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Background: Septins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination., Methods: Sera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression., Results: Immunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies' specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient., Conclusions: Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins., (© 2023. The Author(s).)

Background: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD., Methods: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%))., Results: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001)., Conclusions: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression., Competing Interests: Competing interests: MG has received honoraria as a speaker and for the partecipation to Advisory boards from Roche, UCB and Alexion., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p < 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Idiopathic normal pressure hydrocephalus (iNPH) is a common neurological disorder with unknown etiology. A selective depletion of aquaporin 4 (AQP4) has been shown in iNPH patients. We collected serum and cerebrospinal fluid (CSF) from 43 iNPH patients and 35 with other neurodegenerative conditions, and serum from 43 healthy subjects. All samples were tested for AQP4-IgG/IgA/IgM antibodies using a live cell-based assay. No patients or controls had serum/CSF AQP4-IgG/IgA. One/43 iNPH patient and 0/43 controls tested positive for serum AQP4-IgM. The AQP4-IgM-positive iNPH patient had no clinico-radiological distinctive features. AQP4 antibodies are unlikely to play a role in iNPH pathogenesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection., Methods: Consecutive sera from 204 patients with 'possible MOGAD' (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgG H+L ), and a live-CBA for IgG 1 (LCBA-IgG 1 ). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgG Fcγ ), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgG Fcγ ) . RESULTS: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8-95.9) and specificity 93.3% (CI:88.0-96.7) for LCBA-IgG H+L , and 74.6% (CI:61.0-85.3) and 100% (CI:97.6-100) for LCBA-IgG 1 . Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG 1 ); of these, three with 'possible MOGAD' showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG 2 , whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 'possible MOGAD', 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1-98.4) and specificity 97.0% (CI:83.8-99.9) for LCBA-IgG Fcγ , and 87.2% (CI:72.6-95.7) and 97.0% (CI:83.8-99.9) for FCBA-IgG Fcγ ., Conclusions: LCBA-IgG 1 showed the highest specificity but can miss MOG-IgG 2 reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgG H+L / IgG Fcγ is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgG Fcγ yielded the highest accuracy, and FCBA-IgG Fcγ good specificity, but it was at risk of false-negative results.

Background: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD)., Objective: To describe systematically the CSF profile in children with MOG-EM., Material and Methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively., Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age., Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Background: New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD)., Objective: To describe systematically the CSF profile in MOG-EM., Material and Methods: Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively., Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood-CSF barrier dysfunction was present also during remission in a substantial number of patients., Conclusion: MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD)., Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model)., Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19 + B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses., Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Therapy of autoimmune diseases of the central and peripheral nervous system with intravenous IgG immunoglobulin (IVIg) is well established. Since IVIg is produced from pooled human plasma, autoantibodies can be found in IVIg products and, accordingly, in patient sera after transfusion. The de novo evidence or disappearance of anti-neural autoantibodies after IVIg treatment has so far not been systematically examined., Methods: We screened 50 neurological patients before and after IVIg treatment for classical onconeural and the most common neurological surface autoantibodies as well as for ganglioside autoantibodies and 23 different antinuclear autoantibodies using immunoblot or cell-based indirect immunofluorescence assays. Furthermore, we screened 31 neurological patients with previously known seropositivity for disappearance of the corresponding antibody after treatment., Results: After IVIg treatment, 90% of all sera were de novo positive for antinuclear antibodies, especially for Ro-52. In contrast, 94% of all sera did not show any de novo-positive anti-neural antibodies. In the remaining three cases, titers were very low. Importantly, 12.9% of all tested sera of patients with known antibody positivity turned false negative after IVIg treatment and titers were falsely low in 37% of the remaining sera., Conclusions: Here, we present for the first time results of a broad screening for clinically relevant autoantibodies before and after IVIg treatment in neurological patients. We identified a high specificity but reduced sensitivity for anti-neural antibody testing after IVIg transfusion. In contrast, antinuclear antibody testing is not reliable after IVIg treatment. These results are of high practical importance for diagnostic of neuroimmunological diseases.

