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Multifocal Motor Neuropathy

Motor Neuropathy Mult Cond Blk

Multifocal motor neuropathy is a rare, disabling disease characterized by the presence of anti-ganglioside antibodies that mediate the disruption of the nodes of Ranvier and paranodal areas. The resultant conduction block causes progressive limb weakness and differentiates this entity from clinically similar diseases.

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Presentation

The European Federation of Neurological Societies and the Peripheral Nerve Society have established diagnostic and therapeutic guidelines for physicians dealing with MMN patients [13]. According to these guidelines, there are two clinical core criteria:

  • MMN patients present with a progressive, asymmetric limb weakness. Here, the term asymmetric refers to a difference in muscle strength that becomes more pronounced as the disease progresses. Disease progression is usually slow, and diagnostic delays of several years are not uncommon. Initially, fatigue may be the most striking symptom.
  • Although MMN patients may experience minor vibration sense anomalies, other sensory deficits allow to rule out MMN as a differential diagnosis. In this regards, an overlap of MMN and multifocal acquired demyelinating sensory and motor neuropathy has been reported [14].

In most cases, the patient's arms are more severely affected than their legs. Onset of weakness is most commonly in distal arms (61%) or distal legs (34%) [15]. Tendon reflexes in the respective limbs are often blunted or even absent, but brisk reflexes have also been noted. The distribution of motor deficits generally corresponds to innervation areas of individual peripheral nerves. Compromise of one single nerve is not characteristic of MMN. Despite mild muscle wasting due to inactivity, the muscle tone remains unaltered and fasciculations or cramps may be observed. Because MMN patients respond well to intravenous immunoglobulin, the latter may serve as a diagnostic and therapeutic measure.

Cranial nerve palsies are not characteristic of MMN, although compromise of the abducens and hypoglossal nerves has been described [16]. Furthermore, upper motor neuron signs, marked bulbar involvement,and diffuse symmetric weakness have been defined as exclusion criteria [13].

