Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"Neutropenia Associated With B Cell-Depleting Therapies in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.","authors":"Greer Waldrop, Nikki Sisodia, Shane Poole, Samuel Pleasure, Michael R Wilson, Chu-Yueh Guo, Jeffrey M Gelfand, Scott S Zamvil, Riley Bove","doi":"10.1212/NXI.0000000000200430","DOIUrl":"10.1212/NXI.0000000000200430","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neutropenia is described as a rare adverse event associated with B cell-depleting therapy (BCDT) use in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, little is known about longitudinal clinical outcomes. We estimated the real-world incidence of neutropenia among patients with neuroinflammatory disease treated with BCDT and characterized the clinical course.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using electronic medical records to estimate the incidence rate of neutropenia in adults with MS/NMOSD from a neuroimmunology clinic in California between January 6, 2006, and November 2, 2015, treated with ocrelizumab, rituximab, ofatumumab, ublituximab, or inebilizumab. Each clinical course (recurrence, time to recovery of absolute neutrophil count [ANC], postneutropenia treatment) of neutropenia was then presented in a case series.</p><p><strong>Results: </strong>In this cohort of 1,825 patients (6,009 person-years on BCDT), the largest cohort addressing this question to date, 37 developed neutropenia. The estimated incidence rate of neutropenia was 0.62 (95% CI 0.45-0.85) per 100 person-years. The median time from last infusion of current BCDT was 4 months (interquartile range [IQR] 1-6). The median nadir ANC was 390 (IQR 40-960); the nadir ANC was 0 for 6 patients (16%). All patients ultimately recovered to normal counts, except 2 patients developing fluctuating ANCs for months. Among the 32 patients not receiving filgrastim, the median time to ANC recovery was 11 days (95% CI 7-26). Course severity was asymptomatic/mild in 32% (n = 12) while 54% (n = 20) required hospitalization. A confirmed simultaneous infection or infectious prodrome occurred in 23 (62%). After recovery, 30 patients (81%) continued BCDT and 2 (7%) changed within BCDT class. Neutropenia recurred in 13 patients (35%), including 3 who discontinued BCDT after initial neutropenia. The estimated incidence rate of recurrent neutropenia was 0.22 (95% CI 0.13-0.39) per 100 person-years. The mean (SD) time to recurrence from initial neutropenia was 251 (SD: 355) days.</p><p><strong>Discussion: </strong>This study is comprehensive and reflects a large cohort, examining incidence rates of neutropenia with BCDT in MS and NMOSD. Overall, neutropenia was still rare, occurring at a rate of 0.66 per 100 person-years, and infections were associated triggers in some patients. Yet, of relevance to clinicians, neutropenia was not benign: half required hospitalization and 35% experienced recurrence, which is higher than what was reported in clinical trials.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200430"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing Commercial Tissue-Based Assays for Autoimmune Neurologic Disorders (II): Antibodies to Surface Antigens.","authors":"Claudia Papi, Chiara Milano, Lionel Arlettaz, Pietro Businaro, Laura Marmolejo, Laura Naranjo, Jesús Planagumà, Eugenia Martinez-Hernandez, Thaís Armangué, Mar Guasp, Raquel Ruiz-García, Esther Aguilar, Matteo Gastaldi, Raffaele Iorio, Carles Gaig, Albert Saiz, Lidia Sabater, Francesc Graus, Josep O Dalmau, Marianna Spatola","doi":"10.1212/NXI.0000000000200406","DOIUrl":"10.1212/NXI.0000000000200406","url":null,"abstract":"<p><strong>Background and objectives: </strong>Detecting neural surface antibodies (NSAbs) is essential for diagnosing autoimmune encephalitis. The recommended diagnostic strategy involves initial screening with tissue-based assays (TBAs), followed by confirmation with cell-based assays (CBAs). While specialized centers use in-house TBAs, many clinical laboratories depend on commercial TBAs, whose accuracy is yet to be fully assessed.</p><p><strong>Methods: </strong>We selected 92 CSF and 99 serum samples from patients with autoimmune encephalitis and NSAbs confirmed by in-house TBAs and CBAs (20 samples each for AMPAR, GABA_AR, GABA_BR, IgLON5, LGI1, NMDAR, and CASPR2; 19 for mGluR5; 17 for DPPX; and 15 for mGluR1 antibodies), along with 50 CSF and 50 serum samples from negative controls. We assessed the performance of a commercial indirect immunofluorescence (IIF)-TBA (EUROIMMUN). Slides were evaluated as \"positive\" or \"negative\" by 2 experienced investigators and 2 less experienced raters. Discordant results were re-evaluated through interrater discussion and assessed using Cohen's kappa.