ReviewMultifocal motor neuropathy
Introduction
In 1985, at the annual meeting of the American Academy of Electrodiagnostic Medicine, Parry and Clark presented an account of three patients with a pure motor neuropathy affecting upper limb nerves. All had been diagnosed with motor neuron disease but none had bulbar or upper motor neuron features and electrophysiological testing showed that they had severe conduction block (CB) confined to motor axons. Sensory nerve conduction studies in affected nerves were completely normal. In 1988 they published a full account of these patients and added two further patients. The clinical picture was of a multifocal motor neuropathy (MMN); motor deficits were in the distribution of individual peripheral nerves, not within a spinal segmental pattern as would be expected in a motor neuron disease. Evanescent paresthesias occurred in one patient but none had persistent sensory symptoms such as numbness, tingling or pain and the sensory examination was normal in all.1 The diagnosis was based on electrophysiological testing which showed CB purely affecting the motor axons; sensory nerve conduction studies done through the site of motor CB were normal. In 1986, Roth and Magistris described a further patient with identical clinical and electrophysiological features. It is likely that, prior to these reports, many such patients were classified as having a benign form of amyotrophic lateral sclerosis (ALS) lacking overt upper motor neuron findings and with respiratory and swallowing functions spared. Therefore, unlike with ALS, these patients did not die from their disease. One could speculate that the lack of prior appreciation that MMN was a disorder distinct from ALS was probably because of the failure to recognize that weakness in MMN was in the distribution of individual peripheral nerves rather than in a segmental distribution (as in ALS). It is also likely that the motor CB that may have been seen in these patients was dismissed as being related to technical factors such as suboptimal nerve stimulation, and anomalous innvervation. Lastly, some of the difficulties in diagnosis may be because MMN is a relatively rare disorder compared to ALS, with an incidence of 1 to 3 per 100,000. Nevertheless, the initial recognition of this disorder has over the last two decades facilitated research that has led to better understanding of its pathogenesis, which, in turn, has led to various efficacious treatment strategies.
A decade after the initial description of MMN, a similar disorder but without evidence of CB on routine nerve conduction studies was described.2 Several reports have suggested subsequently that MMN without conduction block (MMNWOCB) is probably the same disease as MMN, and that the inability to demonstrate CB is related to its location (for example very proximal at the nerve root level) and/or to the lack of sensitivity of routine nerve conduction studies in detecting CB, rather than to its absence.[3], [4] The presence of anti-GM1 antibodies in some patients with MMNWOCB and response to treatments that are also effective in MMN further suggests that these diseases may be related and have pathogenetic similarities with differences only in the electrophysiological phenotype.[4], [5], [6]
Section snippets
Pathology and pathophysiology
In view of the characteristic electrophysiological findings of localized motor CB without significant immediate distal axonal degeneration, focal segmental demyelination as the underlying pathological basis was thought to be the most likely. Patches of demyelination (thinly myelinated axons), along with onion bulb formation related to repeated demyelination and remyelination, were seen in ulnar nerve biopsy at the site of motor CB in one patient.7 Similar findings along with endoneurial edema
Clinical features
MMN typically presents with progressive asymmetric distal limb weakness in the distribution of individual peripheral nerves[1], [4], [6], [19], [20] (Table 1). When the neuropathy becomes confluent, it can be difficult to differentiate it from weakness in a segmental distribution such as is seen in motor neuron disorders. The consensus diagnostic criteria require weakness in the distribution of two or more named nerves without objective sensory loss or upper motor neuron signs.21 However, motor
Motor nerve conduction
Electrophysiology is of primary importance in the diagnosis of MMN since motor CB on nerve conduction studies was the initial defining characteristic of the disorder (Fig. 3). The electrophysiological hallmark of MMN is the presence of purely motor CB at non-entrapment sites in two or more named nerves, with normal sensory responses (Fig. 4, Fig. 5) even across the sites of motor CB.[1], [21] MMNWOCB is much more challenging to diagnose and requires an intimate knowledge of myotomes and
Treatment and prognosis
MMN and MMNWOCB are immune mediated neuropathies that respond to immunomodulatory treatments. Unlike some immune mediated disorders, spontaneous improvement has not been described, and is unlikely in our opinion, although the disease can progress very slowly.27 Immunomodulatory treatments tend to be expensive and have potential adverse effects. Therefore, if the disability related to the neuropathy is mild and does not affect activities of daily living and vocational functions in a meaningful
Controversies and future directions
MMN was initially described as a demyelinating neuropathy with CB that was thought to be related to focal segmental demyelination.1 That CB in MMN can remain localized for a long time with minimal distal axonal degeneration would also support this hypothesis. Doubts were cast on this idea when, in one study, pathological findings at the site of CB showed signs of axonal degeneration rather than demyelination.11 It was later proposed that the primary site of pathology may be the axolemma at the
Conflict of interest/disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References (83)
- et al.
