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The early diagnosis of amyotrophic lateral sclerosis (ALS) is often difficult as not all patients meet clinical and electrophysiological criteria.1 Additionally a small per cent of patients have a divergent diagnosis, most commonly multifocal motor neuropathy (MMN) or motor-predominant multifocal acquired demyelinating sensory and motor neuropathy (MADSAM).2 Although motor conduction blocks distinguish MMN and MADSAM from ALS, it is often difficult to find these conduction abnormalities when present at the roots or plexus. Currently biomarkers to assist in the diagnosis of ALS versus MMN and MADSAM are inadequate. Specifically, GM1 (ganglioside monosialo-asialo) autoantibodies can be present in all these disorders, although typically of lower values in ALS. Recently, IgM-gammopathy was suggested to be more common in MMN (7%) compared with healthy (2%) and ALS (1%) controls.3 If true, IgM-gammopathy may forebode for an immune treatment refractory disorder as described in other IgM-gammopathy neuropathies.4
Herein, we address: (1) the occurrence of an IgM-gammopathy in MMN and MADSAM compared with ALS and (2) evaluate the immune treatment response of MMN and MADSAM IgM-monoclonal-gammopathy.
We identified 78 MADSAM, 65 MMN cases and 412 ALS patients matched in gender and age. ALS was considered in the differential diagnosis of 51% (40/78) of MADSAM and 64% (42/65) of MMN patients due to motor predominant progressive symptoms. IgM-gammopathy was significantly (p<0.001; OR estimate of 33, 95% CI) more common in MADSAM 23% (18/78) and MMN 17% (11/65) compared with ALS<1% (2/412) (figure 1). IgM-Kappa was the most common subtype 65% (19/29). In ganglioside autoantibody positive cases IgM-gammopathy was significantly more common (p<0.001) with MADSAM 50% (11/22) and MMN 66% (8/12) compared with ALS; 6% (1/15) (online supplementary figure 1).
Longitudinal treatment follow-up (>3 months, mean 45, range: 3–252) was available in 68% (97/143) with 87% (86/97) having repeat nerve conductions and quantitative neurological examinations. Treatments included intravenous immunoglobulin 94% (134/143), cyclophosphamide 11% (16/143) and azathioprine 10% (14/143). There was no significant difference in overall treatment response in patients with MMN and MADSAM between those with and without IgM-gammopathy, (p=0.64) (online supplementary table 1). Of those with follow-up over 1 year 15 cases were identified and all were on intravenous immunoglobulin (IVIG) (nine MADSAM and six MMN). Of these six MADSAM and five MMN had neurological improvements or stabilisation with some dramatically improving (online supplementary figure 1).
Immune treatment comparisons
Clinical improvements were defined between first and last treatment visit as: (1) modified Rankin score improvement ≥1 (0=no symptoms; 1=no significant disability despite symptoms; 2=mild disability, but able to carry out all usual duties and activities; 3=moderate disability; requiring some help, but able to walk or cloth and eat without assistance; 4=moderately severe disability; unable to walk, cloth self without assistance and unable to attend to own bodily needs without assistance; 5=severe disability; bedridden and requiring constant care and attention; 6=dead) and (2) reduction of >8 points on the motor Neuropathy Impairment Score: (0=normal; 1=25% weak; 2=50% weak; 3=75% weak; 3.25=movement only against gravity; 3.5=movement, gravity eliminated; 3.75; flicker of movement 4=complete paralysis (192=maximal deficit)). To meet electrophysiological improvements: (1) conduction blocks in one or more nerves had to improve ≥40% in conduction amplitude compared with the earlier same site studied and (2) summated compound motor action potentials had to improve ≥20% compared with the earlier study of the same motor nerves (online supplementary table 1). An overall treatment response was noted if improvements occurred in at least two of the three clinical and electrophysiological measures comparing the first to last visits. We then focused on disability and impairment scoring uniformly performed in persons receiving IVIG for at least 12 months and having available quantified repeat neurological testing (online supplementary figure 2).
