RARE DISEASE
Multifocal motor neuropathy
Multifocal motor neuropathy
Multifocal motor neuropathy
Synonyms: MMN, MMNCB, Multifocal motor neuropathy with conduction block
Synonyms: MMN, MMNCB, Multifocal motor neuropathy with conduction block
Synonyms: MMN, MMNCB, Multifocal motor neuropathy with conduction block
Drug discovery
3
drugs
With orphan designations
Overview
Multifocal Motor Neuropathy (MMN) is a rare, immune-mediated motor neuropathy characterized by asymmetric limb weakness, typically affecting distal upper extremities without sensory loss. Diagnosis relies on electrophysiological evidence of multifocal motor conduction blocks and elevated anti-GM1 IgM antibodies in ~50% of patients [1][7][12]. Unlike ALS, MMN progresses slowly, spares cranial/respiratory muscles, and responds to intravenous immunoglobulin (IVIg) [2][4][16]. Early treatment is critical to prevent axonal degeneration and disability [6][13].
Burden
Progressive weakness leads to impaired dexterity, reduced work capacity, and dependence on long-term IVIg [5][12][16].
Chronic disability (e.g., hand atrophy, gait instability) occurs in 30–40% despite treatment [1][17][20].
Psychological distress from delayed diagnosis (often misdiagnosed as ALS) and treatment costs [4][5][12].
Therapies
IVIg (2 g/kg induction, then 1–2 g/kg every 2–8 weeks) is first-line; improves strength in 60–80% of patients [3][6][8].
Subcutaneous immunoglobulin (SCIg) offers comparable efficacy to IVIg with fewer systemic side effects [5][13].
Avoid corticosteroids/plasma exchange (may worsen symptoms); cyclophosphamide or rituximab used in refractory cases [8][12][18].
Categories: rare neurological diseases
Research Papers
306 drug discovery papers about Multifocal motor neuropathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
306 drug discovery papers about Multifocal motor neuropathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-05 | Cladribine treatment in chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: two case reports
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) are immune-mediated peripheral neuropathies that may follow a progressive course and be refractory and poorly tolerated to standard immunomodulatory treatments. Therapeutic options for such patients remain limited. We report two patients with immune-mediated neuropathies—one with typical CIDP and one with MMN—who were treated with low-dose intermittent subcutaneous cladribine. Clinical outcomes were assessed using the Medical Research Council (MRC) sum score and the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Both patients demonstrated clinically meaningful and sustained improvements in muscle strength and functional disability lasting up to 24 months after treatment completion. Cladribine was well tolerated; transient lymphopenia occurred in one patient without serious adverse events. These cases suggest that cladribine may represent a potential therapeutic option for selected patients with CIDP or MMN. Further studies are warranted to confirm efficacy and safety.
2025-11-12 | IgM Anti-Ganglioside Binding and Complement Activation in an iPSC-Derived Motor Neuron Model for Multifocal Motor Neuropathy.
Multifocal motor neuropathy (MMN) is an asymmetric motor neuropathy driven by IgM autoantibodies targeting gangliosides, particularly GM1. In this study, we investigated the relationship between IgM seropositivity, complement activation, and clinical parameters using an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN. We used serum samples from 137 patients with MMN to assess IgM binding and subsequent C3 fixation to iPSC MNs and their correlation with clinical parameters, including muscle strength expressed as MRC sum scores, obtained from patient records. In addition, we tested the efficacy of IV immunoglobulin (IVIg) and specific complement inhibitors to prevent C3 fixation to MNs. We observed increased IgM binding to iPSC MNs using serum samples from patients with MMN compared with those from healthy controls, which correlated with IgM anti-ganglioside antibody titers. Higher antibody binding correlated with levels of C3 fixation, more severe weakness, and the need for higher IVIg doses. Complement activation, but not IgM binding, also correlated with vibration sense abnormalities, brachial plexus MRI abnormalities, and the degree of axonal damage. At therapeutic concentrations, IVIg moderately inhibited complement activation (34%-54%) while specific complement inhibitors were highly effective (89.1%-98.7%) in the iPSC MN model. This study demonstrates that IgM antibodies in serum samples from patients with MMN induce complement activation on iPSC MNs, which correlates significantly with clinical outcomes. In addition, our findings indicate that complement inhibitors offer a potentially targeted novel therapeutic strategy for MMN and that our iPSC MN model is a viable preclinical screening platform.
2025-07-28 | Frequency and Relevance of MYD88L256P Mutation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy.
The myeloid differentiation primary response 88 (MYD88) protein is involved in immune processes through the activation of the toll-like receptors and the interleukin-1 receptor. The acquired MYD88L256P mutation enhances its activity and promotes inflammatory pathways and autoimmune diseases. Our aim was to determine the frequency of the MYD88L256P mutation in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) and multifocal motor neuropathy with conduction blocks (MMN) and to assess its potential effect on the phenotype of the neuropathy. The MYD88L256P mutation was tested in the peripheral blood mononuclear cells of 79 CIDP, 35 MMN, and 57 controls with nonimmune mediated disorders. Disease severity was assessed on disability scores, neurofilament light chain dosages, motor unit counts, and sums of the sensory and motor amplitudes on electrodiagnostic tests. The MYD88L256P mutation was more frequent in MMN patients (12/35, 34%; odds ratio 28 [95% confidence interval 4-1262]; p < 0.001) and in CIDP patients (15/79, 19%; OR 13 [95% confidence interval 2-561]; p < 0.001) than in controls (1/57, 2%). Patients with the MYD88L256P mutation were more likely to have an IgM monoclonal gammopathy (13/27 vs. 8/87, p = 0.001). The MYD88L256P mutation remains more frequent in CIDP and MMN patients, even if patients with IgM monoclonal gammopathy were excluded. All the other characteristics were similar, especially the severity of the disease and the efficacy of intravenous immunoglobulins. The MYD88L256P mutation is frequent in CIDP and MMN patients, suggesting new pathophysiological hypotheses and new therapeutic approaches.