Background: Serum antibodies against myelin-oligodendrocyte-glycoprotein (MOG-IgG) are detectable in a proportion of patients with acute or relapsing neuroinflammation. It is unclear, if neuro-axonal damage occurs only in an attack-dependent manner or also progressively. Therefore, this study aimed to investigate longitudinally intra-retinal layer changes in eyes without new optic neuritis (ON) in MOG-IgG-seropositive patients., Methods: We included 38 eyes of 24 patients without ON during follow-up (F/U) [median years (IQR)] 1.9 (1.0-2.2) and 56 eyes of 28 age- and sex-matched healthy controls (HC). The patient group's eyes included 18 eyes without (Eye ON- ) and 20 eyes with history of ON (Eye ON+ ). Using spectral domain optical coherence tomography (OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIP), inner nuclear layer (INL), and macular volume (MV). High-contrast visual acuity (VA) was assessed at baseline., Results: At baseline in Eye ON- , pRNFL (94.3 ± 15.9 μm, p = 0.36), INL (0.26 ± 0.03 mm 3 , p = 0.11), and MV (2.34 ± 0.11 mm 3 , p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm 3 ; p = 0.008), and VA was reduced (logMAR 0.05 ± 0.15 vs. - 0.09 ± 0.14, p = 0.008) in comparison to HC. Longitudinally, we observed pRNFL thinning in models including all patient eyes (annual reduction - 2.20 ± 4.29 μm vs. - 0.35 ± 1.17 μm, p = 0.009) in comparison to HC. Twelve Eye ON- with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 Eye ON- without other clinical relapses., Conclusions: We observed pRNFL thinning in patients with MOG-IgG during F/U, which was not accompanied by progressive GCIP reduction. This effect could be caused by a small number of Eye ON- with other than ipsilateral ON attacks within 6 months before baseline. One possible interpretation could be a reduction of the swelling, which could mean that MOG-IgG patients show immune-related swelling in the CNS also outside of an attack's target area.

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Co-existence of NMOSD with systemic lupus erythematosus (SLE) putatively suggests susceptibility to antibody-mediated autoimmune disease., Objective: To estimate the prevalence of NMOSD in SLE and investigate the immunogenetic background for an association of NMOSD and SLE., Methods: The study included a predominantly population-based cohort with clinical and serological investigations of 208 patients with SLE, followed prospectively since 1995. All patients received immunosuppressive treatment. NMOSD was evaluated retrospectively based on the 2015 International Panel for NMOSD Diagnosis (IPND) criteria. Polymorphisms in programmed cell death protein 1 (PDCD-1) PD-1.3 G/A were genotyped. AGP4-IgG and other autoantibodies, including myelin oligodendrocyte glycoprotein (MOG), was determined blinded to clinical diagnosis., Results: Of 208 patients with SLE, 45(22%) had neuropsychiatric (NP) SLE, and CNS involvement predominated in 30 of 45 (67%) patients. Serum AQP4-IgG was detected in 2 of 30 (6.7%) neuropsychiatric SLE (NPSLE) patients both of whom had myelitis and antiphospholipid syndrome; one patient also had myasthenia gravis. None had MOG-IgG. PD-1.3A allele was not associated with SLE nor with NPSLE., Conclusion: AQP4-IgG autoimmune syndrome may rarely co-exist with SLE, and such patients have other NMOSD-typical syndromes such as myelitis.