</p><p><strong>Results: </strong>The experienced raters agreed on 94% (133/142) of CSF and 88% (131/149) of serum classifications (Cohen's kappa = 0.87 and 0.75, respectively, <i>p</i> < 0.001). Among CSF samples, 75% (106/142) were correctly identified while 19% (27/142) were misclassified (13 false positives, 14 false negatives). Among serum samples, 66% (98/149) were correctly identified while 22% (33/149) were misclassified (11 false positives, 22 false negatives). The poorest performance was seen in detecting NMDAR, GABA_AR, and mGluR5 Abs, which were not identified in 5 of 10, 6 of 10, and 5 of 9 serum samples and in 4 of 10, 5 of 10, and 5 of 10 CSF samples, respectively. The overall sensitivity of the commercial IIF-TBA was 84% for CSF and 76% for serum while the specificity was 72% for CSF and 73% for serum. Less experienced raters correctly identified 69% (98/142) of CSF samples and 73% (109/149) of serum samples and misclassified 13% (18/142) of CSF samples and 11% (16/149) of serum samples, and 18% (26/142) of CSF samples and 16% (24/149) of serum samples remained discordant.</p><p><strong>Discussion: </strong>The diagnostic performance of EUROIMMUN IIF-TBA in detecting NSAbs in autoimmune encephalitis is suboptimal. NMDAR antibodies, among the most common NSAbs, can be missed in 50% of cases. This commercial TBA should not be used alone as a screening method nor as a confirmatory technique for NSAbs.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200406"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathic Pain and Distinct CASPR2 Autoantibody IgG Subclasses Drive Neuronal Hyperexcitability.","authors":"Margarita Habib, Anna-Lena Wiessler, Patrik Fischer, Michele Niesner, Mareike Selcho, Ligia Abrante, Christian Werner, Annemarie Sodmann, Maximilian Koch, Abdolhossein Zare, Harald Prüss, Justina Dargvainiene, Jan Lewerenz, Robert Handreka, Peter Körtvelyessy, Dirk Reinhold, Franziska S Thaler, Kalliopi Pitarokoili, Robert J Kittel, Michael Briese, Michael Sendtner, Heike Rittner, Frank Leypoldt, Claudia Sommer, Robert Blum, Kathrin Doppler, Carmen Villmann","doi":"10.1212/NXI.0000000000200423","DOIUrl":"10.1212/NXI.0000000000200423","url":null,"abstract":"<p><strong>Background and objectives: </strong>Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain. CASPR2 is an adhesion protein of the neurexin family and part of the voltage-gated potassium channel complex (VGKC complex) in dorsal root ganglia (DRG) neurons. The pathologic mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass; however, previous studies have neglected subclass-dependent effects.</p><p><strong>Methods: </strong>We investigated 49 subclassified patient serum samples positive for CASPR2 aAbs combining superresolution lattice structural illumination microscopy (SIM²) and functional readouts by calcium imaging and electrophysiologic recordings on cultured DRG neurons. CASPR2-positive patient sera subclassified in IgG4 together with at least 1 other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain groups.</p><p><strong>Results: </strong>A decrease of CASPR2 expression along the axons after exposure to CASPR2 aAbs was observed for all patient groups except the group without pain and IgG4. Moreover, binding of CASPR2 aAbs from patients with pain increased the distance between CASPR2 and associated potassium channels along DRG axons determined by SIM² microscopy. CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all 4 CASPR2 aAb subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs only. Replacement of patient aAbs by healthy control serum rescued Kv channel function to normal levels suggesting that the affected potassium channel function is due to structural blockage and disrupted interactions within the VGKC complex. The last might also be rescued on novel protein synthesis and membrane trafficking of CASPR2.</p><p><strong>Discussion: </strong>IgG4 aAbs seem to be the major modifier of potassium channel function. The DRG hyperexcitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAb binding. However, additional unidentified signal pathways contribute to this process in patients with neuropathic pain.