2024-07-17 | Steroid-responsive Multifocal Motor Neuropathy with Cranial Manifestations
The typical presentation of multifocal motor neuropathy (MMN) is progressive asymmetric limb weakness. Cranial neuropathy is rare. We report a 28-year-old woman with cranial and bulbar palsies but with typical electrophysiological features of MMN by multifocal motor conduction blocks and serological markers of anti-ganglioside GM1 antibodies. The previous consensus on the treatment of MMN is intravenous immunoglobulins, but our patient responded to oral steroids and had clinical and electrophysiological improvement under continuous low-dose prednisolone treatment. In summary, MMN is a treatable chronic inflammatory disease of peripheral nerves. Cranial neuropathies can be its initial presentation. Electromyography studies are crucial for MMN diagnosis and helpful in monitoring disease activity and treatment responses. Although the previous guideline did not suggest using steroids for MMN, with careful patient selection, low-dose oral steroids can be an effective treatment in patients with relatively minor symptoms.
2019-09-24 | Immune-mediated neuropathies.
Since the discovery of an acute monophasic paralysis, later coined Guillain-Barré syndrome, almost 100 years ago, and the discovery of chronic, steroid-responsive polyneuropathy 50 years ago, the spectrum of immune-mediated polyneuropathies has broadened, with various subtypes continuing to be identified, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In general, these disorders are speculated to be caused by autoimmunity to proteins located at the node of Ranvier or components of myelin of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. Owing to the numerous subtypes of the immune-mediated neuropathies, making the right diagnosis in daily clinical practice is complicated. Moreover, treating these disorders, particularly their chronic variants, such as CIDP and MMN, poses a challenge. In general, management of these disorders includes immunotherapies, such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the emergence of more disease-specific immunotherapies should broaden the therapeutic options for these disabling diseases.
proteins
2026-08-14 | Multifocal motor neuropathy: А literature review and case report
Multifocal motor neuropathy (MMN) is a rare immune-mediated disease of the peripheral nervous system manifesting as progressive asymmetric muscle weakness and motor conduction blocks. This article presents a clinical case of a patient with verified MMN in whom the use of rituximab was not accompanied by clinical improvement and was associated with further progression of paresis. Subsequent administration of intravenous immunoglobulin (IVIG) led to pronounced positive dynamics with an increase in muscle strength and a decrease in the severity of motor deficit. Introduction. MMN is a rare dysimmune neuropathy clinically characterized by asymmetric muscle weakness, atrophy, and fasciculations with absent or minimal sensory impairments. The most significant diagnostic signs include the detection of IgM antibodies to ganglioside GM1 and the registration of motor conduction blocks during electroneuromyographic examination. IVIG is considered the mainstay of pathogenetic therapy for MMN, while the efficacy of other immunomodulatory drugs, including rituximab, remains insufficiently defined. Materials and methods. We analyzed a clinical case of a female patient born in 1961 who was admitted with complaints of increasing weakness in the left hand, clumsiness during movements, and fasciculations in the muscles of the left upper limb. The diagnostic evaluation included a neurological examination, electroneuromyography, ultrasound examination of peripheral nerves and the brachial plexus, as well as magnetic resonance imaging. To clarify the nosological entity of the process, an analysis of the cerebrospinal fluid and a laboratory assessment of anti-GM1 antibodies were performed. Results. The examination revealed motor conduction blocks outside typical compression sites, as well as an elevated titer of anti-GM1 antibodies, which confirmed the diagnosis of MMN. The administration of rituximab, necessitated in part by organizational and economic limitations of therapy, did not lead to clinical stabilization. After transferring the patient to IVIG therapy, clear positive dynamics were noted in the form of reduced severity of paresis and increased muscle strength. Conclusion. The presented clinical observation emphasizes the importance of timely diagnosis of MMN and early initiation of pathogenetic therapy. In this case, the use of rituximab did not provide clinical stabilization, whereas IVIG demonstrated high therapeutic efficacy. Improving the availability of immunoglobulin therapy and physicians’ awareness of MMN is essential to prevent the progression of motor deficit and patient disability.
2026-07-28 | Discovery and engineering of novel IgM proteases for the treatment of autoimmune and inflammatory diseases 2253144
Abstract Introduction IgM is a multifunctional immunoglobin that acts as the first line of defense against systemic pathogens. IgM’s multimeric structure, together with its complement binding ability, makes IgM a highly potent inflammation driver. The presence of autoreactive IgM antibodies causing complement dependent damage has been described in inflammatory and autoimmune conditions such as Cold Agglutinin Disease (CAD) and Multifocal Motor Neuropathy (MMN) . For this reason, the development of IgM autoantibodies degrading therapy represents an attractive approach. Methods Employing Seismic’s IMPACT platform and evolutionary screening, we identified several novel and selective IgM proteases. Discovered proteases cleave soluble IgM in plasma and the IgM BCR in B cells from healthy individuals. Results CAD is an autoimmune hemolytic anemia, caused by IgM autoantibodies that bind to red blood cells (RBC), causing agglutination and activate complement cascade resulting in RBC death. Seismic’s IgM protease cleaves RBC bound IgM, preventing agglutination in whole blood from CAD donors, an unmet need not targeted by current approved treatment. In addition, IgM cleavage reduced cold-induced complement deposition on RBC from CAD patients. Conclusion Further engineering and optimization with our IMPACT Platform for the novel proteases is currently under way. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2026-07-11 | Intravenous immunoglobulin frequency in multifocal motor neuropathy: a retrospective study of nerve conduction outcomes.
In resource-limited rural settings, patients with multifocal motor neuropathy (MMN) often present late due to limited access to neurophysiology services, by which time significant axonal damage may have occurred, rendering them less responsive to immunotherapy-yet this clinically subgroup is consistently underrepresented in randomized controlled trials. In this study, we aimed to examined the impact of intravenous immunoglobulin (IVIg) frequency on electrophysiological changes in such undertreated MMN patients. A retrospective analysis was conducted across three rural medical centers. Patients receiving > 2 IVIg cycles annually were classified as group A, others as group B. Nerve conduction was assessed at baseline, after the first treatment course, and at the final follow-up. Thirty-nine MMN patients initially identified, 11 patients with confirmed conduction block (CB) were included. 27 nerves exhibited definite CB, with 7 (25.9%) in the median nerve, 8 (29.6%) in the ulnar nerve, and 6 (18.5%) in both the tibial and peroneal nerves. The treatment intervals was 4.9 ± 1.8 (range, 2.6 to 8.0) months, The follow-up period was 17.2 ± 3.3 months (range, 12.0 to 21.0). 7 (63.6%) were in group A, while 4 patients (36.4%) were in group B. There was a clear improvement in mRS scores at the last follow-up compared to baseline (z = -2.795, p = 0.007). We compared the variations in distal compound muscle action potential (CMAP) amplitude at baseline and the last follow-up, after adjusting for baseline CMAP amplitude, it showed significantly greater improvements in distal CMAP amplitude in group A versus group B (F = 40.217, P < 0.001; B = 2.881, 95% CI 1.941 ~ 3.821, P < 0.001), with the model accounting for 71.5% of the variance (adjusted R²= 0.715). The number of CBs decreased from 17 to 14 in group A, with no change in group B (p > 0.05). High frequency IVIg treatment may be associated with improved CMAP amplitude and mRS in undertreated MMN patients, suggesting potential benefits that require further validation.
