Multifocal motor neuropathy

We present a review of the literature on multifocal motor neuropathy (MMN), a rare neurological disorder which has features in common with both chronic inflammatory demyelinating neuropathy and lower motor neuron disease. Clinically, MMN is characterised by slowly progressive asymmetrical limb weakness, usually most prominent in the forearms. Weakness may be associated with muscle wasting, fasciculations and decreased tendon reflexes. Serum anti-GM1 ganglioside antibody titres may be increased. The diagnostic hallmark of MMN is the electrophysiological demonstration of persistent localised motor conduction blocks, with otherwise normal or near-normal motor and sensory conduction velocities. The pathogenesis of MMN has not been elucidated completely. There is, however, substantial evidence for an autoimmune mechanism. Based on the possible involvement of the immune system in the pathogenesis of MMN the therapeutic efficacy of several immunomodulatory drugs has been tested. Treatment of MMN patients with human immunoglobulin or cyclophosphamide is usually followed by a marked improvement of strength. The finding that MMN is a potentially treatable disorder underscores the importance of distinguishing MMN from lower motor neuron disease, for which no effective therapy is currently available. Received: 14 October 1996 Accepted: 28 October 1996     

Antiganglioside antibodies do not necessarily play a role in multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a disorder with a highly characteristic clinical picture and one which is defined by a specific electrodiagnostic abnormality, namely, multifocal conduction block which is confined to motor axons. Sensory axons which traverse segments of severe or even complete motor conduction block conduct normally. A proportion of patients with MMN also have elevated levels of antibodies to GM₁ ganglioside. However, about one half of MMN patients lack elevated levels of these antibodies and many others have only modest elevations, to a degree often seen in other neurological and even non-neurological disorders. Furthermore, clinical and electrophysiological improvement of MMN in response to treatment with high dose intravenous immunoglobulin is achieved in the absence of any change in antiglycolipid levels. Injection of serum from patients with MMN and elevated GM₁ antibody levels produces demyelination in recipient rat nerves, suggesting a pathogenetic role for these antibodies in demyelination. However, sera of patients with identical antibody liters in other motor system diseases produced no demyelination, suggesting that the demyelinating factor resides in some other serum fraction. At present, there is insufficient evidence to support the contention that these antibodies play a critical pathogenetic role in MMN. Until more evidence is available it is important to define MMN on the basis of a characteristic clinical picture and a unique electrodiagnostic abnormality rather than on a pattern of serum antibodies. © 1994 John Wiley & Sons, Inc.     

多灶性运动神经病的临床表现及肌电图特征

目的 探讨多灶性运动神经病(multifocal motor neuropathy,MMN)的临床表现及肌电图(electromyography,EMG)特征.方法 选择2016 年6 月至2019 年12 月南京医科大学附属南京医院(南京市第一医院)收治的7 例MMN 患者,对其临床资料及神经电生理检查结果进行回顾性...     

Childhood-onset multifocal motor neuropathy with IgM antibodies to GM2 and GalNac-GD1a

BackgroundMultifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20–70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies.Case reportA 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment.ConclusionAlthough childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN.     

High-dose cyclophosphamide without stem cell rescue for refractory multifocal motor neuropathy

Patients with multifocal motor neuropathy (MMN) respond to intravenous immune globulin (IVIg) and cyclophosphamide, although the benefit is not sustained. High-dose cyclophosphamide can induce a remission in patients with autoimmune diseases, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We describe a patient with refractory MMN who improved with high-dose cyclophosphamide (50 mg/kg for 4 days) without stem cell rescue. Following treatment she discontinued IVIg. At a 6-month examination, her strength had improved and she had regained the ability to write. High-dose cyclophosphamide may be a successful treatment for patients with MMN refractory to other therapies.     