Objective: To study the prevalence of autoantibodies to synapsin in patients with psychiatric and neurological disorders and to describe clinical findings in synapsin antibody positive patients., Methods: Sera of 375 patients with different psychiatric and neurological disorders and sera of 97 healthy controls were screened (dilution 1:320) for anti-synapsin IgG using HEK293 cells transfected with rat synapsin Ia. Positive sera were further analyzed by immunoblots with brain tissue from wild type and synapsin knock out mice and with HEK293 cells transfected with human synapsin Ia and Ib. Binding of synapsin IgG positive sera to primary neurons was studied using murine hippocampal neurons., Results: IgG in serum from 23 (6.1%) of 375 patients, but from none of the 97 healthy controls (p=0.007), bound to rat synapsin Ia transfected cells with a median (range) titer of 1:1000 (1:320-1:100,000). Twelve of the 23 positive sera reacted with a protein of the molecular size of synapsin I in immunoblots of wild type but not of synapsin knock out mouse brain tissue. Out of 19/23 positive sera available for testing, 13 bound to human synapsin Ia and 16 to human synapsin Ib transfected cells. Synapsin IgG positive sera stained fixed and permeabilized murine hippocampal neurons. Synapsin IgG positive patients had various psychiatric and neurological disorders. Tumors were documented in 2 patients (melanoma, small cell lung carcinoma); concomitant anti-neuronal or other autoantibodies were present in 8 patients., Conclusions: Autoantibodies to human synapsin Ia and Ib are detectable in a proportion of sera from patients with different psychiatric and neurological disorders, warranting further investigation into the potential pathophysiological relevance of these antibodies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder of the central nervous system. NMO and its abortive forms are referred to as NMO spectrum disorders (NMOSD). NMOSD are mostly associated with antibodies to aquaporin-4 (AQP4-IgG). However, recent studies have demonstrated antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in a subset of patients. Data on NMOSD in North Africa are sparse., Objective: To describe the frequency of MOG-IgG and AQP4-IgG among patients with optic neuritis (ON) and/or myelitis in Algeria as well as the clinical and paraclinical features associated with these antibodies., Methods: Retrospective testing of 42 patients with optic neuritis and/or myelitis treated at the teaching hospital of TiziOuzou for MOG-IgG and AQP4-IgG, and retrospective evaluation of the patients' medical records., Results: Six of 42 (14.3%) patients were positive for AQP4-IgG and 3/42 (7.1%) were positive for MOG-IgG. No patient was positive for both AQP4-IgG and MOG-IgG. All antibody-positive patients were women. MOG-IgG was associated with severe episodes of ON in all MOG-IgG-positive patients. Steroid treatment was followed by complete remission in two patients. AQP4-IgG was associated with ON and/or longitudinally extensive transverse myelitis (LETM), often with severe onset. While all six of the AQP4-IgG-positive patients met the 2015 IPND criteria for NMOSD, only one of the three MOG-IgG-positive patients did so. Interestingly, clinically silent extensive spinal cord or brain lesions were present in two of the three MOG-IgG-positive patients, and altered visual evoked potentials without clinical evidence of ON were found in three of the six AQP4-IgG-positive patients., Conclusion: MOG-IgG and AQP4-IgG are found in a substantial subset of Algerian patients with ON and/or myelitis, are present predominantly in women, and may be associated with differences in clinical presentation and, possibly, outcome. Only a subset of MOG-IgG positive patients meets the current diagnostic criteria for NMOSD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In 2010, a novel anti-neuronal autoantibody, termed anti-Ca, was described in a patient with subacute cerebellar ataxia, and Rho GTPase-activating protein 26 (ARHGAP26) was identified as the target antigen. Recently, three additional cases of anti-Ca-positive cerebellar ataxia have been published. In addition to ataxia, cognitive decline and depression have been observed in some patients. Here, we report two new cases of anti-Ca-associated autoimmune cerebellar ataxia. Patient 1 presented with dizziness and acute yet mild limb and gait ataxia. Symptoms stabilized with long-term oral corticosteroid therapy but transiently worsened when steroids were tapered. Interestingly, both initial occurrence and worsening of the patient's neurological symptoms after steroid withdrawal were accompanied by spontaneous cutaneous hematomas. Patient 2 initially presented with an increased startle response and myoclonic jerks, and subsequently developed severe limb and gait ataxia, dysarthria, oculomotor disturbances, head and voice tremor, dysphagia, cognitive symptoms and depression. Steroid treatment was started five years after disease onset. The symptoms then responded only poorly to corticosteroids. At most recent follow-up, 19 years after disease onset, the patient was wheelchair-bound. These cases extend the clinical spectrum associated with anti-ARHGAP26 autoimmunity and suggest that early treatment may be important in patients with this rare syndrome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1-expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology., Methods: Serological and other immunological studies, and retrospective analysis of patient records., Results: The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barré syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A 3 H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization., Conclusions: Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases.