2026-06-30 | Atypical Multifocal Motor Neuropathy Presenting With Isolated Spinal Accessory and Pectoral Nerve Involvement
Multifocal motor neuropathy (MMN) is a rare, immune-mediated disorder typically characterized by slowly progressive, asymmetric distal limb weakness. Cranial nerve involvement is distinctly uncommon, and isolated involvement of the spinal accessory nerve (CN XI) is exceedingly rare. We present the case of a 68-year-old male patient who presented with severe neck and shoulder wasting and a profound head drop. Despite the fact that standard conduction studies failed to demonstrate classic motor conduction blocks due to the highly proximal nature of the nerve involvement, a clinical diagnosis of MMN was suspected based on the asymmetric motor-only presentation, elevated Anti-GM1 antibodies, and steroid nonresponsiveness. The patient showed a robust and sustained functional recovery following treatment with intravenous immunoglobulin (IVIG), highlighting the importance of clinical judgment in atypical presentations of treatable neuropathies.
2026-03-01 | 4CPS-264 Analysis and 10 year comparison of intravenous immunoglobulins utilisation in a tertiary hospital: evaluation of clinical appropriateness and economic impact
Intravenous immunoglobulins (IVIg) are used across diverse clinical conditions, including primary and secondary immunodeficiencies, autoimmune, neurological, and haematological disorders. Despite expanding applications, approved (on-label) indications remain limited. Given its substantial cost and limited global supply, evaluating prescribing practices is essential to support evidence-based use and optimise healthcare resources. This study aimed to characterise IVIg utilisation in inpatient and outpatient settings at a tertiary hospital over one year (September 2024–September 2025) and compare findings with institutional data from 2014. Objectives included assessing adherence to approved indications, quantifying off-label and non-recommended use, and evaluating economic impact. A retrospective observational study was conducted using data from electronic health records and pharmacy information systems. Patient demographics, IVIg indications, and direct treatment costs were analysed. Indications were classified according to the British Clinical Guidelines for Immunoglobulin Use (3rd edition, 2021). Comparative analysis was performed against data from 2014. A total of 153 patients received IVIg during the study period (median age: 65 years; 50.9% female), with 40.3% managed as inpatients. On-label indications accounted for 72.5% of prescriptions, most commonly common variable immunodeficiency (48/153, 31.4%) and secondary immunodeficiency (26/153, 17.0%). Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, 16/153, 10.5%) and multifocal motor neuropathy (MMN,1/153, 0.7%) were newly classified as on-label. Evidence-supported off-label use represented 20.3%, with myasthenia gravis being the most common indication (13/153, 8.5%). While unsupported off-label and non-recommended indications accounted for 4.6% and 2.6%, respectively. Compared to 2014, the number of patients treated increased by 10.9%. On-label use improved (67.4% in 2014 vs. 72.5% in 2024), with reductions in non-recommended indications. Despite increased patient volume, IVIg expenditure declined from 1,730,002€ to 1,681,662€, reflecting enhanced cost-efficiency and prescribing behaviour. This analysis shows a positive trend toward more appropriate and economically sustainable IVIg use in comparison with 2014. The formal inclusion of CIDP and MMN as on-label indications, alongside enhanced guideline adherence and reduced unsupported use, reflects effective stewardship. Reduced expenditure despite increased utilisation underscores improved resource management, optimising healthcare expenditure. No conflict of interest
cell therapies
2008-08-01 | The clinical value of therapeutic plasma exchange in multifocal motor neuropathy
Objective Although there is evidence for a pathogenic role of humoral factors in multifocal motor neuropathy (MMN), plasma exchange (PE) is assumed to be an ineffective treatment. We set out to elucidate possible reasons for this apparent contradiction. Methods A retrospective analysis of seven patients with MMN, who underwent 4 to 18 sessions of PE. Clinical response, electrophysiological parameter and anti-ganglioside antibody titers were reviewed. Results Two patients, who had anti-ganglioside antibodies, exhibited transient clinical responses to PE, manifested by improved neurological function. Whereas electrophysiological parameters continued to worsen in all patients, anti-ganglioside antibody titers declined during PE, but increased after PE. Conclusion PE is of limited therapeutic value in patients with MMN, who do not respond to established treatment options. It may only be useful as an adjunctive treatment in a subset of patients. The transient decrease of anti-ganglioside-antibodies titers suggests that pathogenic humoral factors in MMN are only temporarily reduced. Further, PE treatment alone is insufficient to prevent axons from continuing degeneration, which may explain the failure of PE to substantially influence the disease course of patients with MMN.
antibodies
2026-07-29 | Revisiting multifocal motor neuropathy: mechanisms, diagnosis and future directions.
