial. These
patients may either have low undetectable titers of anti-GM1 or probably different antibodies
present that are directed against different antigens. However, the clinical characteristics are t
same in MMNCB patients with or without anti-GM1 antibodies.[10]

History and Physical

Affected persons with MMN present clinically with subacute to chronic progressive asymmetr
muscle weakness. Unilateral wrist drop, finger weakness, or foot drop may be the initiating
complaint. Although upper limb muscles are predominantly affected, leg weakness may also o
Weakness may be aggravated by the cold. Sensory symptoms of pain and tingling are not
uncommon but are typically minimal. Some patients may complain of muscle cramps, twitchi
fasciculation, or excessive fatigue. The involvement of cranial nerves, bulbar, and respiratory
muscles is unusual in these patients.[3][5]
Physical examination reveals the weakness of distal muscles in the distribution of the motor
nerves. For instance, with radial nerve involvement, the wrist and finger extensors are more
affected than the triceps. Muscles of the same myotome may be spared innervated by a differ
nerve. For example, although both abductor pollicis brevis (APB) and abductor digiti minimi (
are of the same myotome (C8-T1), only APB will be affected if the median nerve is involved. M
atrophy may be present late in the course of the disease and is often disproportionately mild a
compared to the weakness. Deep tendon reflexes may be normal or asymmetrically reduced.
motor neuron signs are typically absent, differentiating from amyotrophic lateral sclerosis
(ALS). Myokymia may be seen in the affected muscles.[3][5]

Evaluation
Electrophysiological Studies

In multifocal motor neuropathy, electrophysiological studies are consistent with motor neuro
with normal sensory nerve conduction studies. There may be evidence of demyelination mark
by prolonged motor nerve latencies and slow conduction velocities. F-wave responses may be
absent or prolonged. However, the hallmark finding of MMNCB is a motor conduction block a
temporal dispersion. When the conduction block is absent or cannot be assessed by routine n
conduction studies due to a more proximal location, the diagnosis is termed as MMN. Needle
electromyography findings may reveal reduced recruitment of muscle unit action potentials
(MUAPs) in weak muscles due to proximal conduction blocks.[11]

Conduction block is defined as a more than 50% reduction in compound muscle action potent
(CMAP) amplitude or area between proximal and distal nerve stimulation sites and is often
indicative of an acquired etiology. In MMNCB, the conduction block characteristically occurs a
non-compressible sites. Therefore, the presence of conduction block across the known nerve
entrapment sites (e.g., the median nerve at the wrist) cannot be used in the diagnosis of MMN
Besides MMNCB, conduction block is also seen in acquired demyelinating conditions, e.g., chr
inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS).[3][1

Laboratory Investigations

Routine blood and urine laboratory investigations are unremarkable in patients with MMN. T
cerebrospinal fluid (CSF) protein level is often normal or mildly increased. It is one of the
important features to differentiate MMN from CIDP.[3][11]

Anti-GM1 ganglioside antibodies are present in about half of the cases of MMN. However, the
GM1 titers do not correlate with the treatment. Anti-GM1 antibodies are not specific for MMN
are also seen in acute motor axonal neuropathy (AMAN) variant of GBS, but their presence
supports the diagnosis.[3][11] The sensitivity of antibody detection can be enhanced by testing
GM1/galactocerebroside (GM1/GalC) complexes.