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200423"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biopsy-Confirmed Small Vessel Primary CNS Vasculitis: Clinical Features and Impact of Early Intensive Treatment on Remission.","authors":"Sumanth P Reddy, Sara C LaHue, Sarah Goglin, Sharon A Chung, Shane Poole, Riley Bove, Melike Pekmezci, Tarik Tihan, Jeffrey M Gelfand","doi":"10.1212/NXI.0000000000200397","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200397","url":null,"abstract":"<p><strong>Background and objectives: </strong>This single-center retrospective cohort study sought to characterize the clinical spectrum of small vessel predominant primary CNS vasculitis (sv-PCNSV) and to investigate the impact of early intensive immunosuppressive therapy on remission.</p><p><strong>Methods: </strong>We analyzed data of patients diagnosed with biopsy-proven sv-PCNSV at our institution between 2009 and 2023. \"Early intensive treatment\" (EIT) was defined by cyclophosphamide therapy within 3 months of immunosuppressive treatment initiation. Patients in the \"escalation treatment\" (ESC) group initially received glucocorticoids, either as monotherapy or in conjunction with azathioprine, mycophenolate mofetil, or methotrexate.</p><p><strong>Results: </strong>Twenty-six patients (50% female) met the study criteria, including 7 with amyloid-beta-related angiitis (ABRA). The median age at onset was 55.5 years (range 20-82), and headache (76.9%) and altered mental status (61.5%) were common presenting symptoms. Neuroimaging commonly showed bihemispheric T2/FLAIR lesions (77%) and abnormal gadolinium enhancement (88.5%), but intracranial vascular irregularities indicating large or medium vessel involvement were rare (11.5%). Among patients with non-ABRA sv-PCNSV (n = 19), some demonstrated spinal cord involvement (15.8%) and others exhibited isolated unihemispheric disease (21.1%). Although CSF testing (n = 23) often demonstrated mild pleocytosis, a notable minority of patients (17.4%) had a normal CSF analysis. Six patients (23.1%) underwent repeat brain biopsy because of initial nondiagnostic findings. Remission was achieved in all patients in the EIT group (n = 12/12), in contrast to 78.6% of patients in the ESC group (n = 11/14). Time to remission was significantly shorter among patients in the EIT group compared with the ESC group (median 5 vs 19 months, hazard ratio = 0.24, 95% CI [0.10-0.63], <i>p</i> < 0.005). Most patients achieving remission continued maintenance therapy, with an overall relapse rate of 19%.</p><p><strong>Discussion: </strong>This study highlights the considerable clinical heterogeneity in sv-PCNSV, a rare but serious condition. Early, aggressive treatment with cyclophosphamide is associated with a shorter time to remission, and further validation in prospective studies is warranted.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200397"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the Lab Slip: Why Laboratory Expertise Matters in Neuronal Antibody Testing and Why Clinicians Should Care.","authors":"Frank Leypoldt","doi":"10.1212/NXI.0000000000200425","DOIUrl":"10.1212/NXI.0000000000200425","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200425"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-Inflammatory Molecules Implicated in Multiple Sclerosis Divert the Development of Human Oligodendrocyte Lineage Cells.","authors":"Gabriela J Blaszczyk, Abdulshakour Mohammadnia, Valerio E C Piscopo, Julien Sirois, Qiao-Ling Cui, Moein Yaqubi, Thomas M Durcan, Raphael Schneider, Jack P Antel","doi":"10.1212/NXI.0000000000200407","DOIUrl":"10.1212/NXI.0000000000200407","url":null,"abstract":"<p><strong>Background and objectives: </strong>Oligodendrocytes (OLs) and their myelin-forming processes are lost during the disease course of multiple sclerosis (MS), targeted by infiltrating leukocytes and their effector cytokines. Myelin repair is considered to be dependent on recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). The basis of remyelination failure during the disease course of MS remains to be defined. The aim of this study was to determine the impact of the proinflammatory molecules tumor necrosis factor-⍺ (TNF⍺) and interferon-<i>γ</i> (IFN<i>γ</i>) on the differentiation of human OPCs.</p><p><strong>Methods: </strong>We generated human OPCs from induced pluripotent stem cells with a reporter gene under the OL-specific transcription factor SOX10. We treated the cells in vitro with TNF⍺ or IFN<i>γ</i> and evaluated effects regarding cell viability, expression of OL lineage markers, and coexpression of astrocyte markers. To relate our findings to the molecular properties of OPCs as found in the MS brain, we reanalyzed publicly available single-nuclear RNA sequencing (RNAseq) datasets.