Background: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies., Objective: To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-d-aspartate-type glutamate receptors (NMDAR) and 25 other anti-neural antibodies in pattern II MS., Methods: Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients (n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABA B R), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase-related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2)., Results: Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown., Conclusion: This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS., (© The Author(s), 2016.)

Background: A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG)., Objective: To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes., Methods: Retrospective multicenter study., Results: The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases., Conclusion: Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Background: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders., Objective: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers., Methods: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells., Results: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment., Conclusions: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.

Objective: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD)., Methods: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1)., Results: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples., Conclusions: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.

Background: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed., Objectives: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS., Patients and Methods: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections., Results: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed., Conclusions: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.

Neuromyelitis optica (NMO, Devic's syndrome) is a clinical syndrome characterized by optic neuritis and (mostly longitudinally extensive) myelitis. If untreated, NMO usually takes a relapsing course and often results in blindness and tetra- or paraparesis. The discovery of autoantibodies to aquaporin-4, the most abundant water channel in the CNS, in 70-80% of patients with NMO (termed NMO-IgG or AQP4-Ab) and subsequent investigations into the pathogenic impact of this new reactivity have led to the recognition of NMO as an autoimmune condition and as a disease entity in its own right, distinct from classic multiple sclerosis. Here, we comprehensively review the current knowledge on the role of NMO-IgG/AQP4-Ab, B cells, T cells, and the innate immune system in the pathogenesis of NMO., (© 2014 Elsevier Inc. All rights reserved.)

Here we report on a case of contactin-associated protein-2 (Caspr2) antibody positive but voltage gated potassium channel (VGKC) antibody negative limbic encephalitis associated with cerebellar ataxia, myoclonus and dyskinesias with favorable response to immunotherapy. This case underlines the importance of Caspr2-specific antibody testing and demonstrates that Caspr2 antibodies are associated with a broader clinical spectrum than hitherto described., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Recently, we discovered a novel serum and cerebrospinal fluid (CSF) autoantibody (anti-Ca) to Purkinje cells in a patient with autoimmune cerebellar ataxia (ACA) and identified the RhoGTPase-activating protein 26 (ARHGAP26; alternative designations include GTPase regulator associated with focal adhesion kinase pp125, GRAF, and oligophrenin-1-like protein, OPHN1L) as the target antigen. Here, we report on two new cases of ARHGAP26 autoantibody-positive ACA that were first diagnosed after publication of the index case study. While the index patient developed ACA following an episode of respiratory infection with still no evidence for malignancy 52 months after onset, neurological symptoms heralded ovarian cancer in one of the patients described here. Our finding of anti-Ca/anti-ARHGAP26 antibodies in two additional patients supports a role of autoimmunity against ARHGAP26 in the pathogenesis of ACA. Moreover, the finding of ovarian cancer in one of our patients suggests that anti-Ca/anti-ARHGAP26-positive ACA might be of paraneoplastic aetiology in some cases. In conclusion, testing for anti-Ca/anti-ARHGAP26 should be included in the diagnostic work-up of patients with ACA, and an underlying tumour should be considered in patients presenting with anti-Ca/ARHGAP26 antibody-positive ACA.

Introduction: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases., Objective: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD., Patients and Methods: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting., Results: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups., Conclusions: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.

Background: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved., Results: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels., Conclusions: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Anti-Ma2/Ta antibodies are rare paraneoplastic antibodies, which are mostly associated with limbic encephalitis in male patients with testicular cancer. We report on a 50-year-old woman with a pure progressive spastic paraparesis. Next, she was diagnosed as having a Sjögren syndrome, with serological positivity for anti-SS-Ro antibodies. The patient's serum and cerebrospinal fluid samples were positive for anti-Ma2/Ta antibodies, which were also proved to be intrathecally produced. These findings, and the coexistence of systemic autoimmunity, led us to treat the patient with corticosteroids first, and then with plasma exchange. Neurological symptoms scarcely responded to both the therapies. The search for cancer was negative up to 4 years after the disease onset. Our case expands the spectrum of clinical syndromes associated with anti-Ma2/Ta antibodies.