Dutch
  • SNP frequencies were determined by means of TaqMan SNP genotyping assay and direct sequencing of candidate genes in 92 Dutch patients with MMN and 1152 healthy controls.[ncbi.nlm.nih.gov]
Muscle Weakness
  • A 25-year-old woman presenting with progressive muscle weakness in the distal extremities in the absence of sensory involvement for 2 years was diagnosed with multifocal motor neuropathy (MMN).[ncbi.nlm.nih.gov]
  • Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy (MMN) is a chronic immune-mediated disorder leading to slowly progressive muscle weakness and wasting.[ncbi.nlm.nih.gov]
  • Most patients showed not only muscle weakness but also fatigue, limited dexterity, and limited walking ability.[ncbi.nlm.nih.gov]
  • The initial high-dose intravenous immunoglobulin treatment significantly improved left upper limb muscle weakness. Continued monthly intravenous immunoglobulin treatment gradually improved muscle strength for several months initially.[ncbi.nlm.nih.gov]
Muscular Atrophy
  • Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies.[ncbi.nlm.nih.gov]
  • We investigated symptoms of cold paresis in 50 MMN patients, 48 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 35 progressive spinal muscular atrophy (PSMA) patients, and 25 chronic idiopathic axonal polyneuropathy patients.[ncbi.nlm.nih.gov]
  • Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430[ncbi.nlm.nih.gov]
  • atrophy. ( 26298317 ) Vlam L....van der Pol W.L. 2015 29 CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy. ( 26280014 ) Furukawa T....Kaji R. 2015 30 Improving the detection of IgM antibodies against glycolipids[malacards.org]
  • MMN must be differentiated from other lower motor neuron syndromes, in particular the adult form of progressive spinal muscular atrophy.[neurology.org]
Muscle Cramp
  • Signs and symptoms of MMN include weakness in the hands and lower arms; muscle cramping; involuntary muscle contractions or twitching; and wasting of the involved muscles. The leg muscles may also be affected in some people.[medicinenet.com]
  • While MMN usually involves no pain (except for muscle cramps) and is rarely fatal, it can lead to significant disability, with loss of function in hands affecting ability to work and perform everyday tasks, and foot drop leading to inability to stand[autoimmunesociety.org]
  • Discussion: Multifocal Motor Neuropathy (MMN) is an acquired autoimmune demyelinating neuropathy with slowly progressive weakness, fasciculation, and muscle cramping without loss of sensation.[shmabstracts.com]
  • Affected patients also complain of muscle cramps and fasciculations. Tendon reflexes are reduced in affected regions. Sensory complaints are unusual.[mmcneuro.wordpress.com]
Limb Weakness
  • Multifocal motor neuropathy is a disorder characterized by slowly progressive asymmetrical limb weakness and multiple motor conduction blocks.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated chronic disorder characterized by asymmetric distal limb weakness and conduction block.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy (MMN) is typically associated with distal upper limb weakness and wasting. However, proximal muscle bulk, particularly of biceps brachii, may be well preserved even in the presence of severe proximal weakness.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy (MMN) is characterized by slowly progressive, predominantly distal, asymmetric limb weakness and partial conduction blocks (CB) of motor axons. Cranial nerve involvement and respiratory failure are uncommon.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy with conduction block (MMNcb) is a relatively rare disease characterized clinically by asymmetric limb weakness with spared sensation and electrophysiologically by persistent focal motor conduction block.[ncbi.nlm.nih.gov]
Foot Drop
  • Clinically, it is characterized by slowly progressive asymmetrical predominantly distal weakness; unilateral wrist drop, grip weakness, and foot drop are the commonest initial manifestations.[ncbi.nlm.nih.gov]
  • Wrist drop and foot drop (leading to trips and falls) are common symptoms. Other effects can include gradual loss of finger extension, leading to a clawlike appearance.[en.wikipedia.org]
  • While MMN usually involves no pain (except for muscle cramps) and is rarely fatal, it can lead to significant disability, with loss of function in hands affecting ability to work and perform everyday tasks, and foot drop leading to inability to stand[autoimmunesociety.org]
  • The most common initial symptoms are wrist drop, grip weakness, and foot drop. Weakness progresses asymmetrically, but usually remains more prominent in the arms than in the legs.[mmcneuro.wordpress.com]
Hyperreflexia
  • Atrophy may be present, but hyperreflexia and spasticity are not seen. Electrophysiological studies reveal motor conduction blocks at sites not prone to compression with normal sensory responses. Immunoglobulin M anti-GM1 titers may be elevated.[ncbi.nlm.nih.gov]
  • MMN can usually be distinguished from ALS by its more slowly progressive disease course, the absence of upper-motor-neuron signs such as spasticity and hyperreflexia and the lack of difficulty with speech and swallowing.[mmcneuro.wordpress.com]
  • Upper motor neuron signs (spasticity, hyperreflexia, extensor plantar response).[clinicaltrials.gov]
  • Oshima et al. investigated patients with hyperreflexia who exhibited paralysis with CB.[marmaramedicaljournal.org]
  • However, hyperreflexia and spasticity typical of ALS never occur in MMN. Conduction block Amount of block increases with more proximal stimulation. B.[neuromuscular.wustl.edu]
Mononeuropathy
  • The mononeuropathy multiplex progresses over time with increasing axonal loss.[ncbi.nlm.nih.gov]
  • […] differentiate the disorder from ALS (purely motor but with UMN signs), the Lewis-Sumner Syndrome variant of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (similar to MMN but usually with significant sensory loss), and “vasculitis” (a type of multiple mononeuropathy[en.wikipedia.org]
  • Mononeuropathy Damage to a single peripheral nerve is called mononeuropathy. Physical injury or trauma such as from an accident is the most common cause.[webmd.com]
  • Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy. J Periph Nerv Syst 1997;2:362–369.[link.springer.com]
Areflexia
  • We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies.[ncbi.nlm.nih.gov]
  • An acute tetraparesis with diffuse areflexia but little or no sensory disturbance was the clinical picture. Serial electrophysiological tests showed persistent multifocal motor conduction blocks with absent F waves in most tested motor nerves.[ncbi.nlm.nih.gov]
  • There was diffuse areflexia, but no evidence of sensory, autonomic, or cranial nerve dysfunction.[jnnp.bmj.com]

Workup

According to the aforecited guidelines, the diagnosis of MMN is based on the patient's clinical presentation and the result of electrophysiological studies. With regards to the latter, a demonstration of conduction blocks greatly supports the tentative diagnosis of MMN. To this end, compound muscle action potential (CMAP) negative peak area reductions of more than 50% are highly indicative of a conduction block if accompanied by CMAP negative peak amplitudes of >1 mV and >20% of the lower limit of normal [13]. The former value is obtained after evaluating responses to proximal and distal nerve stimulation; the latter is based on stimulation of the distal part of the nerve segment. Additionally, proximal to distal increases of negative peak CMAP duration do not usually exceed 30% in MMN patients. Less pronounced reductions of CMAP negative peak areas or greater increases of negative peak CMAP duration may also indicate an MMN-associated conduction block.

