Clinical outcomes in multifocal motor neuropathy

Herraets, Ingrid J.T.; Rosmalen, Marieke van; Bos, Jeroen W.; Eijk, Ruben van; Cats, Elisabeth A.; Jongbloed, Bas A.; Vlam, Lotte; Piepers, Sanne; Asseldonk, Jan-Thies Van; Goedee, H. Stephan; Berg, Leonard van den; Pol, W. Ludo van der

doi:10.1212/wnl.0000000000010538

Cited by 17 publications

(30 citation statements)

References 35 publications

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“…Our patients with motor-onset MADSAM had better prognosis and long-term treatment responsiveness relative to our and other historical MMN cohorts. 17,18 Asymmetrical, single or bilateral, upper limb onset, observed here in 61% (46/76), remains the most common presentation of MADSAM. 6,20 However, a significant proportion (29%) presented with single or bilateral lower limb involvement.…”

Section: Discussionmentioning

confidence: 80%

“…[14][15][16] Long-term treatment resistance to IV immunoglobulin (IVIg), the current mainstay of immunotherapy, is typical in MMN. 17,18 In contrast, these same immunotherapies are effective in long-term classic CIDP and variant CIDP forms with few long-term treatment reports in MADSAM. [5][6][7]17,19 Monoclonal gammopathy of undetermined significance (MGUS) has been reported in some patients with MADSAM 6,7,20 ; however, its presence has been utilized as an exclusionary finding for diagnosis by others.…”

Section: Classification Of Evidencementioning

confidence: 99%

“…Stable or improved (0) 1 ( 7) onset appear fundamentally different from historical MMN cohorts, where almost all patients develop long-term neurologic declines despite immunotherapy. 17,18 There are limitations to the study. Selection bias is inherent in retrospective studies carried out at tertiary referral centers where atypical presentations are common.…”

Section: Dual Agent Therapymentioning

confidence: 99%

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Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

et al. 2021

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Objectives:To longitudinally investigate patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, quantifying timing and location of sensory involvements in motor-onset patients, along with clinico-histopathological and electrophysiological findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS).Methods:Patients with MADSAM neuropathy seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies, were retrospectively reviewed (January 1st, 2007-December 31st, 2018).Results:Of 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed as multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% IgM subtype), associating with ganglioside autoantibodies (p<0.001) and higher IgM titers (p<0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor-onset patients was 18 months (range: 6-180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory 35% (14/40), outside 20% (8/40), or both 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n=9) more frequently demonstrated onion-bulb pathology (p=0.001) and endoneurial inflammation (p=0.01) than distal biopsies (n=17). MRI and biopsy findings were similar amongst patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p=0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8 point reduction occurred in 75% (49/65) irrespective of MGUS or motor-onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p=0.02).Discussion:Pure motor-onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology and nerve pathology help distinguish motor-onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor-onset MADSAM compared to MMN reports. Patients having MGUS commonly require dual immunotherapy.Classification of Evidence:This study provides Class II evidence that most clinical, electrophysiological, and histopathological findings were similar between patients with MADSAM with and without monoclonal gammopathy of unknown significance.

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Section: Discussionmentioning

confidence: 80%

Section: Classification Of Evidencementioning

confidence: 99%

Section: Dual Agent Therapymentioning

confidence: 99%

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Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

et al. 2021

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“…9,10 This treatment often improves muscle strength-but needs to be repeated regularly in the short term-and is less effective at preventing progression of axonal loss in the long term. 1,11 The immunomodulatory effects of high-dose IVIg include the inhibition of the classical pathway of the complement system, which is the main effector mechanism of IgM antibodies. 12 Therefore, it can be postulated that IgM anti-GM1 antibodies bound to the axolemma disturb the function of MNs by classical pathway activation and the subsequent formation of C3 and C5 convertases and formation of the membrane attack complex (MAC).…”

mentioning

confidence: 99%

Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy

Budding

Johansen

Walle

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesTo determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.MethodsiPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.ResultsiPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.DiscussionBinding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.

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“…Multifocal motor neuropathy (MMN) is a rare, slowly progressive inflammatory neuropathy, characterized by asymmetrical distal muscle weakness, which responds to immunoglobulin treatment. [6][7][8] MMN is associated with specific HLA haplotypes, suggesting genetic susceptibility underlying disease pathogenesis. 9 The selective motor neuron vulnerability seen in MMN is not fully explained.…”

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confidence: 99%

SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis

et al. 2021

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ObjectiveTo assess the association between copy number (CN) variation in the survival motor neuron (SMN) locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of SMN1 and SMN2 CN with MMN, PMA, and PLS disease course.MethodsIn this monocenter study, we used multiplex ligation-dependent probe amplification to determine SMN1 and SMN2 CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for SMN1 and SMN2 CN. We analyzed SMN1 and SMN2 exons 1–6, intron 6, and exon 8 CN to study the genetic architecture of SMN1 duplications.ResultsSMN1 and SMN2 CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in SMN1 or SMN2. By contrast, patients with PMA more often than controls carried SMN1 duplications (≥3 SMN1 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43–4.91), p 0.0020). SMN1 and SMN2 CN status was not associated with MMN, PLS, or PMA disease course. In case of SMN1 exon 7 duplications, exons 1–6, exon 8, and introns 6 and 7 were also duplicated, suggesting full SMN1 duplications.ConclusionsSMN1 duplications are associated with PMA, but not with PLS and MMN. SMN1 duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered SMN CN on lower motor neurons.

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Clinical outcomes in multifocal motor neuropathy

Cited by 17 publications

References 35 publications

Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy

SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis

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