Multifocal Motor Neuropathy

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 IVIG support this consideration. The abundance of GM1 in the myelin of motor nerves as compared to sensory nerves can explain the characteristic motor involvement in MMN.

Earlier it was believed that the conduction block seen on electrophysiological studies in MMN is due to severe focal demyelination, but increasing evidence suggests that anti-GM1 antibodies cause sodium and potassium channel dysfunction at or around the node of Ranvier of myelinated motor axons that play an important part in the conduction block. Hence the term ‘nodo-paranodopathy’ is 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 less than 1 per 100,000 people. The reported prevalence of MMN is 0.65 in Austria [7] and 0.29 in Japan per 100,000 people.[8] It is 2.7 times more common in men as compared to women.[3] Furthermore, 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. GM1 is present in greater concentration in peripheral motor nerves as compared to the sensory nerves. Even in peripheral motor nerves, the greater concentration of GM1 is present around the nodes of 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 of 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 absence of 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 are present that are directed against different antigens. However, the clinical characteristics are the 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 asymmetric 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 occur. 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, twitching, 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 different nerve. For example, although both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) are of the same myotome (C8-T1), only APB will be affected if the median nerve is involved. Muscle atrophy may be present late in the course of the disease and is often disproportionately mild as compared to the weakness. Deep tendon reflexes may be normal or asymmetrically reduced. Upper 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 neuropathy with normal sensory nerve conduction studies. There may be evidence of demyelination marked 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 and/or temporal dispersion. When the conduction block is absent or cannot be assessed by routine nerve 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 potential (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 at 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 MMNCB. Besides MMNCB, conduction block is also seen in acquired demyelinating conditions, e.g., chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS).[3][11]

Laboratory Investigations

Routine blood and urine laboratory investigations are unremarkable in patients with MMN. The 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 anti-GM1 titers do not correlate with the treatment. Anti-GM1 antibodies are not specific for MMN and 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 for GM1/galactocerebroside (GM1/GalC) complexes.

Imaging Studies

Nerve ultrasound (US) and magnetic resonance imaging (MRI) can offer important diagnostic data, 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 advanced axonal loss. Spinal MRI may reveal T2 hyperintense signals in the brachial plexus with or without contrast enhancement in about half of the patients with MMN and CIDP. In MMN, these signals are 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 with 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 Society (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 motor nerve distribution of at least two nerves, for at least 1 month (usually more than 6 months). If 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 the 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, indeed, 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. Most of the patients need periodic IVIg infusions. In spite of regular IVIg infusions, motor deficits may 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 of 2 g/kg. Some clinicians administer IVIG in 2 days by administering at 1 g/kg per day. The follow-up 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, often for years, the subcutaneous route has been investigated. Clinical investigations showed that the subcutaneous immunoglobulin (SCIG) is safe, equally effective, feasible, and the patients can self-administer themselves at home. The dose of SCIG is the same as that of IVIG.[4][14][15](A1)

In non-responders, the treatment options are limited. Different immunomodulatory agents such as cyclophosphamide, mycophenolate mofetil, azathioprine, and rituximab, have been reported in the literature with variable results.[4] Oral cyclophosphamide has been reported effective in sustaining disease remission and reducing IGIg frequency but has significant adverse effects.[16] In 2007, an RCT comprising of 28 patients did not reveal a significant difference when mycophenolate mofetil 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.(A1)

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

Differential Diagnosis

The important differential diagnoses of multifocal motor neuropathy are ALS, CIDP, and hereditary neuropathy with liability to pressure palsies (HNPP). The other diagnoses that can be considered 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 typically slow in MMNCB as compared to ALS. Further, the absence of upper motor neuron findings as well 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 follow 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 fasciculation are prominent. Split hand sign may be present and is typical for ALS. Pseudobulbar affect may be 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 the treatment.

2. Chronic Inflammatory Demyelinating Polyneuropathy

CIDP presents with chronic muscle weakness with reduced or absent deep tendon reflexes, and conduction block may be present on electrodiagnostic studies, but the muscle weakness in CIDP is often symmetrical, and legs are affected more than the arms. Sensory involvement is common in CIDP (unlike MMN), but purely motor variants of CIDP are also uncommonly encountered, making 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 also respond favorably to corticosteroids and plasmapheresis.[3][18]

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is an uncommon CIDP variant that affects single nerves and resembles MMN. However, marked sensory signs and 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 and 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 nerve at the elbow). Further, the sensory symptoms are prominent in HNPP. Affected persons often have a positive family history as it is inherited as an autosomal dominant condition. HNPP occurs due to the deletion of peripheral myelin protein 22 (PMP-22) gene and can be confirmed by genetic tested. 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 weakness progresses slowly, and the majority of the patients are able to perform activities of daily living. In 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 muscles. 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, transfusion-related acute lung injury.
• Cyclophosphamide may cause bone marrow suppression, hemorrhagic cystitis, and interstitial pneumonitis.[4]