Blood samples should be obtained to assess concentrations of autoantibodies directed against GM1 and GM2. Although such tests are of low sensitivity, detection of high titers facilitates the diagnosis of MMN. Low titers are non-specific and may also be detected in patients suffering from amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy, and other neuropathies. Antibody titers do not usually correlate with disease severity, and are largely inadequate monitoring tools [17]. In this context, muscle strength has been shown to increase as soon as the concentrations of autoantibodies diminish. Additional diagnostic measures may include laboratory analyses of cerebrospinal fluid (normal cell counts, total protein <1 g/l) and magnetic resonance imaging of the brachial plexus (diffuse nerve swelling observable in T2-weighted images). Nerve biopsies are not usually indicated, unless doubts remain as to a more severe differential diagnosis.

Treatment

Intravenous immunoglobulin is indicated in all patients diagnosed with symptomatic MMN, and response rates have been reported range between 71 and 94% [15] [18]. Initially, a cumulative dose of 2 g/kg should be administered over up to five days [1]. Intravenous application of immunoglobulin may subsequently be repeated at a dose of 1 g/kg every two to four weeks or at a dose of 2 g/kg monthly or bimonthly. Patients may show a complete response to therapy, regain muscle strength and become independent of this treatment. They may also show an incomplete response, characterized by an initial improvement but exacerbation upon cessation of therapy. These people require long-term administration of immunoglobulins. Eventually, intravenous application of immunoglobulin may be replaced by subcutaneous self-infusion, with the latter augmenting patient autonomy. Furthermore, subcutaneous administration of immunoglobulin is associated with lower peaks of serum concentrations, and this may reduce the probability of dose-dependent side effects. A small minority of MMN patients do not respond to immunoglobulin therapy at all. Responsiveness to therapy may be affected by the patient's condition and the progression of axonal injury at the time of diagnosis [19].

Of note, MMN patients do not usually benefit from immunosuppressive therapies as applied in case of autoimmune disease or distinct immune-mediated neuropathy. Despite compounds such as cyclophosphamide and eculizumab not having been evaluated in controlled clinical trials, there are case reports implying their usefulness [20]. Such options should seriously be considered in case of non-responders. Mycophenolate mofetil has been proven ineffective [21].

Prognosis

MMN is potentially curable. Affected individuals have a normal life expectancy, and although MMN may be associated with considerable morbidity, most patients respond well to therapy and regain muscle strength in their arms and legs. On the other hand, progressive deterioration with neurological deficits has also been reported. Retrospective studies suggest the patient's neurological condition at the time of diagnosis, the presence of detectable conduction blocks and young age are favorable prognostic factors [12].

Etiology

The etiology of MMN remains poorly understood. The presence of serum antibodies directed against ganglioside GM1 (mainly immunoglobulin type M, about 49% of MMN patients) or ganglioside GM2 (also of type M, only 6% of MMN patients) implies an immune-mediated process, but the trigger of such an autoimmune response as well as the underlying molecular mechanisms are still unknown [3]. Interestingly, increased incidence rates of Hashimoto's thyroiditis, diabetes mellitus type 1 and celiac disease have been observed in families affected by MMN [4]. Although these epidemiological findings further support the hypothesis of MMN being an autoimmune disease, considerable number of MMN patients test negative for any type of autoantibody related to the disease [3]. On the other hand, MMN has repeatedly been reported as an adverse event of treatment with infliximab, an anti-tumour necrosis factor-α (TNF-α) monoclonal antibody [5]. However, studies on serum cytokine levels of MMN patients yielded contradictory results, and symptom onset or disease progression could not unequivocally be related to altered concentrations of TNF-α or other mediators [6] [7].