</p><p><strong>Results: </strong>Our analysis indicated that both TNF⍺ and IFN<i>γ</i> decreased the proportion of cells differentiating into the OL lineage, consistent with previous reports. Uniquely, we now observe that the TNF⍺ effect is linked to aberrant OPC differentiation in that a subset of O4+, reporter-positive cells coexpressing the astrocytic marker aquaporin-4. At the transcriptomic level, the cells acquire an astrocyte-like signature alongside a conserved reactive phenotype while downregulating OL lineage genes. Analysis of single-nuclear RNAseq datasets from the human MS brain revealed a subset of OPCs expressing an astrocytic signature.</p><p><strong>Discussion: </strong>In the context of MS, these results imply that OPCs are present but inhibited from differentiating along the OL lineage, with a subset acquiring a reactive and stem cell-like phenotype, reducing their capacity to contribute toward repair. These findings help define a potential basis for the impaired myelin repair in MS and provide a prospective route for regenerative treatment.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200407"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal Lobe Epilepsy Associated With Glutamic Acid Decarboxylase Antibodies: Defining a Distinct Epilepsy Syndrome.","authors":"Anna Rada, Lea Marie Reisch, Anne Hagemann, Friedrich G Woermann, Christian G Bien","doi":"10.1212/NXI.0000000000200422","DOIUrl":"10.1212/NXI.0000000000200422","url":null,"abstract":"<p><strong>Background and objectives: </strong>Epilepsy associated with glutamic acid decarboxylase antibodies (GAD-abs) often presents as temporal lobe epilepsy (TLE). However, detailed data on this condition are lacking. The aim of this study was to demonstrate that TLE with GAD-abs (GAD-TLE) is distinct from other forms of TLE and to describe the subgroup of patients with epilepsy and GAD-abs but no evidence of TLE.</p><p><strong>Methods: </strong>Inpatients from 2011 to 2022 with high serum GAD-abs (≥1:80, confirmed by a cell-based assay and typical staining pattern on a tissue-based assay) were included. The control group comprised patients with mesial TLE (EMU-mTLE) with hippocampal sclerosis or nonlesional epilepsy diagnosed on the epilepsy monitoring unit (EMU) and having negative results on a broad panel of neural antibodies. Data were retrospectively collected from first admission (visit 1 [V1]) and most recent follow-up (visit 2 [V2]). Parameters included demographic data, comorbidities, seizure characteristics, electroencephalography findings, MRI results, verbal memory performance, GAD-ab titers (V1), therapies, seizure and memory outcomes, and occupational status (V2).</p><p><strong>Results: </strong>Of 81 GAD-ab-positive patients, 71 (88%) had TLE. Compared with 40 EMU-mTLE controls, patients with GAD-TLE were more often female (84% vs 33%, <i>p</i> < 0.001), more frequently had autoimmune comorbidities (46% vs 2.5%, <i>p</i> < 0.001), musicogenic seizures (18% vs 0%, <i>p</i> = 0.004), and seizure clusters (25% vs 5%, <i>p</i> = 0.002) but less frequently had hippocampal sclerosis (25% vs 54%, <i>p</i> = 0.007). At follow-up (GAD-TLE: median 5 years; EMU-mTLE: 2 years), only 14% of patients with GAD-TLE were terminally seizure-free for ≥1 year, compared with 39% of patients with EMU-mTLE (<i>p</i> = 0.04). Verbal memory remained stable, and occupational status was unchanged. Ten GAD-ab-positive cases without evidence of TLE were identified, including 3 with generalized features.</p><p><strong>Discussion: </strong>Epilepsy associated with GAD-abs predominantly manifests as TLE and as such is an epilepsy syndrome (GAD-TLE). In comparison with EMU-confirmed patients with mTLE without GAD-abs, the seizure outcome is inferior but the neuropsychological performance is usually normal and remains stable. A subset of patients with epilepsy with high-titer GAD-abs do not have TLE, some presenting with generalized features.