Subcutaneous immunoglobulin therapy for multifocal motor neuropathy

The objective of this study was to investigate whether subcutaneous immunoglobulin (SCIg) treatment is feasible and safe in maintaining muscle strength of patients with multifocal motor neuropathy (MMN). Patients fulfilling the EFNS/PNS criteria for definite MMN treated with intravenous immunoglobulin (IVIg) were switched to weekly SCIg in a single-center, open-label pilot intervention study. The first group of patients started with a SCIg dose equivalent to 50% of the IVIg maintenance dose. In case of deterioration, patients received a loading dose of IVIg and doubling of SCIg dose. The second group started with a dose equivalent to the IVIg maintenance dose. Primary outcome was the Medical Research Council (MRC) sum score from 10 muscle groups. Secondary outcomes were grip and pinch strength, dexterity, disability, quality of life, adverse events, and serum immunoglobulin concentrations. Ten patients were included, five in both groups. In the first group, one patient withdrew informed consent due to local adverse events, four deteriorated. In the second group, four out of five patients maintained muscle strength with SCIg during the 6 months follow-up. Local adverse events were frequent, especially during first weeks of treatment, but generally well tolerated. Seven mild systemic adverse events were reported, all but one in the first week of treatment. In some, but not all MMN patients in this study, SCIg therapy was feasible and safe and maintained strength as well as IVIg. SCIg may be a viable alternative maintenance therapy in some patients with MMN currently receiving IVIg.     

Multifocal motor neuropathy: Clinical and electrophysiological findings

Multifocal motor neuropathy (MMN) can be differentiated from motor neuron disease by electrophysiological evidence of conduction block. To increase the probability of recording conduction block, we studied the whole nerve length including proximal segments in 84 patients with pure motor syndromes, using a special stimulation technique. In 8 patients, the diagnosis of MMN was confirmed by electrophysiological evidence of conduction block or temporal dispersion. The typical clinical picture of MMN with chronic progressive, asymmetrical, marked distal weakness was observed in our patients. Electrophysiological routine tests of distal nerves were usually normal except in nerve segments with conduction block. In 4 patients, conduction block could be recorded only in proximal nerve segments or spinal roots. All patients showed rapid improvement of clinical features and parallel reduction of conduction block during or after highdose intravenous immunoglobulin (ivIG) therapy, supporting the diagnosis of an immune-mediated neuropathy. Three of them are now in remission without any therapy, whereas 5 still receive a regular ivIG course every 2-12 weeks as long-term treatment. In all patients with pure or predominantly motor syndromes and normal findings in electrophysiological routine tests of distal nerve segments, there should be proximal conduction block studies to avoid overlooking a treatable disorder such as MMN.     

Monitoring the short-term effect of intravenous immunoglobulins in multifocal motor neuropathy using motor unit number index

Objective

To determine whether motor unit number index (MUNIX) is pertinent to monitor the effect of intravenous immunoglobulins (IVIg) in multifocal motor neuropathy (MMN).

Disease severity in multifocal motor neuropathy and its association with the response to immunoglobulin treatment

Disease progression in multifocal motor neuropathy (MMN) was studied by comparing severity and duration of disease. We assessed disease severity by determining muscle weakness, disability, conduction block (CB), and distal and proximal compound muscle action potential (CMAP)- amplitude in 38 patients with MMN in whom disease duration ranged from 6 months to 34 years. As indicator for an ongoing immune-mediated process, the response to one course of IVIg treatment was measured in 34 patients and associated with disease severity. With increasing disease duration, weakness and disability became significantly more severe, and the distal and proximal CMAP-amplitude decreased significantly. The number of CBs was significantly higher in patients with a disease duration longer than 10 years than in those affected less than 10 years. Thirty of the 34 patients responded to IVIg treatment. Non-responsiveness to IVIg was not associated with any of the disease variables. Severe and widespread weakness was significantly associated with a response ≥ 2 on the MRC-sumscore. Our results provide evidence for a slowly progressive disease course of MMN. The good response to IVIg treatment in patients with severe and prolonged disease indicates that progression may be the result of an ongoing immune-mediated process. These findings imply that early treatment may prevent future progression of weakness and disability in patients with MMN. Received: 26 April 2001, Received in revised form: 25 July 2001, Accepted: 2 August 2001     

Monofocal motor neuropathy: Improvement with intravenous immunoglobulin

Multifocal motor neuropathy (MMN) is a chronic, immune-mediate, peripheral myelinopathy. Inherent in its name, MMN implies involvement of two or more motor nerves. We report three patients with weakness and partial motor conduction block restricted to a single nerve and localized to sites that are not at risk for entrapment or compression injury. None of the patients had sensory involvement and all showed a favorable response to intravenous immunoglobulin therapy. Based on these observations and reports of three additional patients, we believe that monofocal motor neuropathy is a partial form of MMN and should be treated as such.     

Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies

Increased titers of anti-GM1 antibodies have been associated with motor neuron disease and motor neuropathy with or without conduction block. To investigate the pathogenetic role of anti-GM1 antibodies we injected into rat tibial nerves sera from patients with multifocal motor neuropathy and conduction block (MMN) or progressive spinal muscular atrophy (PMA), both presenting anti-GM1 antibodies. Sera of patients with MMN produced reduction of amplitude and dispersion of compound muscle action potential from proximal stimulation. Morphometry revealed demyelination in 6.2% of fibers. Sera of patients with PMA did not produce clear-cut electrophysiological or morphological changes. Differential effects of sera from patients presenting high-titer anti-GM1 antibodies, but with distinct clinical syndromes, might depend on differences in anti-GM1 antibody affinity, valency, or ability to fix complement. Alternatively, circulating factors other than, or in addition to, anti-GM1 antibodies present in sera of patients with MMN, but not of PMA patients, might be responsible for conduction abnormalities and reproduce them after passive transfer. © 1993 John Wiley & Sons, Inc.     

A controlled trial of intravenous immunoglobulin in multifocal motor neuropathy

Intravenous immunoglobulin (IVIG) has become the standard treatment for multifocal motor neuropathy (MMN) based on limited data. To critically assess the efficacy, safety, and tolerability of 10% liquid IVIG (IVIG), 44 adults with MMN were randomized 1 : 1 to either double‐blind treatment of IVIG followed by placebo for 12 weeks each or the reverse. Open‐label IVIG was administered for 12 weeks at the beginning and end of the study for clinical stabilization, and between double‐blinded periods to prevent a carry‐over effect. To avoid potential worsening, switching to open‐label IVIG was permitted if deterioration occurred during blinded treatment. Mean maximal grip strength of the more affected hand declined 31.38% during placebo and increased 3.75% during IVIG (p = 0.005). In 35.7% of participants, Guy's Neurological Disability scores for upper limbs worsened during placebo and not during IVIG, whereas the converse was true in 11.9% (p = 0.021). Sixty‐nine percent (69.0%) switched prematurely from placebo to open‐label IVIG and 2.4% switched from blinded to open‐label IVIG (p < 0.001). One serious adverse reaction (pulmonary embolism) and 100 non‐serious reactions (69 mild, 20 moderate, and 11 severe) to IVIG occurred. IVIG was effective in improving disability and muscle strength, and was safe and well tolerated in adults with MMN.     

Anti-GM1 antibodies and impaired blood–nerve barrier may interfere with remyelination in multifocal motor neuropathy

Multifocal motor neuropathy has pure motor manifestation and nonremittent clinical courses. Antiganglioside antibodies, though variable in titers, are characteristically elevated in the majority of these patient. In our cases, pathological findings at the site of conduction block suggested impaired remyelination and disruption of blood–nerve barrier. These findings lead us to postulate that antibodies toward gangliosides or toward unknown antigens containing gangliosides initiate motorspecific demyelination. The lesion, once produced, may persist as a result of impaired remyelination caused by disrupted blood–nerve barrier. The antibodies bound to denuded axons may also interfere with a remyelinative process. If so, antibodies may not always be circulating, thus accounting for variable levels of titers. © 1994 John Wiley & Sons, Inc.     