Serological evidence for infection with Campylobacter jejuni/coli in patients with multifocal motor neuropathy
J Clin Neurosci
(1998) - et al.
Long-term follow-up of multifocal motor neuropathy with conduction block under intravenous immunoglobulin
Rev Neurol (Paris)
(2007) - et al.
Beneficial effect of rituximab monotherapy in multifocal motor neuropathy
Neuromuscul Disord
(2009) - et al.
Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease
Muscle Nerve
(1988) - et al.
Multifocal motor neuropathy without overt conduction block
Muscle Nerve
(1998) - et al.
Axonal multifocal motor neuropathy without conduction block or other features of demyelination
Neurology
(2002) - et al.
Multifocal motor neuropathy: clinical and immunological features and response to IVIg in relation to the presence and degree of motor conduction block
J Neurol Neurosurg Psychiatry
(2002) - et al.
Multifocal motor neuropathy with and without conduction block: a single entity?
Neurology
(2006) - et al.
Multifocal motor neuropathy: the diagnostic spectrum and response to treatment
Neurology
(2007) - et al.
Neuropathy with onion bulb formations and pure motor manifestations
Can J Neurol Sci
(1989)
Pathological findings at the site of conduction block in multifocal motor neuropathy
Ann Neurol
Anti-GM1 antibodies and impaired blood-nerve barrier may interfere with remyelination in multifocal motor neuropathy
Muscle Nerve
Sensory nerve pathology in multifocal motor neuropathy
Ann Neurol
Multifocal motor neuropathy: pathologic alterations at the site of conduction block
J Neuropathol Exp Neurol
Increased frequency of HLA-DRB1∗15 in patients with multifocal motor neuropathy
Neurology
Multifocal motor neuropathy caused by a B-cell lymphoma producing a monoclonal IgM autoantibody against peripheral nerve myelin glycolipids GM1 and GD1b
Br J Haematol
Multifocal motor neuropathy with conduction block in a patient with rheumatoid arthritis on infliximab therapy
Rheumatology (Oxford)
Multifocal motor neuropathy with conduction block associated with metastatic lymphoma of the nervous system
J Neurooncol.