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200422"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing Commercial Tissue-Based Assays for Autoimmune Neurologic Disorders (I): Antibodies to Intracellular Antigens.","authors":"Chiara Milano, Pietro Businaro, Claudia Papi, Lionel Arlettaz, Laura Marmolejo, Laura Naranjo, Matteo Gastaldi, Raffaele Iorio, Albert Saiz, Jesús Planagumà, Esther Aguilar, Chiara Pizzanelli, Eugenia Martinez-Hernandez, Thaís Armangué, Mar Guasp, Raquel Ruiz-García, Lidia Sabater, Josep O Dalmau, Francesc Graus, Marianna Spatola","doi":"10.1212/NXI.0000000000200410","DOIUrl":"10.1212/NXI.0000000000200410","url":null,"abstract":"<p><strong>Background and objectives: </strong>Current strategies to detect autoantibodies against intracellular neural antigens (IC-Abs) include tissue-based assays (TBAs) alongside line blots or cell-based assays (CBAs). Many clinical laboratories use commercially available TBAs as a screening test, but their diagnostic yield has not been assessed. We determined the performance of 2 commercial TBAs in detecting IC-Abs.</p><p><strong>Methods: </strong>We analyzed samples from 100 patients with autoimmune or paraneoplastic neurologic syndromes harboring IC-Abs (confirmed by in-house TBAs and line blots or CBAs) and 50 negative controls. IC-Abs samples included serum (10 each for Hu, Yo, Ri, SOX1, CV2, Ma2, Tr, amphiphysin, and GAD65 antibodies) or CSF (10 with GFAP antibodies) samples. Two commercial indirect immunofluorescence (IIF) TBAs (INOVA and EUROIMMUN) were assessed by 2 experienced investigators and 3 less experienced raters, all blinded to antibody status. Discordant results were re-evaluated through interrater discussion and assessed using Cohen's kappa.</p><p><strong>Results: </strong>The 2 experienced raters showed substantial agreement (85% for INOVA, 83% for EUROIMMUN) on negative/positive results, which increased to >95% after interrater discussion (Cohen's kappa 0.95 and 0.93, respectively). With IIF-INOVA, they correctly identified 118 of 150 samples (79%) and misclassified 28 of 150 (19%, 2 false positives and 26 false negatives) while results remained discordant in the remaining 4 of 150 samples (2%). With IIF-EUROIMMUN, they correctly identified 105 of 150 samples (70%) and misclassified 40 of 150 (27%, 6 false positives, 34 false negatives), with discordance in 5 of 150 samples (3%). Overall, the sensitivity was 73% for IIF-INOVA and 66% for IIF-EUROIMMUN. The specificity was 96% for IIF-INOVA and 88% for IIF-EUROIMMUN. Both TBAs showed low sensitivity in detecting CV2, SOX1, and amphiphysin antibodies while Ma2 antibodies were missed mainly by IIF-EUROIMMUN and Hu/Ri antibodies by IIF-INOVA. Antibody-specific immunostaining patterns were correctly identified in 62 of 100 positive samples with IIF-INOVA and 55 of 100 with IIF-EUROIMMUN (<i>p</i> = 0.34). Less experienced raters showed higher rates of false-positive results (up to 22% with IIF-EUROIMMUN).</p><p><strong>Discussion: </strong>The performance of commercial IIF-TBAs for IC-Abs detection is suboptimal, exhibiting high false-negative rates of 25%-35%. Therefore, commercial TBAs should not be used alone for IC-Abs screening, but alongside more sensitive techniques, such as line blots. Discordant results between 2 techniques should prompt retesting in reference centers with in-house TBAs, particularly when the suspicion of an autoimmune or paraneoplastic syndrome is high.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200410"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bruton Tyrosine Kinase in Lesions of Multiple Sclerosis and 3 of Its Models.","authors":"Cenxiao Li, Marlene T Morch, Rianne Gorter, Brian Lozinski, Samira Ghorbani, Yifei Dong, Yun-An Shen, Christopher Harp, Stephanie Zandee, Wendy Klement, Alexandre Prat, V Wee Yong","doi":"10.1212/NXI.0000000000200413","DOIUrl":"10.1212/NXI.0000000000200413","url":null,"abstract":"<p><strong>Background and objectives: </strong>The pathophysiology of multiple sclerosis (MS) is contributed by B lymphocytes, macrophages, and microglia. Bruton tyrosine kinase (BTK) is an intracellular enzyme within these cells that modulates their inflammatory properties. Thus, central nervous system-penetrant inhibitors of BTK may counter immune dysregulation, and this aspiration is highlighted by 11 phase 3 clinical trials in MS to inhibit this enzyme. Despite the keen interest, the spatial and temporal elevation of BTK in lesions of MS and its models is not well characterized.</p><p><strong>Methods: </strong>We used quantitative fluorescence immunohistology to assess the expression of BTK and a phosphorylated activated form in different lesion types of MS and 3 of its models: inflammatory experimental autoimmune encephalomyelitis (EAE), toxin-induced demyelination of lysolecithin, and oxidized phosphatidylcholine injuries. GDC-0853 (fenebrutinib), a BTK inhibitor in phase 3 clinical trials in MS, was evaluated in EAE for its capacity to alter disease course.