Multifocal Motor Neuropathy (MMN) is an immune-mediated, pure motor neuropathy characterized by slowly progressive, asymmetric limb weakness. It predominantly affects men in mid-adulthood and often presents with distal upper-limb weakness, such as wrist or finger drop. Although the disease course is typically chronic, slowly and sometimes stepwise progressive, timely recognition is critical, as early immunotherapy can prevent irreversible axonal loss and long-term disability. This review aims to provide a comprehensive and clinically integrated overview of MMN, spanning pathogenesis, clinical presentation, diagnostic challenges, and current and emerging therapeutic strategies. Emphasis is placed on translating mechanistic insights into practical diagnostic and treatment frameworks, and on identifying priorities for future research. Pathophysiologically, MMN is best understood as an antibody-mediated nodo-paranodopathy. IgM antibodies directed against GM1 gangliosides bind to GM1-enriched domains at the nodes of Ranvier, activate the classical complement cascade, and disrupt sodium channel clustering and axo-glial integrity. The resulting conduction block constitutes the electrophysiological hallmark of the disease and may initially be reversible. Persistent immune-mediated injury, however, can lead to secondary axonal degeneration and fixed disability. While GM1 IgM antibodies are detected in a substantial proportion of patients, seronegativity does not exclude MMN, potentially reflecting mechanistic heterogeneity and/or assay limitations. Diagnosis relies on the combination of a characteristic clinical phenotype and electrophysiological evidence of motor conduction block with preserved sensory conduction. However, conduction block can be difficult to demonstrate because of proximal lesions, temporal dispersion, or superimposed axonal loss, contributing to diagnostic uncertainty. High-resolution nerve ultrasound and magnetic resonance neurography offer valuable complementary information by revealing focal nerve enlargement or plexus abnormalities, though neither technique is independently diagnostic. Intravenous immunoglobulin (IVIg) remains the established standard of care and the only approved therapy, producing rapid but often transient improvement that necessitates individualized maintenance regimens. Subcutaneous immunoglobulin provides an effective long-term alternative for many patients. Conventional immunosuppressants have shown limited efficacy, whereas emerging complement inhibitors targeting upstream components of the classical pathway represent a promising, mechanism-based strategy currently under clinical evaluation. Despite advances, significant gaps remain. Reliable biomarkers to predict treatment response, monitor disease activity, and detect early axonal injury are lacking. Future progress will require integrated translational models, harmonized outcome measures, and well-designed clinical trials to move toward more durable and personalized therapeutic approaches in MMN.
2026-06-08 | Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.
Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.
2026-02-17 | Plasma neurofilament light chain is associated with clinical instability in chronic autoimmune neuropathies.
Neurofilament light chain (NfL) is a sensitive biomarker of axonal damage, but its clinical relevance in chronic autoimmune neuropathies remains incompletely defined. This study evaluated plasma NfL levels in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), compared with hereditary neuropathy (Charcot–Marie–Tooth disease type 1 A, CMT1A) and healthy controls, focusing on disease activity rather than diagnostic discrimination. Plasma NfL concentrations were measured using single molecule array (Simoa) technology in 41 patients (CIDP n = 16, MMN n = 7, CMT1A n = 18) and 25 age- and sex-matched controls. Disease severity was assessed using the Inflammatory Rasch-built Overall Disability Scale for autoimmune neuropathies and the Charcot–Marie–Tooth Neuropathy Score version 2 for CMT. Plasma NfL levels were significantly higher in patients with autoimmune neuropathies and CMT compared with controls. No significant differences were observed between inflammatory and hereditary neuropathies, and NfL levels did not correlate with disability scores. However, patients with autoimmune neuropathies and an unstable disease course, defined by more than two relapses, exhibited significantly higher plasma NfL levels. Across all groups, NfL concentrations showed a strong correlation with age. These findings suggest that while plasma NfL lacks diagnostic specificity among chronic neuropathies, it may be associated with disease instability in autoimmune neuropathies.
2026-02-09 | Successful Treatment of Multifocal Demyelinating Sensory-Motor Neuropathy (Lewis-Sumner Syndrome) With Rituximab: A Case Report.
BACKGROUND Multifocal acquired demyelinating sensory-motor neuropathy (MADSAM) is recognized as a variant of chronic inflammatory demyelinating polyneuropathy. The primary characteristics of MADSAM include multifocal sensory loss and muscle weakness, which are frequently asymmetrical and predominantly affect the upper limbs. Involvement of the lower limbs is less commonly observed in MADSAM. CASE REPORT A 27-year-old female patient presented with recurrent numbness and weakness in her left lower limb was admitted to our hospital. Her medical history included episodes of left peripheral facial paralysis and lower-limb numbness and weakness, which had previously improved after short-term oral steroid therapy. In addition to motor and sensory peripheral nerve impairment in the left lower limb, the neurological examination revealed atrophy of the tongue muscle and a leftward deviation of the tongue. Cerebrospinal fluid examination and magnetic resonance imaging indicated no abnormalities. Electromyography suggested demyelination of motor and sensory nerves in the left lower limb. Sural nerve biopsy demonstrated demyelination changes and axonal degeneration. A diagnosis of multifocal sensory and motor neuropathy was considered, and the patient was administered corticosteroids and tacrolimus. As the condition progressed, electromyography showed gradual involvement of both lower limbs, leading to the consideration of MADSAM. Despite treatment with corticosteroids and tacrolimus, the patient experienced relapse. Rituximab was initiated, resulting in symptoms improvement and reduced recurrence without adverse events. CONCLUSIONS Corticosteroids, plasma exchange, and immunoglobulins have been demonstrated to be effective treatments for CIDP. In our MADSAM case, rituximab proved effective when the patient did not respond to corticosteroids and tacrolimus. We propose that rituximab may serve as an alternative option for patients with MADSAM.
2026-01-28 | Blood-Nerve Barrier Breakdown Induced by Immunoglobulin G in Typical and Multifocal Chronic Inflammatory Demyelinating Polyneuropathy and Multifocal Motor Neuropathy.
Impairment of the blood-nerve barrier (BNB) is associated with the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). This research analyzes the molecular mechanisms of immunoglobulin (Ig) G in patients with typical CIDP, CIDP variants (multifocal CIDP), and multifocal motor neuropathy in BNB-endothelial cells. IgG was purified from the sera of patients with typical CIDP (n = 15), multifocal CIDP (n = 14), multifocal motor neuropathy (MMN; n = 12), and healthy controls (HCs; n = 14). Molecular changes in the RNA-seq/high-content imaging system and permeability were evaluated after the incubation of human peripheral nerve microvascular endothelial cells (PnMECs) with IgG. RNA-seq and a pathway analysis using PnMECs showed that TNF-α, CCL20 (MIP-3α), and ICAM-1 were the centers of the upregulated gene pathways in patients with typical CIDP. TNF-α, VCAM-1, NF-κB, and CSF2 (GM-CSF) are important molecules in patients with multifocal CIDP. The high-content imaging system demonstrated that MIP-3, GM-CSF, and VCAM-1 increased after exposure to typical CIDP-IgG, claudin-5 decreased after exposure to IgG from patients with multifocal CIDP, and TNF-α and VCAM-1 increased after exposure to IgG from patients with MMN. The 10 kDa dextran permeability using coculture with PnMECs and pericytes increased after exposure to IgG from patients with typical CIDP and multifocal CIDP. This effect was reversed after incubation with GM-CSF neutralizing antibodies. Upregulation of MIP-3, GM-CSF, and VCAM-1 may contribute to the infiltration of leukocytes/lymphocytes/monocytes across the BNB into the PNS in typical CIDP. IgG from typical CIDP and multifocal CIDP may decrease barrier properties through autocrine GM-CSF from PnMECs. VCAM-1 upregulation through autocrine TNF secretion in PnMECs may induce lymphocyte entry across the BNB in MMN.