Epidemiology

The overall prevalence of MMN has been estimated to 0.6 per 100,000 individuals[1]. No racial predilection has been reported, but men are affected significantly more often than women. The male-to-female ratio may be as high as 3:1 [4]. Symptom onset typically occurs in adulthood, at a median age of 40 years. MMN has occasionally been reported in pediatric patients, all of whom were males [8].

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, considerable knowledge gaps remain regarding the etiology and pathogenesis of MMN. About half of MMN patients test positive for autoantibodies directed against ganglioside GM1, and this molecule has been proven to be essential for neurogenesis as well as recovery from nerve injury. GM1 may be encountered in the axolemma of nodes of Ranvier and perinodal Schwann cells, and autoantibodies have been assumed to mediate demyelination of these areas. Demyelination may be associated with decelerated impulse propagation or conduction blocks typical of MMN [9]. Furthermore, axonal injury and consequent dysfunction of ion channels and sodium–potassium pumps may impair the transmission of action potentials. It has been proposed that anti-GM1 antibodies primarily mediate tissue damage by means of complement activation and deposition, and that these processes may be inhibited by intravenous immunoglobulin, which is the current gold standard of MMN therapy [10].

The fact that GM1 expression levels are highest in peripheral motor nerves may partially explain why MMN patients suffer from progressive muscle weakness without showing sensory deficits [1]. The aforementioned pathophysiological events provoke remodelling processes that may be observed histopathologically. In brief, motor nerve biopsy samples obtained from MMN patients show a markedly reduced number of myelinated fibers, decreased mean fiber diameters, degenerating axons, thin myelin sheaths, and ongoing nerve regeneration [11]. Perivascular lymphocyte infiltrates imply a concomitant inflammatory reaction. Of note, histopathological analyses may reveal minor lesions in sensory nerves of MMN patients. Nevertheless, these lesions do not usually provoke any symptoms.

Prevention

No specific measures can be recommended to prevent MMN.

Summary

Multifocal motor neuropathy (MMN) is a rare disorder characterized by progressive, asymmetric limb weakness due to conduction blocks in motor nerves [1]. Its etiology remains largely unknown, although available data implies an autoimmune response directed against ganglioside GM1 or other molecules expressed in motor neurons as accounting for symptom onset in most cases. Inflammatory processes mainly occur in close proximity to the nodes of Ranvier of peripheral motor nerves and thus, MMN patients typically do not experience sensory anomalies.

Symptom onset is usually in distal arms or distal legs, but progression is slow and patients may not complain of any symptoms other than fatigue for prolonged periods of time. Reduced motor control, blunted or absent reflexes and mild muscle atrophy are commonly observed in MMN patients. Most patients are adults; few case reports exist regarding MMN in pediatric patients.

MMN patients generally respond well to intravenous immunoglobulin, but not to corticosteroids. Muscle strength typically improves within a month of the initiation of treatment, and affected individuals have a normal life expectancy. Nevertheless, follow-up studies have reported contradictory results regarding the long-term efficacy of treatment: while some authors report a slowly progressive neurological deterioration over the course of years, others state that therapy effectively diminishes disability and to promotes reinnervation [2].

Patient Information

Multifocal motor neuropathy (MMN) is a rare disorder characterized by progressive, asymmetric limb weakness. While fatigue is the most common non-specific symptom, most patients eventually observe lack of motor control of hands or lower legs. Over time, the patient's condition deteriorates and the disease may become disabling. Of note, sensory deficits are not typical of MMN. Affected people may note minor alterations of their vibration sense, but more extensive sensory anomalies are considered an exclusion criterion for MMN.

Little is known about the causes of MMN. Current knowledge implies an autoimmune process to account for symptom onset, i.e., the patient's immune cells produce antibodies against endogenous structures that are subsequently destroyed. In case of MMN, these antibodies may be directed at gangliosides, which are expressed in certain parts of peripheral motor nerves. The corresponding nerve segments are called nodes of Ranvier, and they are crucial for the conduction of action potentials along the nerve. Dysfunction of nodes of Ranvier results in an inability to transmit excitatory signals to the muscles in the arms and legs.

