OBJECTIVE:To analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN). METHODS:Patients with anti-CNTN1+ autoimmune nodopathy detected in our laboratory from which clinical information was available were included. Clinical features and treatment response were retrospectively collected. Autoantibody, serum neurofilament light chain (sNfL), and serum CNTN1 levels (sCNTN1) were analyzed at baseline and follow up. RESULTS:A total of 31 patients were included. Patients presented with progressive sensory motor neuropathy (76.7%) with proximal (74.2%) and distal involvement (87.1%), ataxia (71.4%), and severe disability (median INCAT at nadir of 8). A total of 11 patients (35%) showed kidney involvement. Most patients (97%) received intravenous immunoglobulin, but only 1 achieved remission with intravenous immunoglobulin. A total of 22 patients (71%) received corticosteroids, and 3 of them (14%) did not need further treatments. Rituximab was effective in 21 of 22 patients (95.5%), with most of them (72%) receiving a single course. Four patients (12.9%) relapsed after a median follow up of 25 months after effective treatment (12-48 months). Anti-CNTN1 titers correlated with clinical scales at sampling and were negative after treatment in all patients, but 1 (20/21). sNfL levels were significantly higher and sCNTN1 significantly lower in anti-CNTN1+ patients than in healthy controls (sNfL: 135.9 pg/ml vs 7.48 pg/ml, sCNTN1: 25.03 pg/ml vs 22,186 pg/ml, p < 0.0001). Both sNfL and sCNTN1 returned to normal levels after successful treatment. INTERPRETATION:Patients with anti-CNTN1+ autoimmune nodopathy have a characteristic clinical profile. Clinical and immunological relapses are infrequent after successful treatment, suggesting that continuous treatment is unnecessary. Anti-CNTN1 antibodies, sNfL, and sCNTN1 levels are useful to monitor disease status in these patients. ANN NEUROL 2025;97:529-541.

ABSTRACTOBJECTIVETo perform a nationwide epidemiological study of Guillain-Barré syndrome (GBS) in Spain, analysing background incidences and seasonal variation and trying to identify incidence changes during the COVID-19 years.METHODSObservational study collecting all GBS diagnoses from National Epidemiological Surveillance Network (RENAVE) collected by the Ministry of Health. Patients discharged with GBS as main diagnosis and admitted during 2018-2021 were included. Data on the incidence of SARS-CoV-2 infections and vaccinations were obtained from the National Epidemiology Centre.RESULTSIn total, 3147 cases were included, 832 in 2018, 861 in 2019, 670 in 2020 and 784 in 2021. Nationwide hospital incidence was 1.78 in 2018, 1.71 in 2019, 1.41 in 2020 and 1.66 in 2021, with an increased frequency in males, elderly population, and in the winter season. Eleven percent of GBS patients needed ventilatory support. GBS and SARS-CoV-2 incidences did not correlate with one another (r=-0.29, p=0.36). GBS incidence decreased during 2020 and during COVID-19 lockdown period in comparison to the same months of 2018-2019. No relationship was found between vaccines and GBS cases during vaccination roll-out in 2021.INTERPRETATIONIncidence of GBS in Spain is similar to that of other countries. Despite prior reports describing a significant increase in COVID-19-associated GBS in Spain, we detected a significant drop of GBS incidence during the SARS-CoV-2 pandemic, probably due to prevention measures. No relationship was found between SARS-CoV-2 or vaccinations and GBS incidences at the population level but data on relationship of vaccinations and GBS at the individual level were not available.

AbstractThe clinical status and treatment response of patients with peripheral neuropathies (PN) rely on subjective and inaccurate clinical scales. Wearable sensors have shown success in evaluating gait and balance in individuals with other neurological disorders. We aimed to explore the ability of biomechanical analysis via wearable technology to monitor disease activity in PN by conducting a single-center, longitudinal study to analyze gait parameters in PN patients and healthy controls using wearable sensors. First, we analyzed the sensor’s ability to detect changes in ataxia and steppage gait severity and found significant differences in spatiotemporal and angular variables. Second, we found correlations between biomechanical features and clinical scales linked to specific gait phenotypes. Finally, we demonstrated that this technology captures clinical changes in gait features over time. Our study provides proof-of-concept that wearable technology effectively detects and grades gait impairment, captures clinically relevant changes, and could enhance gait assessment in routine care and research for PN patients.