Criteria for early detection of conduction block in multifocal motor neuropathy (MMN): a study based on control populations and follow-up of MMN patients

Motor conduction block (MCB) has been used as the main diagnostic criterion in multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block currently exists; the proposed required percent decrement of proximal compound muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of this work was to evaluate, through a follow-up study of patients with MMN, the behaviour of MCB over time. The percent decrement and temporal dispersion of proximal CMAP have also been calculated in normal controls and in patients affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in patients with MMN is a dynamic entity which greatly varies over time and that a > 50% CMAP amplitued reduction may well be preceded by a smaller decrement that is nonetheless indicative of focal myelin damage in the appropriate clinical context. This datum and the results obtained in the control group and in patients with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases with clinical and electrophysiological data strongly indicative of MMN, should be considered. Since MMN is a treatable disorder, the use of the proposed less restrictive criteria for the identification of MCB could allow for a promp and more effective treatment. Received: 31 December 1996 Received in revised form: 1 August 1997 Accepted: 13 August 1997     

Secondary amyloidosis as a life-ending event in multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a disorder of peripheral nerve often associated with a high monosialoganglioside (GM1) antibody and multifocal conduction block. It has a chronic, indolent course with involvement of predominantly peripheral motor nerves, usually in an asymmetric fashion. There have been few reported cases of progression to frank quadriplegia. Secondary amyloidosis refers to the deposition of amyloid in various tissues due to an underlying chronic inflammatory state. We report the first case, to our knowledge, of a patient with MMN associated with high titer of GM1 antibody who developed acute paraplegia with both cranial nerve and worsening sensory involvement associated with multiorgan compromise due to a secondary amyloidosis involving the myocardium.     

Circulating levels of cytokines and their modulation by intravenous immunoglobulin in multifocal motor neuropathy

We found comparable levels of tumor necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-2, IL-4, IL-10, and IL-12 in the sera of 22 patients with multifocal motor neuropathy (MMN), 12 with amyotrophic lateral sclerosis (ALS), 12 multiple sclerosis, seven chronic inflammatory demyelinating polyneuropathy, five myasthenia gravis, and 13 healthy controls (NS). TNF-alpha levels, however, were higher in 15 (68%) MMN patients than in any NS. In all but one MMN patient tested, TNF-alpha levels repeatedly, albeit slightly, increased after each intravenous immunoglobulin infusion in parallel with clinical improvement and decreased 3-4 weeks after therapy, while in both ALS patients tested, they decreased or remained unchanged. The possible pathogenetic relevance of serum TNF-alpha modification in MMN remains to be clarified.     

Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial

Background and purpose:  For treatment of multifocal motor neuropathy (MMN), we hypothesized that (i) infusion of equivalent dosages of subcutaneous immunoglobulin (SCIG) is as effective as intravenous immunoglobulin (IVIG) and that (ii) subcutaneous infusion at home is associated with a better quality of life.
Methods:  In a randomized single-blinded cross-over study, nine IVIG responsive patients were allocated to receive either SCIG or IVIG for a period equivalent to three IVIG treatment intervals and, subsequently, crossed over to the other treatment. Primary end-points were (i) dynamometric strength of affected muscles and (ii) the SF-36 quality of life questionnaire.
Results:  The two treatments were equally effective, the mean change in muscle strength after SCIG being 3.6% (95% CI −3.6% to 10.9%) vs. 4.3% (−1.3% to 10.0%) after IVIG ( P  = 0.86). One patient had sustained erythema and oedema at the injection sites for a few weeks. All other adverse effects during SCIG were mild and transient. No differences between treatments of health-related quality of life occurred.
Conclusion:  In MMN, short-term subcutaneous infusion of immunoglobulin is feasible, safe and as effective as intravenous infusion. Subcutaneous administration is an alternative option that adds flexibility to the treatment schedule.     

Anti-GM1 antibodies in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) treated with intravenous immunoglobulin (IVIg)

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and with a chronic polyneuropathy (non-CIDP) were studied for the presence of anti-GM1 antibodies. In pretreatment sera of CIDP patients, we found IgG anti-GM1 antibodies in 23%, IgM in 7%, and IgA in 14%. Predominantly motor involvement was associated with IgG and IgM anti-GM1 antibodies in CIDP patients (P = 0.002). Improvement after intravenous immunoglobulin (IVIg) therapy was not associated with anti-GM1 antibody titer before or after treatment. Anti-GM1 antibody titers before onset of treatment was not related to poor clinical outcome, although large clinical improvements after IVIg therapy were observed less often (P = 0.057) in patients with high titer anti-GM1 antibodies before treatment.