small molecules
2026-08-05 | Cladribine treatment in chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: two case reports
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) are immune-mediated peripheral neuropathies that may follow a progressive course and be refractory and poorly tolerated to standard immunomodulatory treatments. Therapeutic options for such patients remain limited. We report two patients with immune-mediated neuropathies—one with typical CIDP and one with MMN—who were treated with low-dose intermittent subcutaneous cladribine. Clinical outcomes were assessed using the Medical Research Council (MRC) sum score and the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Both patients demonstrated clinically meaningful and sustained improvements in muscle strength and functional disability lasting up to 24 months after treatment completion. Cladribine was well tolerated; transient lymphopenia occurred in one patient without serious adverse events. These cases suggest that cladribine may represent a potential therapeutic option for selected patients with CIDP or MMN. Further studies are warranted to confirm efficacy and safety.
2025-11-12 | IgM Anti-Ganglioside Binding and Complement Activation in an iPSC-Derived Motor Neuron Model for Multifocal Motor Neuropathy.
Multifocal motor neuropathy (MMN) is an asymmetric motor neuropathy driven by IgM autoantibodies targeting gangliosides, particularly GM1. In this study, we investigated the relationship between IgM seropositivity, complement activation, and clinical parameters using an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN. We used serum samples from 137 patients with MMN to assess IgM binding and subsequent C3 fixation to iPSC MNs and their correlation with clinical parameters, including muscle strength expressed as MRC sum scores, obtained from patient records. In addition, we tested the efficacy of IV immunoglobulin (IVIg) and specific complement inhibitors to prevent C3 fixation to MNs. We observed increased IgM binding to iPSC MNs using serum samples from patients with MMN compared with those from healthy controls, which correlated with IgM anti-ganglioside antibody titers. Higher antibody binding correlated with levels of C3 fixation, more severe weakness, and the need for higher IVIg doses. Complement activation, but not IgM binding, also correlated with vibration sense abnormalities, brachial plexus MRI abnormalities, and the degree of axonal damage. At therapeutic concentrations, IVIg moderately inhibited complement activation (34%-54%) while specific complement inhibitors were highly effective (89.1%-98.7%) in the iPSC MN model. This study demonstrates that IgM antibodies in serum samples from patients with MMN induce complement activation on iPSC MNs, which correlates significantly with clinical outcomes. In addition, our findings indicate that complement inhibitors offer a potentially targeted novel therapeutic strategy for MMN and that our iPSC MN model is a viable preclinical screening platform.
2025-07-28 | Frequency and Relevance of MYD88L256P Mutation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy.
The myeloid differentiation primary response 88 (MYD88) protein is involved in immune processes through the activation of the toll-like receptors and the interleukin-1 receptor. The acquired MYD88L256P mutation enhances its activity and promotes inflammatory pathways and autoimmune diseases. Our aim was to determine the frequency of the MYD88L256P mutation in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) and multifocal motor neuropathy with conduction blocks (MMN) and to assess its potential effect on the phenotype of the neuropathy. The MYD88L256P mutation was tested in the peripheral blood mononuclear cells of 79 CIDP, 35 MMN, and 57 controls with nonimmune mediated disorders. Disease severity was assessed on disability scores, neurofilament light chain dosages, motor unit counts, and sums of the sensory and motor amplitudes on electrodiagnostic tests. The MYD88L256P mutation was more frequent in MMN patients (12/35, 34%; odds ratio 28 [95% confidence interval 4-1262]; p < 0.001) and in CIDP patients (15/79, 19%; OR 13 [95% confidence interval 2-561]; p < 0.001) than in controls (1/57, 2%). Patients with the MYD88L256P mutation were more likely to have an IgM monoclonal gammopathy (13/27 vs. 8/87, p = 0.001). The MYD88L256P mutation remains more frequent in CIDP and MMN patients, even if patients with IgM monoclonal gammopathy were excluded. All the other characteristics were similar, especially the severity of the disease and the efficacy of intravenous immunoglobulins. The MYD88L256P mutation is frequent in CIDP and MMN patients, suggesting new pathophysiological hypotheses and new therapeutic approaches.
2024-07-17 | Steroid-responsive Multifocal Motor Neuropathy with Cranial Manifestations
The typical presentation of multifocal motor neuropathy (MMN) is progressive asymmetric limb weakness. Cranial neuropathy is rare. We report a 28-year-old woman with cranial and bulbar palsies but with typical electrophysiological features of MMN by multifocal motor conduction blocks and serological markers of anti-ganglioside GM1 antibodies. The previous consensus on the treatment of MMN is intravenous immunoglobulins, but our patient responded to oral steroids and had clinical and electrophysiological improvement under continuous low-dose prednisolone treatment. In summary, MMN is a treatable chronic inflammatory disease of peripheral nerves. Cranial neuropathies can be its initial presentation. Electromyography studies are crucial for MMN diagnosis and helpful in monitoring disease activity and treatment responses. Although the previous guideline did not suggest using steroids for MMN, with careful patient selection, low-dose oral steroids can be an effective treatment in patients with relatively minor symptoms.
2019-09-24 | Immune-mediated neuropathies.