MMN and MADSAM diagnosed patients seen in our neuromuscular practice were identified. All patients had to have undergone nerve conductions, EMG, serum monoclonal protein and ganglioside autoantibody testing (1 January 2007–31 December 2018). ALS patients having undergone similar serological testing were matched in age and gender to MMN and MADSAM. Ganglioside autoantibody testing for GM1 (monosialo-asialo (IgM; IgG)) and GD1b (disialo (IgG, IgM)) were performed by an in-house validated ELISA. All patients underwent serum protein electrophoresis and serum immunofixation electrophoresis in discovery of their monoclonal proteins. Demographics for gender, age and positive laboratory testing are shown in online supplementary table 2.
Association between monoclonal gammopathies (ie, IgM and IgA/IgG), ganglioside autoantibodies, and MADSAM, MMN, ALS was evaluated by the Fisher’s exact test. Associations were quantified as ORs with 95% CIs using logistic regression. All statistical tests were two-sided and p values less than 0.05 were considered statistically significant. Statistical analyses were performed using SAS V.9.4.
IgM-monoclonal gammopathy is common in both MMN and MADSAM, occurring in approximately one-quarter of patients. The presence of IgM-gammopathy strongly (OR=33) favours MMN and MADSAM over matched ALS controls, and does not exclude autoimmune treatment response. Specifically, we note many with IgM-gammopathy and MMN or MADSAM responded to treatment, sometimes dramatically. Clinicians should consider ordering a serum immunofixation for their patients where diagnostic uncertainty exists. Additionally, in patients with a low or indeterminate value of GM1-IgM autoantibody (<1:10 000 dilution) the presence of IgM-gammopathy favours the diagnosis of MMN and MADAM over ALS. This work expands the neuropathy phenotypes and treatment response associated with IgM-gammopathy. Specifically, in contrast to IgM gammopathy associated distal acquired demyelinating sensory neuropathy, those patients typically do not improve with immunotherapy.4
Earlier studies have shown that the presence of ganglioside autoantibodies correlate with prolonged (median >60 months) MMN and MADSAM treatment responses.5 The pathogenesis of MADSAM and MMN remains unknown. As both MMN and MADSAM had anti-gangliosides with IgM-gammopathy (66% MMN, 50% MADSAM), our results might suggest a shared immune-mediated mechanism between a subset of patients. Specifically, IgM-gammopathy occurrence could reflect proliferation of an autoreactive B-cell clone that recognises yet unidentified antigens expressed locally in axons at the sites of conduction block, as has been suggested with GM1-IgG autoimmunity.
The authors thank the patients who agreed to participate in this research.
Contributors SS, JM, CJK: study design. SS, CJK: writing the manuscript. SS, JRM, JMM-T, MMR, JM, JDT, MM, DD, SP, CJK: data collection. All co-authors: manuscript revision.
Funding The Mayo Clinic Foundation and its Center for Individualized Medicine have provided time to allow the authors to complete this work.
Disclaimer All the views expressed are those of the authors and not necessarily those of the Mayo Clinic Foundation.
Competing interests SJP: reports affiliation with Grifols, Alexion and Medimmune pharmaceuticals. He receives no personal compensation as all moneys are paid directly to Mayo Clinic; MM: reports receiving honorarium from Ackea related to TTR amyloidosis; DD Has received research support from Center of Multiple Sclerosis and Autoimmune Neurology, and Grifols pharmaceuticals. DD has consulted for UCB pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic; CJK reports receiving honorarium from Ackea related to TTR amyloidosis and Fabry disease. He has also been a consultant at Pfizer but received no personal compensation.
Patient consent for publication Not required.
Ethics approval Approval for this study was obtained by the Institutional Review Board at the Mayo Clinic and all patients provided written consent to participate.
Provenance and peer review Not commissioned; externally peer reviewed.
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