BACKGROUND AND OBJECTIVES:Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).METHODS:A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples.RESULTS:Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies.DISCUSSION:Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Background Intravenous immunoglobulin (IVIG) and rituximab are considered the first-line and second-line treatments for Chronic Ataxic Neuropathy and Ophthalmoplegia with IgM-paraprotein, cold Agglutinins, and anti-Disialosyl antibodies (CANOMAD), with an overall clinical response around 50%. New anti-CD38 daratumumab, targeting long-lived plasma cells, has been reported as a promising therapy for treatment-refractory antibody-mediated disorders. We report the first case of a severe refractory CANOMAD, successfully treated with daratumumab.Methods A patient in their 70s with severe relapsing CANOMAD, refractory to IVIG, steroids, rituximab and ibrutinib developed severe tetraparesis and respiratory failure. Plasma exchange (PE) improved motor and ventilatory function; however, after 6 weeks, patient remained PE dependent. Intravenous daratumumab was initiated at 16 mg/kg weekly for 3 weeks, every 2 weeks for the second and third month, and monthly afterwards.Results After 3 weeks of starting daratumumab, PE was discontinued and, since then, the patient evolved to complete recovery. Antidisialosyl antibody titres decreased after PE and remained stable during daratumumab. Serum neurofilament light-chain levels were elevated in the exacerbation phase and normalised after daratumumab. The patient remains in clinical remission under monthly daratumumab, 12 months after initiation.Conclusions The first patient with aggressive treatment-refractory CANOMAD treated with daratumumab provides proof-of-principle evidence that daratumumab may be an effective treatment in IgM-related neuropathies.

BACKGROUND:The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS:Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS:We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS:Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum (n = 252) and CSF (n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis.

BACKGROUND AND OBJECTIVE:In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens.METHODS:This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens.RESULTS:Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred.DISCUSSION:In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Objective: To examine the role of B cell tolerance dysfunction in the immunopathology of anti-neurofascin 155 (NF-155) autoantibody-mediated chronic inflammatory demyelinating polyneuropathy (CIDP). Background: Autoantibodies against paranodal protein NF-155 are present in 5% of patients fulfilling CIDP diagnostic criteria. These patients have distinct clinical phenotypes and usually respond to B cell depletion therapy. However, the underlying B cell dysfunction driving the pathomechanism of NF-155-mediated CIDP remains unknown. In this study, we examined B cell tolerance dysfunction in patients with NF-155-mediated CIDP, which can lead to aberrant autoantibody production, and has been implicated in myasthenia gravis, neuromyelitis optica, and other autoimmune diseases. Design/Methods: Using a well-established approach, we generated recombinant monoclonal antibodies from single B cells from the new emigrant (NE) and mature naïve (MN) compartments from patients with NF-155-mediated CIDP. The frequency of polyreactive NE B-cell clones was measured by ELISA against dsDNA, insulin, and lipopolysaccharide, to assess the central B cell tolerance checkpoint defect. Similarly, the frequency of HEp-2 cell lysate-specific autoreactive MN B-cell clones was measured to identify a peripheral B cell tolerance checkpoint defect. Results: A total of 74 and 30 unique clones of monoclonal antibodies were generated from the NE and MN B cells of 3 patients with NF-155-mediated CIDP, respectively, and 47% (± 36.2%) clones from the NE B cells and 32.3% (± 13.2%) clones from the MN B cells were polyreactive, compared to expected 5–11% polyreactivity from healthy controls. Assessment of the peripheral tolerance checkpoint defect and phenotyping of the NE and MN B cells at the single-cell level by simultaneously profiling gene expression and full-length paired B-cell receptors is ongoing. Conclusions: This preliminary analysis suggests that CIDP associated with NF-155 may have early checkpoint tolerance defects. Further studies are warranted to understand the implication of such B cell dysfunction in the disease immunopathology. Disclosure: Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Roy has stock in Cabaletta bio. . The institution of Dr. Roy has received research support from Martin Shubik Fund for IBM at Yale University. Ms. Obaid has nothing to disclose. Ms. Ohashi has nothing to disclose. Mrs. Coppola has nothing to disclose. Mr. Das has nothing to disclose. Amanda Hernandez has nothing to disclose. Dr. Masi has nothing to disclose. Mrs. Martín-Aguilar has nothing to disclose. Dr. Lleixa has nothing to disclose. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Momenta . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cabaletta Bio . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viela Bio. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cour Pharma. The institution of Dr. Nowak has received research support from Ra Pharma. The institution of Dr. Nowak has received research support from Alexion . The institution of Dr. Nowak has received research support from Momenta . The institution of Dr. Nowak has received research support from Immunovant . Dr. Nowak has received research support from argenx. Dr. Nowak has received research support from Viela Bio . Dr. Nowak has a non-compensated relationship as a Member of the Board of Directors with Myasthenia Gravis Foundation of America (MGFA) that is relevant to AAN interests or activities. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CSL Behring. The institution of Dr. Querol has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. The institution of Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson & Johnson. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ArgenX. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Grifols. The institution of Dr. Querol has received research support from GBS-CIDP Foundation International. The institution of Dr. Querol has received research support from Grifols. The institution of Dr. Querol has received research support from ISCIII. The institution of Dr. Querol has received research support from CIBERER. The institution of Dr. Querol has received research support from UCB. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Viela Bio. Kevin O'Connor has received stock or an ownership interest from Cabaletta.

To assess the performance of neurofilament light chain (NfL) testing in anti-NMDAR encephalitis (NMDARe) and its differential diagnosis.