Since the discovery of an acute monophasic paralysis, later coined Guillain-Barré syndrome, almost 100 years ago, and the discovery of chronic, steroid-responsive polyneuropathy 50 years ago, the spectrum of immune-mediated polyneuropathies has broadened, with various subtypes continuing to be identified, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In general, these disorders are speculated to be caused by autoimmunity to proteins located at the node of Ranvier or components of myelin of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. Owing to the numerous subtypes of the immune-mediated neuropathies, making the right diagnosis in daily clinical practice is complicated. Moreover, treating these disorders, particularly their chronic variants, such as CIDP and MMN, poses a challenge. In general, management of these disorders includes immunotherapies, such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the emergence of more disease-specific immunotherapies should broaden the therapeutic options for these disabling diseases.
proteins
2026-08-14 | Multifocal motor neuropathy: А literature review and case report
Multifocal motor neuropathy (MMN) is a rare immune-mediated disease of the peripheral nervous system manifesting as progressive asymmetric muscle weakness and motor conduction blocks. This article presents a clinical case of a patient with verified MMN in whom the use of rituximab was not accompanied by clinical improvement and was associated with further progression of paresis. Subsequent administration of intravenous immunoglobulin (IVIG) led to pronounced positive dynamics with an increase in muscle strength and a decrease in the severity of motor deficit. Introduction. MMN is a rare dysimmune neuropathy clinically characterized by asymmetric muscle weakness, atrophy, and fasciculations with absent or minimal sensory impairments. The most significant diagnostic signs include the detection of IgM antibodies to ganglioside GM1 and the registration of motor conduction blocks during electroneuromyographic examination. IVIG is considered the mainstay of pathogenetic therapy for MMN, while the efficacy of other immunomodulatory drugs, including rituximab, remains insufficiently defined. Materials and methods. We analyzed a clinical case of a female patient born in 1961 who was admitted with complaints of increasing weakness in the left hand, clumsiness during movements, and fasciculations in the muscles of the left upper limb. The diagnostic evaluation included a neurological examination, electroneuromyography, ultrasound examination of peripheral nerves and the brachial plexus, as well as magnetic resonance imaging. To clarify the nosological entity of the process, an analysis of the cerebrospinal fluid and a laboratory assessment of anti-GM1 antibodies were performed. Results. The examination revealed motor conduction blocks outside typical compression sites, as well as an elevated titer of anti-GM1 antibodies, which confirmed the diagnosis of MMN. The administration of rituximab, necessitated in part by organizational and economic limitations of therapy, did not lead to clinical stabilization. After transferring the patient to IVIG therapy, clear positive dynamics were noted in the form of reduced severity of paresis and increased muscle strength. Conclusion. The presented clinical observation emphasizes the importance of timely diagnosis of MMN and early initiation of pathogenetic therapy. In this case, the use of rituximab did not provide clinical stabilization, whereas IVIG demonstrated high therapeutic efficacy. Improving the availability of immunoglobulin therapy and physicians’ awareness of MMN is essential to prevent the progression of motor deficit and patient disability.
2026-07-28 | Discovery and engineering of novel IgM proteases for the treatment of autoimmune and inflammatory diseases 2253144
Abstract Introduction IgM is a multifunctional immunoglobin that acts as the first line of defense against systemic pathogens. IgM’s multimeric structure, together with its complement binding ability, makes IgM a highly potent inflammation driver. The presence of autoreactive IgM antibodies causing complement dependent damage has been described in inflammatory and autoimmune conditions such as Cold Agglutinin Disease (CAD) and Multifocal Motor Neuropathy (MMN) . For this reason, the development of IgM autoantibodies degrading therapy represents an attractive approach. Methods Employing Seismic’s IMPACT platform and evolutionary screening, we identified several novel and selective IgM proteases. Discovered proteases cleave soluble IgM in plasma and the IgM BCR in B cells from healthy individuals. Results CAD is an autoimmune hemolytic anemia, caused by IgM autoantibodies that bind to red blood cells (RBC), causing agglutination and activate complement cascade resulting in RBC death. Seismic’s IgM protease cleaves RBC bound IgM, preventing agglutination in whole blood from CAD donors, an unmet need not targeted by current approved treatment. In addition, IgM cleavage reduced cold-induced complement deposition on RBC from CAD patients. Conclusion Further engineering and optimization with our IMPACT Platform for the novel proteases is currently under way. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2026-07-11 | Intravenous immunoglobulin frequency in multifocal motor neuropathy: a retrospective study of nerve conduction outcomes.
In resource-limited rural settings, patients with multifocal motor neuropathy (MMN) often present late due to limited access to neurophysiology services, by which time significant axonal damage may have occurred, rendering them less responsive to immunotherapy-yet this clinically subgroup is consistently underrepresented in randomized controlled trials. In this study, we aimed to examined the impact of intravenous immunoglobulin (IVIg) frequency on electrophysiological changes in such undertreated MMN patients. A retrospective analysis was conducted across three rural medical centers. Patients receiving > 2 IVIg cycles annually were classified as group A, others as group B. Nerve conduction was assessed at baseline, after the first treatment course, and at the final follow-up. Thirty-nine MMN patients initially identified, 11 patients with confirmed conduction block (CB) were included. 27 nerves exhibited definite CB, with 7 (25.9%) in the median nerve, 8 (29.6%) in the ulnar nerve, and 6 (18.5%) in both the tibial and peroneal nerves. The treatment intervals was 4.9 ± 1.8 (range, 2.6 to 8.0) months, The follow-up period was 17.2 ± 3.3 months (range, 12.0 to 21.0). 7 (63.6%) were in group A, while 4 patients (36.4%) were in group B. There was a clear improvement in mRS scores at the last follow-up compared to baseline (z = -2.795, p = 0.007). We compared the variations in distal compound muscle action potential (CMAP) amplitude at baseline and the last follow-up, after adjusting for baseline CMAP amplitude, it showed significantly greater improvements in distal CMAP amplitude in group A versus group B (F = 40.217, P < 0.001; B = 2.881, 95% CI 1.941 ~ 3.821, P < 0.001), with the model accounting for 71.5% of the variance (adjusted R²= 0.715). The number of CBs decreased from 17 to 14 in group A, with no change in group B (p > 0.05). High frequency IVIg treatment may be associated with improved CMAP amplitude and mRS in undertreated MMN patients, suggesting potential benefits that require further validation.