Background: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation., Objectives: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms., Methods: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) (n = 54), possible CTD (n = 42), or vasculitis (n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4., Results: AQP4-Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON (n = 69)., Conclusion: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients.

Neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting the optic nerves and spinal cord. Recent findings showed an underlying humoral abnormality in NMO, characterized by a serum antibody against aquaporin-4 (Aqp-4-Ab). In this study, we evaluated the Aqp-4-Ab status among Turkish patients with NMO to determine the clinical and prognostic relevance. Serum samples from 35 consecutive patients with NMO followed at a single center and diagnosed according to the 2006 revised criteria, were evaluated for Aqp-4-Ab. All samples were obtained during a relapse prior to any immunosuppressive treatment. Aqp-4-Ab was positive in 21/35 (60%) patients. Among these cases, 11 had an EDSS of 6.0 or more, whereas only two patients in the seronegative group had such severe disability (p < 0.05). Overall, seropositive cases had a mean EDSS score of 5.1 ± 2.2 compared with 3.5 ± 1.7 in seronegative cases (p < 0.01). There were trends towards female predominance in seropositive cases and a monophasic course predominance in seronegative cases. Disease duration, age at onset, number of attacks and time to definite NMO did not differ between groups. Our findings in this single-center cohort suggest that the presence of Aqp-4-Ab might have a prognostic significance indicating a more severe disease course.

Background: In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum auto-antibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG). Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO., Objective: To assess the frequency, syndrome specificity, diagnostic relevance, and origin of cerebrospinal fluid (CSF) AQP4-Ab in patients with NMO spectrum disorders (NMOSD)., Methods: 87 CSF samples from 37 patients with NMOSD and 42 controls with other neurological diseases were tested for AQP4-Ab in a cell based assay using recombinant human AQP4. Twenty-three paired CSF and serum samples from AQP4-Ab seropositive NMOSD patients were further analysed for intrathecal IgG synthesis to AQP4., Results: AQP4-Ab were detectable in 68% of CSF samples from AQP4-Ab seropositive patients with NMOSD, but in none of the CSF samples from AQP4-Ab seronegative patients with NMOSD and in none of the control samples. Acute disease relapse within 30 days prior to lumbar puncture, AQP4-Ab serum titres >1:250, and blood-CSF barrier dysfunction, but not treatment status, predicted CSF AQP4-Ab positivity. A positive AQP4-specific antibody index was present in 1/23 samples analysed., Conclusions: AQP4-Ab are detectable in the CSF of most patients with NMOSD, mainly during relapse, and are highly specific for this condition. In the cohort analysed in this study, testing for CSF AQP4-Ab did not improve the sensitivity and specificity of the current diagnostic criteria for NMO. The substantial lack of intrathecal AQP4-Ab synthesis in patients with NMOSD may reflect the unique localisation of the target antigen at the blood brain barrier, and is important for our understanding of the immunopathogenesis of the disease.

Background: Neuromyelitis optica (NMO, Devic syndrome) is an inflammatory disorder of the central nervous system of putative autoimmune etiology that primarily affects the optic nerves and spinal cord. NMO is frequently associated with immunoglobulin G (IgG) antibodies to aquaporin-4 (AQP4-IgG), which are thought to be involved in the patho-genesis of the disease. The frequency and diagnostic relevance of immunoglobulin M (IgM) antibodies to aquaporin-4 (AQP4-IgM) in patients with NMO is essentially not known. Testing for AQP4-IgM may be of importance since 20%-30% of patients with NMO are negative for AQP4-IgG. Moreover, IgM antibodies are more potent activators of complement compared with IgG, and are detectable at NMO lesional sites., Methods: Serum samples from 42 patients with NMO spectrum disorders (NMOSD) and from 66 controls were tested for IgM AQP4-Ab using a cell-based assay employing HEK293 cells transfected with human full length AQP4. To control for possible interactions between IgG and IgM, serum was depleted of IgG prior to testing by indirect immunofluorescence., Results: IgM AQP4-Ab were detectable in 4/42 samples from patients with NMOSD, but in none of the 66 control samples. In three patients, titers were higher following depletion of total IgG from the samples. One sample was positive only after precipitation of total IgG., Conclusions: AQP4 antibodies of the IgM class exist in almost 10% of patients with NMO and might contribute to lesion pathology. Routine testing for AQP4-IgM appears to not be justified, as all AQP4-IgM positive patients were also positive for AQP4-IgG, and none of the AQP4-IgG negative samples were positive for AQP4-IgM.