</p><p><strong>Results: </strong>We observed low expression of BTK and a phosphorylated form (pBTK) in murine spinal cord but significant upregulation in white matter lesions inflicted by oxidized phosphatidylcholine, lysolecithin, and EAE. Expression predominantly localized to microglia/macrophages shown through colocalization analysis by Imaris 3-dimensional rendering. GDC-0853 (fenebrutinib) significantly reduced clinical severity of EAE when administered prophylactically and marginally ameliorated disability when initiated from onset of clinical disability. Finally, we report the increase in BTK expression in microglia/macrophages in active plaques and in the hypercellular rim of chronic active lesions of MS. In the inactive core of chronic active MS lesions, the few remaining HLA-DR⁺ myeloid cells were still BTK immunoreactive.</p><p><strong>Discussion: </strong>Our results demonstrate that BTK immunoreactivity is normally undetectable in uninjured areas or normal-appearing white matter of human and murine CNS, but that expression becomes prominent in lesions with hypercellular aggregates of microglia and macrophages. Staining for pBTK reveals that its upregulation declines in the later stage of lysolecithin and chronic stage of EAE injury while BTK upregulation is maintained. Our collective results support the rationale of using brain-penetrant BTK inhibitors to modulate the elevation of this enzyme in microglia/macrophages within inflamed plaques of MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200413"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rituximab Use for Relapse Prevention in Anti-NMDAR Antibody-Mediated Encephalitis: A Multicenter Cohort Study.","authors":"Nabil Seery, Robb Wesselingh, Paul Beech, Laurie McLaughlin, Tiffany Rushen, Amy J Halliday, Liora Ter Horst, Sarah P Griffith, Mirasol Forcadela, Tracie H Tan, Christina Kazzi, Cassie Nesbitt, James Broadley, Katherine Buzzard, Andrew Duncan, Wendyl J D'Souza, Yang Tran, Anneke Van Der Walt, Genevieve Skinner, Bruce V Taylor, Andrew Swayne, Amy Brodtmann, David Gillis, Ernest Gerard Butler, Tomas Kalincik, Udaya K Seneviratne, Richard A Macdonell, Stefan Blum, Sudarshini Ramanathan, Charles B Malpas, Stephen W Reddel, Todd A Hardy, Terence J O'Brien, Paul G Sanfilippo, Helmut Butzkueven, Mastura Monif","doi":"10.1212/NXI.0000000000200395","DOIUrl":"10.1212/NXI.0000000000200395","url":null,"abstract":"<p><strong>Background and objectives: </strong>Rituximab is an anti-CD20 monoclonal antibody used in patients with anti-NMDAR antibody (Ab)-mediated encephalitis as both an acute escalation therapy and a longer term relapse risk-reduction treatment. The potential long-term benefit of a single course administered during the acute disease phase on future relapse risk is uncertain. Moreover, the optimal dosing duration to reduce relapse risk is unknown. The aim of this study was to evaluate the effect of a single course of rituximab on relapse incidence. We also studied the duration of effect of a course of rituximab in adult patients with anti-NMDAR Ab-mediated encephalitis.</p><p><strong>Methods: </strong>We recruited 67 patients with anti-NMDAR Ab-mediated encephalitis from 10 Australian hospitals. Rituximab exposure was quantified as a time-varying covariate in Cox proportional hazard models.</p><p><strong>Results: </strong>A single course of rituximab was associated with longer time to first relapse (hazard ratio [HR] 0.11, 95% CI 0.02-0.70, <i>p</i> = 0.02). For patients in whom redosing is considered, rituximab was associated with longer time to first relapse at 6 months after the last infusion, after adjusting for concurrent immunotherapies and the presence of ovarian teratoma at disease onset (HR 0.05, 95% CI 0.00-0.48, <i>p</i> = 0.005). The treatment effect did not persist out to 12 months after a given course (HR 0.60, 95% CI 0.15-2.44, <i>p</i> = 0.47).</p><p><strong>Discussion: </strong>A single course of rituximab reduces the risk of relapse of anti-NMDAR antibody-mediated encephalitis. In select patients for whom redosing of rituximab is considered, administration at 6 months delays relapses.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that rituximab delays relapses in patients with anti-NMDAR antibody-mediated encephalitis.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200395"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}