2026-06-30 | Atypical Multifocal Motor Neuropathy Presenting With Isolated Spinal Accessory and Pectoral Nerve Involvement
Multifocal motor neuropathy (MMN) is a rare, immune-mediated disorder typically characterized by slowly progressive, asymmetric distal limb weakness. Cranial nerve involvement is distinctly uncommon, and isolated involvement of the spinal accessory nerve (CN XI) is exceedingly rare. We present the case of a 68-year-old male patient who presented with severe neck and shoulder wasting and a profound head drop. Despite the fact that standard conduction studies failed to demonstrate classic motor conduction blocks due to the highly proximal nature of the nerve involvement, a clinical diagnosis of MMN was suspected based on the asymmetric motor-only presentation, elevated Anti-GM1 antibodies, and steroid nonresponsiveness. The patient showed a robust and sustained functional recovery following treatment with intravenous immunoglobulin (IVIG), highlighting the importance of clinical judgment in atypical presentations of treatable neuropathies.
2026-03-01 | 4CPS-264 Analysis and 10 year comparison of intravenous immunoglobulins utilisation in a tertiary hospital: evaluation of clinical appropriateness and economic impact
Intravenous immunoglobulins (IVIg) are used across diverse clinical conditions, including primary and secondary immunodeficiencies, autoimmune, neurological, and haematological disorders. Despite expanding applications, approved (on-label) indications remain limited. Given its substantial cost and limited global supply, evaluating prescribing practices is essential to support evidence-based use and optimise healthcare resources. This study aimed to characterise IVIg utilisation in inpatient and outpatient settings at a tertiary hospital over one year (September 2024–September 2025) and compare findings with institutional data from 2014. Objectives included assessing adherence to approved indications, quantifying off-label and non-recommended use, and evaluating economic impact. A retrospective observational study was conducted using data from electronic health records and pharmacy information systems. Patient demographics, IVIg indications, and direct treatment costs were analysed. Indications were classified according to the British Clinical Guidelines for Immunoglobulin Use (3rd edition, 2021). Comparative analysis was performed against data from 2014. A total of 153 patients received IVIg during the study period (median age: 65 years; 50.9% female), with 40.3% managed as inpatients. On-label indications accounted for 72.5% of prescriptions, most commonly common variable immunodeficiency (48/153, 31.4%) and secondary immunodeficiency (26/153, 17.0%). Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, 16/153, 10.5%) and multifocal motor neuropathy (MMN,1/153, 0.7%) were newly classified as on-label. Evidence-supported off-label use represented 20.3%, with myasthenia gravis being the most common indication (13/153, 8.5%). While unsupported off-label and non-recommended indications accounted for 4.6% and 2.6%, respectively. Compared to 2014, the number of patients treated increased by 10.9%. On-label use improved (67.4% in 2014 vs. 72.5% in 2024), with reductions in non-recommended indications. Despite increased patient volume, IVIg expenditure declined from 1,730,002€ to 1,681,662€, reflecting enhanced cost-efficiency and prescribing behaviour. This analysis shows a positive trend toward more appropriate and economically sustainable IVIg use in comparison with 2014. The formal inclusion of CIDP and MMN as on-label indications, alongside enhanced guideline adherence and reduced unsupported use, reflects effective stewardship. Reduced expenditure despite increased utilisation underscores improved resource management, optimising healthcare expenditure. No conflict of interest
cell therapies
2008-08-01 | The clinical value of therapeutic plasma exchange in multifocal motor neuropathy
Objective Although there is evidence for a pathogenic role of humoral factors in multifocal motor neuropathy (MMN), plasma exchange (PE) is assumed to be an ineffective treatment. We set out to elucidate possible reasons for this apparent contradiction. Methods A retrospective analysis of seven patients with MMN, who underwent 4 to 18 sessions of PE. Clinical response, electrophysiological parameter and anti-ganglioside antibody titers were reviewed. Results Two patients, who had anti-ganglioside antibodies, exhibited transient clinical responses to PE, manifested by improved neurological function. Whereas electrophysiological parameters continued to worsen in all patients, anti-ganglioside antibody titers declined during PE, but increased after PE. Conclusion PE is of limited therapeutic value in patients with MMN, who do not respond to established treatment options. It may only be useful as an adjunctive treatment in a subset of patients. The transient decrease of anti-ganglioside-antibodies titers suggests that pathogenic humoral factors in MMN are only temporarily reduced. Further, PE treatment alone is insufficient to prevent axons from continuing degeneration, which may explain the failure of PE to substantially influence the disease course of patients with MMN.
antibodies
2026-07-29 | Revisiting multifocal motor neuropathy: mechanisms, diagnosis and future directions.
Multifocal Motor Neuropathy (MMN) is an immune-mediated, pure motor neuropathy characterized by slowly progressive, asymmetric limb weakness. It predominantly affects men in mid-adulthood and often presents with distal upper-limb weakness, such as wrist or finger drop. Although the disease course is typically chronic, slowly and sometimes stepwise progressive, timely recognition is critical, as early immunotherapy can prevent irreversible axonal loss and long-term disability. This review aims to provide a comprehensive and clinically integrated overview of MMN, spanning pathogenesis, clinical presentation, diagnostic challenges, and current and emerging therapeutic strategies. Emphasis is placed on translating mechanistic insights into practical diagnostic and treatment frameworks, and on identifying priorities for future research. Pathophysiologically, MMN is best understood as an antibody-mediated nodo-paranodopathy. IgM antibodies directed against GM1 gangliosides bind to GM1-enriched domains at the nodes of Ranvier, activate the classical complement cascade, and disrupt sodium channel clustering and axo-glial integrity. The resulting conduction block constitutes the electrophysiological hallmark of the disease and may initially be reversible. Persistent immune-mediated injury, however, can lead to secondary axonal degeneration and fixed disability. While GM1 IgM antibodies are detected in a substantial proportion of patients, seronegativity does not exclude MMN, potentially reflecting mechanistic heterogeneity and/or assay limitations. Diagnosis relies on the combination of a characteristic clinical phenotype and electrophysiological evidence of motor conduction block with preserved sensory conduction. However, conduction block can be difficult to demonstrate because of proximal lesions, temporal dispersion, or superimposed axonal loss, contributing to diagnostic uncertainty. High-resolution nerve ultrasound and magnetic resonance neurography offer valuable complementary information by revealing focal nerve enlargement or plexus abnormalities, though neither technique is independently diagnostic. Intravenous immunoglobulin (IVIg) remains the established standard of care and the only approved therapy, producing rapid but often transient improvement that necessitates individualized maintenance regimens. Subcutaneous immunoglobulin provides an effective long-term alternative for many patients. Conventional immunosuppressants have shown limited efficacy, whereas emerging complement inhibitors targeting upstream components of the classical pathway represent a promising, mechanism-based strategy currently under clinical evaluation. Despite advances, significant gaps remain. Reliable biomarkers to predict treatment response, monitor disease activity, and detect early axonal injury are lacking. Future progress will require integrated translational models, harmonized outcome measures, and well-designed clinical trials to move toward more durable and personalized therapeutic approaches in MMN.