Imaging Studies

Nerve ultrasound (US) and magnetic resonance imaging (MRI) can offer important diagnostic
especially when electrophysiological investigations are not conclusive. The diagnosis of MMN
indeed, can be a challenge when conduction blocks are not detectable, or in the case of advan
axonal loss. Spinal MRI may reveal T2 hyperintense signals in the brachial plexus with or with
contrast enhancement in about half of the patients with MMN and CIDP. In MMN, these signal
asymmetric and often unilateral, but these are bilateral and symmetrical in CIDP.[11][12]
In MMN, an increase in the cross-sectional area of the median and ulnar nerves may be seen w
high-resolution US (HRUS). This finding is helpful when a clinical distinction is difficult with
amyotrophic lateral sclerosis (ALS) in which the nerve diameters are typically reduced.[11][12

Diagnostic Criteria

In 2010, the European Federation of Neurological Societies (EFNS) and Peripheral Nerve Socie
(PNS) Task Force revised the following diagnostic criteria to help in the diagnosis of MMN.[13]

Core Criteria (both must be present)

1. Slowly progressive, focal, asymmetric limb weakness, that is, motor involvement in the m
nerve distribution of at least two nerves, for at least 1 month (usually more than 6 month
symptoms and signs are present only in the distribution of one nerve, only a possible
diagnosis can be made.

2. No objective sensory abnormalities except for minor vibration sense abnormalities in th

lower limbs.

Supportive Clinical Criteria

1. Predominant upper limb involvement

2. Decreased or absent tendon reflexes in the affected limb

3. Absence of cranial nerve involvement

4. Cramps and fasciculations in the affected limb

5. Response to immunomodulatory treatment

Exclusion Criteria

1. Upper motor neuron signs

2. Marked bulbar involvement

3. Sensory impairment more marked than minor vibration loss in the lower limbs

4. Diffuse symmetric weakness during the initial weeks

Treatment / Management
The use of IVIg represents the main pharmacological treatment option for MMNCB. Of note, in
more than three-quarters of the patients respond to IVIG. The response in muscle strength
improvement is, however, short-term, and only 20% of patients achieve prolonged remission.
of the patients need periodic IVIg infusions. In spite of regular IVIg infusions, motor deficits m
slowly progress due to secondary axonal damage. In a Cochrane review, IVIG was considered
superior to placebo in the treatment of MMNCB (NNT 1.4, 95% CI 1.1-1.8).[4]

IVIG is initially administered at a dose of 0.4 g/kg/day for five consecutive days for a total dose
g/kg. Some clinicians administer IVIG in 2 days by administering at 1 g/kg per day. The follow-
maintenance IVIg infusion dose ranges from 0.4 g/kg once weekly to 2 g/kg every 8 weeks
depending upon the patient’s condition. Because Ig is generally administered for long periods
for years, the subcutaneous route has been investigated. Clinical investigations showed that th
subcutaneous immunoglobulin (SCIG) is safe, equally effective, feasible, and the patients can s
administer themselves at home. The dose of SCIG is the same as that of IVIG.[4][14][15]
In non-responders, the treatment options are limited. Different immunomodulatory agents su
cyclophosphamide, mycophenolate mofetil, azathioprine, and rituximab, have been reported
literature with variable results.[4] Oral cyclophosphamide has been reported effective in sust
disease remission and reducing IGIg frequency but has significant adverse effects.[16] In 2007
RCT comprising of 28 patients did not reveal a significant difference when mycophenolate mo
was combined with IVIG as compared to IVIG alone in patients with MMN.[17] Multiple
comparative randomized controlled trials (RCTs) are needed to establish the efficacy of
immunomodulatory drugs in MMN.

Corticosteroids and plasmapheresis are ineffective in patients with MMN.[4]

Differential Diagnosis
The important differential diagnoses of multifocal motor neuropathy are ALS, CIDP, and hered
neuropathy with liability to pressure palsies (HNPP). The other diagnoses that can be consider
are radiculopathy, entrapment neuropathies, mononeuritis multiplex, hereditary motor
neuropathies, porphyria, and lead intoxication.[3][18]

1. Amyotrophic Lateral Sclerosis

Both ALS and MMN present with progressive pure motor weakness, but the progression is typ
slow in MMNCB as compared to ALS. Further, the absence of upper motor neuron findings as
as sparing of respiratory and cranial muscles differentiate MMN from ALS.