Fortunately, MMN is curable. The aforedescribed chain of pathophysiological events may be interrupted by treating with immunoglobulins. Most patients regain muscle strength within about a month of therapy. However, recurrence after cessation of therapy is also common. Affected individuals are considered immunoglobulin-dependent and require monthly or bimonthly infusions for prolonged periods of time. A minority of MMN patients do not respond to intravenous immunoglobulin therapy. They may require treatment with additional immunomodulatory compounds with considerable side effects. In general, responsiveness to immunoglobulins is increased if the disease is diagnosed during early stages. Neuronal damage may be irreversible if therapy is delayed.

References

Article

  1. Léger JM, Guimarães-Costa R, Iancu Ferfoglia R. The pathogenesis of multifocal motor neuropathy and an update on current management options. Ther Adv Neurol Disord. 2015; 8(3):109-122.
  2. Vucic S, Black KR, Chong PS, et al. Multifocal motor neuropathy: decrease in conduction blocks and reinnervation with long-term IVIg. Neurology. 2004; 63(7):1264-1269.
  3. Cats EA, Jacobs BC, Yuki N, et al. Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology. 2010; 75(22):1961-1967.
  4. Cats EA, Bertens AS, Veldink JH,et al. Associated autoimmune diseases in patients with multifocal motor neuropathy and their family members. J Neurol. 2012; 259(6):1137-1141.
  5. Rowan CR, Tubridy N, Cullen G. Multifocal Motor Neuropathy Associated with Infliximab. J Crohns Colitis. 2015; 9(12):1174-1175.
  6. Furukawa T, Matsui N, Fujita K, et al. Increased proinflammatory cytokines in sera of patients with multifocal motor neuropathy. J Neurol Sci. 2014; 346(1-2):75-79.
  7. Vlam L, Stam M, de Jager W, et al. Cytokine profiles in multifocal motor neuropathy and progressive muscular atrophy. J Neuroimmunol. 2015; 286:1-4.
  8. Ishigaki H, Hiraide T, Miyagi Y, et al. Childhood-Onset Multifocal Motor Neuropathy With Immunoglobulin M Antibodies to Gangliosides GM1 and GM2: A Case Report and Review of the Literature. Pediatr Neurol. 2016; 62:51-57.
  9. Franssen H. The node of Ranvier in multifocal motor neuropathy. J Clin Immunol. 2014; 34 Suppl 1:S105-111.
  10. Yuki N, Watanabe H, Nakajima T, Spath PJ. IVIG blocks complement deposition mediated by anti-GM1 antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry. 2011; 82(1):87-91.
  11. Taylor BV, Dyck PJ, Engelstad J, et al. Multifocal motor neuropathy: pathologic alterations at the site of conduction block. J Neuropathol Exp Neurol. 2004; 63(2):129-137.
  12. Lehmann HC, Meyer Zu Horste G, Kieseier BC, Hartung HP. Pathogenesis and treatment of immune-mediated neuropathies. Ther Adv Neurol Disord. 2009; 2(4):261-281.
  13. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst. 2010; 15(4):295-301.
  14. Lambrecq V, Krim E, Rouanet-Larriviere M, Lagueny A. Sensory loss in multifocal motor neuropathy: a clinical and electrophysiological study. Muscle Nerve. 2009; 39(2):131-136.
  15. Cats EA, van der Pol WL, Piepers S, et al. Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology. 2010; 75(9):818-825.
  16. Galassi G, Albertini G, Valzania F, Barbieri A. Cranial nerve involvement as presenting sign of multifocal motor neuropathy. J Clin Neurosci. 2012; 19(12):1733-1735.
  17. Léger JM, Chassande B, Musset L, et al. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain. 2001; 124(Pt 1):145-153.
  18. Delmont E, Azulay JP, Uzenot D, et al. [Long-term follow-up of multifocal motor neuropathy with conduction block under intravenous immunoglobulin]. Rev Neurol (Paris). 2007; 163(1):82-88.
  19. Terenghi F, Cappellari A, Bersano A, et al. How long is IVIg effective in multifocal motor neuropathy? Neurology. 2004; 62(4):666-668.
  20. Umapathi T, Hughes RA, Nobile-Orazio E, Leger JM. Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy. Cochrane Database Syst Rev. 2012; (4):Cd003217.
  21. Piepers S, Van den Berg-Vos R, Van der Pol WL, et al. Mycophenolate mofetil as adjunctive therapy for MMN patients: a randomized, controlled trial. Brain. 2007; 130(Pt 8):2004-2010.

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Last updated: 2018-06-21 20:41