2026-06-08 | Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.
Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.
2026-02-17 | Plasma neurofilament light chain is associated with clinical instability in chronic autoimmune neuropathies.
Neurofilament light chain (NfL) is a sensitive biomarker of axonal damage, but its clinical relevance in chronic autoimmune neuropathies remains incompletely defined. This study evaluated plasma NfL levels in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), compared with hereditary neuropathy (Charcot–Marie–Tooth disease type 1 A, CMT1A) and healthy controls, focusing on disease activity rather than diagnostic discrimination. Plasma NfL concentrations were measured using single molecule array (Simoa) technology in 41 patients (CIDP n = 16, MMN n = 7, CMT1A n = 18) and 25 age- and sex-matched controls. Disease severity was assessed using the Inflammatory Rasch-built Overall Disability Scale for autoimmune neuropathies and the Charcot–Marie–Tooth Neuropathy Score version 2 for CMT. Plasma NfL levels were significantly higher in patients with autoimmune neuropathies and CMT compared with controls. No significant differences were observed between inflammatory and hereditary neuropathies, and NfL levels did not correlate with disability scores. However, patients with autoimmune neuropathies and an unstable disease course, defined by more than two relapses, exhibited significantly higher plasma NfL levels. Across all groups, NfL concentrations showed a strong correlation with age. These findings suggest that while plasma NfL lacks diagnostic specificity among chronic neuropathies, it may be associated with disease instability in autoimmune neuropathies.
2026-02-09 | Successful Treatment of Multifocal Demyelinating Sensory-Motor Neuropathy (Lewis-Sumner Syndrome) With Rituximab: A Case Report.
BACKGROUND Multifocal acquired demyelinating sensory-motor neuropathy (MADSAM) is recognized as a variant of chronic inflammatory demyelinating polyneuropathy. The primary characteristics of MADSAM include multifocal sensory loss and muscle weakness, which are frequently asymmetrical and predominantly affect the upper limbs. Involvement of the lower limbs is less commonly observed in MADSAM. CASE REPORT A 27-year-old female patient presented with recurrent numbness and weakness in her left lower limb was admitted to our hospital. Her medical history included episodes of left peripheral facial paralysis and lower-limb numbness and weakness, which had previously improved after short-term oral steroid therapy. In addition to motor and sensory peripheral nerve impairment in the left lower limb, the neurological examination revealed atrophy of the tongue muscle and a leftward deviation of the tongue. Cerebrospinal fluid examination and magnetic resonance imaging indicated no abnormalities. Electromyography suggested demyelination of motor and sensory nerves in the left lower limb. Sural nerve biopsy demonstrated demyelination changes and axonal degeneration. A diagnosis of multifocal sensory and motor neuropathy was considered, and the patient was administered corticosteroids and tacrolimus. As the condition progressed, electromyography showed gradual involvement of both lower limbs, leading to the consideration of MADSAM. Despite treatment with corticosteroids and tacrolimus, the patient experienced relapse. Rituximab was initiated, resulting in symptoms improvement and reduced recurrence without adverse events. CONCLUSIONS Corticosteroids, plasma exchange, and immunoglobulins have been demonstrated to be effective treatments for CIDP. In our MADSAM case, rituximab proved effective when the patient did not respond to corticosteroids and tacrolimus. We propose that rituximab may serve as an alternative option for patients with MADSAM.
2026-01-28 | Blood-Nerve Barrier Breakdown Induced by Immunoglobulin G in Typical and Multifocal Chronic Inflammatory Demyelinating Polyneuropathy and Multifocal Motor Neuropathy.
Impairment of the blood-nerve barrier (BNB) is associated with the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). This research analyzes the molecular mechanisms of immunoglobulin (Ig) G in patients with typical CIDP, CIDP variants (multifocal CIDP), and multifocal motor neuropathy in BNB-endothelial cells. IgG was purified from the sera of patients with typical CIDP (n = 15), multifocal CIDP (n = 14), multifocal motor neuropathy (MMN; n = 12), and healthy controls (HCs; n = 14). Molecular changes in the RNA-seq/high-content imaging system and permeability were evaluated after the incubation of human peripheral nerve microvascular endothelial cells (PnMECs) with IgG. RNA-seq and a pathway analysis using PnMECs showed that TNF-α, CCL20 (MIP-3α), and ICAM-1 were the centers of the upregulated gene pathways in patients with typical CIDP. TNF-α, VCAM-1, NF-κB, and CSF2 (GM-CSF) are important molecules in patients with multifocal CIDP. The high-content imaging system demonstrated that MIP-3, GM-CSF, and VCAM-1 increased after exposure to typical CIDP-IgG, claudin-5 decreased after exposure to IgG from patients with multifocal CIDP, and TNF-α and VCAM-1 increased after exposure to IgG from patients with MMN. The 10 kDa dextran permeability using coculture with PnMECs and pericytes increased after exposure to IgG from patients with typical CIDP and multifocal CIDP. This effect was reversed after incubation with GM-CSF neutralizing antibodies. Upregulation of MIP-3, GM-CSF, and VCAM-1 may contribute to the infiltration of leukocytes/lymphocytes/monocytes across the BNB into the PNS in typical CIDP. IgG from typical CIDP and multifocal CIDP may decrease barrier properties through autocrine GM-CSF from PnMECs. VCAM-1 upregulation through autocrine TNF secretion in PnMECs may induce lymphocyte entry across the BNB in MMN.
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Drug Discovery Landscape
3 orphan drug designations for Multifocal motor neuropathy, including 1 approved therapy.
3 orphan drug designations for Multifocal motor neuropathy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Empasiprubart | antibodies | EMA | 2025-06-20 | — | Argenx |
empasiprubart | antibodies | FDA | 2024-06-05 | — | argenx BV |
immune globulin infusion (human) [Gammagard Liquid] | antibodies | FDA | 2006-07-20 | 2012-06-22 | Takeda Pharmaceuticals U.S.A., Inc. |
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