The muscle weakness in MMN typically is in the distribution of motor nerves and does not fol
myotomes, as explained above. Muscle atrophy is less marked early in the disease.
Electrodiagnostic studies reveal a demyelinating pattern with conduction blocks.

In ALS, the entire myotome is usually affected at the same time. Muscle atrophy and fascicula
are prominent. Split hand sign may be present and is typical for ALS. Pseudobulbar affect may
present. Nerve conduction studies are normal. Needle EMG may reveal signs of denervation.[3
[18] It is very important to differentiate MMN from ALS as the former has a good response to
treatment.

2. Chronic Inflammatory Demyelinating Polyneuropathy

CIDP presents with chronic muscle weakness with reduced or absent deep tendon reflexes, an
conduction block may be present on electrodiagnostic studies, but the muscle weakness in CID
often symmetrical, and legs are affected more than the arms. Sensory involvement is common
CIDP (unlike MMN), but purely motor variants of CIDP are also uncommonly encountered, ma
it difficult to differentiate from MMN. In CIDP, CSF studies reveal raised protein and marked
cytoalbuminologic dissociation. Anti-GM1 antibodies are often absent. The patients with CIDP
respond favorably to corticosteroids and plasmapheresis.[3][18]

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is an uncommo

CIDP variant that affects single nerves and resembles MMN. However, marked sensory signs a
symptoms, as well as electrodiagnostic studies revealing the involvement of sensory nerves in
MADSAM, distinguish it from MMN.[3]

3. Hereditary Neuropathy with Liability to Pressure Palsies

HNPP presents with asymmetric motor weakness in the distribution of multiple motor nerves
the presence of conduction block on electrodiagnostic studies, but the conduction blocks are
typically at known nerve entrapment sites (e.g., the median nerve at the wrist and ulnar nerv
the elbow). Further, the sensory symptoms are prominent in HNPP. Affected persons often ha
positive family history as it is inherited as an autosomal dominant condition. HNPP occurs du
the deletion of peripheral myelin protein 22 (PMP-22) gene and can be confirmed by genetic t
Treatment is supportive, and most patients recover spontaneously.[3]

Prognosis
The prognosis of multifocal motor neuropathy is usually good. Approximately 80% of patients
respond to IVIG treatment. About 20% of the patients achieve long-term remission, while the
remaining require periodic IVIG or SCIG treatments. Even in non-responders, muscle weakne
progresses slowly, and the majority of the patients are able to perform activities of daily living
one study, more than 94% remained employed.[4][19] In 2015, researchers from the PeriNomS
Study Group validated the Rasch-built Overall Disability Scale for MMN. It is a 25-item tool
developed for monitoring the course of disease and response to treatment.[20]

Complications
Multifocal motor neuropathy is rarely fatal due to the sparing of cranial and respiratory musc
Most complications are treatment-related.

IVIG may cause thromboembolic events (myocardial infarctions, stroke, or deep venous
thrombosis), renal failure, anaphylactic reactions, aseptic meningitis, and rarely, transfu
related acute lung injury.

Cyclophosphamide may cause bone marrow suppression, hemorrhagic cystitis, and

interstitial pneumonitis.[4]

Deterrence and Patient Education

At present, no effective strategies are known to prevent this syndrome. Patient education rega
the diagnosis and natural history of the disease is important. Most patients will require long-t
IVIg and SCIg treatments, which may be costly and may result in unwanted adverse effects. Th
disease may further progress despite regular treatment but is often non-fatal.

Since multifocal motor neuropathy predominantly affects hand muscles, the writing and skill
hand movements may be limited; therefore, alternate employment options should also be
discussed and considered.

Enhancing Healthcare Team Outcomes

Patients need regular outpatient follow-up with a primary neurologist as well as physical and
occupational therapists. Since multifocal motor neuropathy predominantly affects the distal
muscles of the upper limbs, the writing and skilled hand movements may be severely affected
Therefore, regular physiotherapy and occupational therapy are recommended.

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References