We report on a young lady suffering from adult neuroblastoma and anti-Hu associated paraneoplastic encephalomyelitis (PEM) with a tumour free survival of nine years up to now. Treatment included tumour surgery, radiation, high dose chemotherapy, and stem cell transplantation. Serological testing demonstrated a marked decline in anti-Hu antibody titres under therapy, and subsequent disappearance of the antibody 31 months after second tumour resection.

Background: Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients., Methods and Findings: Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive)., Conclusions: In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.

Background: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies. Objective: To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-d-aspartate-type glutamate receptors (NMDAR) and 25 other anti-neural antibodies in pattern II MS. Methods: Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients (n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABABR), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor–related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase–related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2). Results: Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown. Conclusion: This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS. [ABSTRACT FROM AUTHOR]

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments. [ABSTRACT FROM PUBLISHER]

Background: In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum autoantibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG). Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO. Objective: To assess the frequency, syndrome specificity, diagnostic relevance, and origin of cerebrospinal fluid (CSF) AQP4-Ab in patients with NMO spectrum disorders (NMOSD). Methods: 87 CSF samples from 37 patients with NMOSD and 42 controls with other neurological diseases were tested for AQP4-Ab in a cell based assay using recombinant human AQP4. Twenty-three paired CSF and serum samples from AQP4-Ab seropositive NMOSD patients were further analysed for intrathecal IgG synthesis to AQP4. Results: AQP4-Ab were detectable in 68% of CSF samples from AQP4-Ab seropositive patients with NMOSD, but in none of the CSF samples from AQP4-Ab seronegative patients with NMOSD and in none of the control samples. Acute disease relapse within 30 days prior to lumbar puncture, AQP4-Ab serum titres >1:250, and blood-CSF barrier dysfunction, but not treatment status, predicted CSF AQP4-Ab positivity. A positive AQP4-specific antibody index was present in 1/23 samples analysed. Conclusions: AQP4-Ab are detectable in the CSF of most patients with NMOSD, mainly during relapse, and are highly specific for this condition. In the cohort analysed in this study, testing for CSF AQP4-Ab did not improve the sensitivity and specificity of the current diagnostic criteria for NMO. The substantial lack of intrathecal AQP4-Ab synthesis in patients with NMOSD may reflect the unique localisation of the target antigen at the blood brain barrier, and is important for our understanding of the immunopathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Since the launch of our journal as Nature Clinical Practice Neurology in 2005, we have seen remarkable progress in many areas of neurology research, but what does the future hold? Will advances in basic research be translated into effective disease-modifying therapies, and will personalized medicine finally become a reality? For this special Viewpoint article, we invited a panel of Advisory Board members and other journal contributors to outline their research priorities and predictions in neurology for the next 10 years. [ABSTRACT FROM AUTHOR]

Abstract: Recently, we identified a novel Purkinje cell-specific autoantibody (termed anti-Ca) targeting rhoGTPase-activating-protein-26 (ARHGAP26) in a patient with cerebellar ataxia. Here we describe a new case of anti-Ca/ARHGAP26 antibody-positive cerebellar ataxia. Cerebellar ataxia was associated with signs of possible limbic encephalitis in this case. The 24-year-old man presented with subacute pancerebellar ataxia, flattened affect, and cognitive decline. Neuropsychological testing revealed working memory deficits, compromised verbal learning and recall, attention deficits, slowed information processing, interference difficulty, and reduced spatial recognition. MRI showed severe pancerebellar atrophy. Serological examinations revealed high-titre anti-Ca/anti-ARHGAP26 antibodies. The antibodies belonged to the IgG1 subclass and were produced intrathecally. This case further corroborates the association of anti-Ca antibodies with cerebellar ataxia, expands the clinical spectrum, and highlights the necessity of antigen-specific diagnostic testing in immune-mediated cerebellar ataxia. [Copyright &y& Elsevier]