Multifocal motor neuropathy with conduction block following treatment with infliximab
J Rheumatol
PONM12 multifocal motor neuropathy due to infliximab
J Neurol Neurosurg Psychiatry
A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside
Ann Neurol
Multifocal motor neuropathy: clinical and electrophysiological findings
J Neurol
Consensus criteria for the diagnosis of multifocal motor neuropathy
Muscle Nerve
Demyelination and axonal loss in multifocal motor neuropathy: distribution and relation to weakness
Brain
Demyelinating symmetric motor polyneuropathy with high titers of anti-GM1 antibodies
Muscle Nerve
Multifocal motor neuropathy with conduction block: a study of 24 patients
J Neurol Neurosurg Psychiatry
Multifocal motor neuropathy: electrodiagnostic features
Muscle Nerve
Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy
Neurology
Natural history of 46 patients with multifocal motor neuropathy with conduction block
Muscle Nerve
Sleep hypoventilation syndrome and respiratory failure due to multifocal motor neuropathy with conduction block
Muscle Nerve
Multifocal motor neuropathy–unusual cause of hypoglossal palsy
Lakartidningen
Cold paresis in multifocal motor neuropathy
J Neurol
Clinical and neurophysiological assessment of immunoglobulin therapy in five patients with multifocal motor neuropathy
J Neurol Neurosurg Psychiatry
Human immunoglobulin treatment of multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy
J Neurol Neurosurg Psychiatry
Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment
Brain
Motor nerve conduction study in cauda equina with high-voltage electrical stimulation in multifocal motor neuropathy and amyotrophic lateral sclerosis
Muscle Nerve
Transcutaneous cervical root stimulation in the diagnosis of multifocal motor neuropathy with conduction block
J Neurol Neurosurg Psychiatry
Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy
Muscle Nerve
Persistent increased threshold of electrical stimulation selective to motor nerve in multifocal motor neuropathy
Muscle Nerve
Abnormal sensory nerve conduction in multifocal demyelinating neuropathy with persistent conduction block
Neurology
A syndrome of asymmetric limb weakness with motor conduction block
Neurology
Cited by (27)
Electrodiagnostic Testing for the Diagnosis and Management of Amyotrophic Lateral Sclerosis
2018, Physical Medicine and Rehabilitation Clinics of North AmericaCitation Excerpt :Hallmarks of MMN on electrodiagnostic studies include normal sensory responses with motor conduction blocks at nonentrapment sites of 2 or more nerves, demonstrating demyelination as the pathologic basis rather than anterior horn cell loss. Patchy symptoms and electrodiagnostic findings strongly suggest MMN, because this disease affects individual peripheral nerves rather than the diffuse myotomal involvement expected in ALS.20 Challenges include identifying proximal conduction block as well as the possibility of MMN without overt conduction block.
Cerebrospinal fluid findings in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathies
2017, Handbook of Clinical NeurologyCitation Excerpt :The characteristic electrophysiologic feature is conduction block of the peripheral nerves. The disease is progressive in about 80% of cases, and relapses are exceptional (Nobile-Orazio et al., 2005; Muley and Parry, 2012). Antibody-mediated complement activation at the nodal axolemma has been considered as the major pathogenic factor: in about 30–80% of patients, mono- or polyclonal IgM antibodies against ganglioside GM1 can be identified in the sera similar to AMAN/AMSAN, nevertheless without preceding infection with C. jejuni.
Evaluation and Management of Amyotrophic Lateral Sclerosis
2015, Primary Care - Clinics in Office PracticeCitation Excerpt :Multifocal motor neuropathy: a demyelinating LMN disease that affects one limb progressing to other limbs, with weakness out of proportion to atrophy, without UMN involvement. Anti-GM1 antibodies are often seen.46 Spinal muscular atrophy: a variable lower MND with a genetic mutation of the SMN1 gene, with Type IV of the disease presenting in adulthood with proximal leg weakness that does not progress or affect life expectancy.47
High ultrasound variability in chronic immune-mediated neuropathies. Review of the literature and personal observations
2013, Revue NeurologiqueCitation Excerpt :Multifocal motor neuropathy (MMN) is a multiple motor neuropathy characterized by motor deficits in the distribution of individual peripheral nerves rather than in a segmental distribution; sensory deficits are absent. The precise mechanism remains unknown, but the pathogenesis is mainly immune-mediated, as supported by several data as anti-GM1 antibodies and response to intravenous immunoglobulin (IVIg) treatment; the role of infection or genetic predisposition has also been proposed (Muley and Parry, 2012). The electrophysiology, crucial for reaching the diagnosis, mostly shows nerve conduction block in affected nerve outside the common entrapment sites.
Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders
2013, Trends in Pharmacological SciencesDiagnostic biopsy of the pronator teres and a motor branch of the median nerve: Indications and technique
2012, Journal of Hand Surgery