Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"Serum Neurofilament Light Chain as a Biomarker for CIDP Diagnosis, Severity, and Treatment Outcome.","authors":"Rafael Klimas, Felix Kohle, Lea Horstkemper, Pascal Benkert, Adriana Rehm, Aylin Seibert, Moritz Riesner, Melissa Sgodzai, Thomas Grüter, Niklas Rilke, Barbara Gisevius, Léon Beyer, Klaus Gerwert, Jens Kuhle, Michael Schroeter, Helmar C Lehmann, Ralf Gold, Anna Lena Fisse, Jeremias Motte, Kalliopi Pitarokoili","doi":"10.1212/NXI.0000000000200419","DOIUrl":"10.1212/NXI.0000000000200419","url":null,"abstract":"<p><strong>Background and objectives: </strong>The aim of this study was to characterize serum neurofilament light chain (sNFL) levels in a large cohort of patients with autoimmune neuropathies to provide every-day clinical practice recommendations.</p><p><strong>Methods: </strong>In this retrospective cohort study, we recruited 191 patients with immune-mediated neuropathies from 2 referral centers. sNFL was measured using the Simoa NF-light kit (Quanterix), and age-corrected and BMI-corrected z-scores (zNFL) were calculated. Clinical data were correlated with zNFL and adjusted for different disease subsets. A receiver operator characteristic analysis was performed. Treatments and longitudinal disease course of patients with typical chronic inflammatory demyelinating polyneuropathy (CIDP) in early disease stage were analyzed.</p><p><strong>Results: </strong>One hundred ten patients had typical CIDP, and 67 had atypical CIDP. Fourteen patients had other immune neuropathies. zNFL of all patients correlated significantly with the Inflammatory Neuropathy Cause and Treatment Scale-overall disability sum score (<i>r</i> = 0.160), Medical Research Council Scale for Muscle Strength score (<i>r</i> = -0.242), modified Rankin Scale score (<i>r</i> = 0.151), and distal tibial compound muscle action potential (<i>r</i> = -0.151). The correlations remained only in the cohort of typical CIDP. zNFL >2 within the first 24 months of illness differentiated patients with atypical and typical CIDP with a sensitivity of 93%. Patients with early-stage typical CIDP with zNFL >2 (n = 9) presented with the most severe manifestation and did not respond to first-line (<i>p</i> < 0.0001) but to second-line treatments.</p><p><strong>Discussion: </strong>We established sNFL as a promising biomarker for assessing disease activity in patients with typical CIDP. Elevated zNFL in early-stage typical CIDP indicate severe inflammatory-mediated axonal damage that requires aggressive immunotherapy.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200419"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234683","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":"The Italian Multiple Sclerosis Register Experience With Cladribine: Impact on Relapses, PIRA, and Treatment Sequencing Strategies Evaluation.","authors":"Tommaso Guerra, Massimiliano Copetti, Chiara Zanetta, Francesco Patti, Clara Grazia Chisari, Elena Barbuti, Emilio Portaccio, Matteo Foschi, Antonella Conte, Diana Ferraro, Eleonora E Cocco, Roberta Fantozzi, Giorgia Teresa Maniscalco, Giuseppe Salemi, Carla Tortorella, Damiano Paolicelli, Massimo Filippi, Maria Pia Amato, Maria Trojano, Pietro Iaffaldano","doi":"10.1212/NXI.0000000000200415","DOIUrl":"10.1212/NXI.0000000000200415","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cladribine is an immune reconstitution therapy approved for relapsing multiple sclerosis (RMS). This multicentric retrospective study of the Italian Multiple Sclerosis Register (RISM) aimed to assess the effect of cladribine on the annualized relapse rate (ARR) and progression independent of relapse activity (PIRA) phenomena, also evaluating the strategies of disease-modifying treatment (DMT) continuation after cladribine termination.</p><p><strong>Methods: </strong>Patients with RMS treated with at least one cycle of cladribine recorded in RISM after 2018 were retrospectively included in the analysis. Patients previously treated with other DMTs were stratified into moderately and highly effective DMTs. Adjusted ARR and PIRA events were calculated in the overall cohort and stratified by age at cladribine start (<50 vs ≥ 50 years) and by previous DMT. ARRs were compared between groups using negative binomial models. PIRA was analyzed using the Ghosh-Lin Cox-type regression for the marginal mean. DMTs prescribed after cladribine cycles were analyzed.</p><p><strong>Results: </strong>A total of 2,329 patients treated with cladribine were identified in RISM, with a median (IQR) age of 36.5 (29.2-45.2) years at treatment start. 1,488 patients (63.9%) received 2 courses of cladribine. ARR decreased (<i>p</i> < 0.0001) from 0.96 (95% CI 0.91-1.02) in the 2 years preceding cladribine start to 0.09 (0.08-0.11) during the 2 years after in the overall cohort. One hundred thirty-three PIRA events were reported during the noncladribine treatment period and 54 during cladribine therapy (HR 0.711, 95% CI 0.531-0.952, <i>p</i> = 0.0219) in the entire cohort. All the analyses stratified by age and previous treatment confirmed the significant reduction in PIRA events and the suppression of relapse activity. After cladribine, most DMTs prescribed were ocrelizumab, ofatumumab, and natalizumab. Eight patients re-treated with an additional cycle of cladribine were also identified.</p><p><strong>Discussion: </strong>For patients with RMS, both naïve and switchers, as well as younger and older patients, cladribine is an effective treatment in reducing relapses and PIRA. Different therapeutic strategies after cladribine are currently reported.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that for patients with relapsing multiple sclerosis, cladribine treatment is associated with a reduction in ARR and PIRA events.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200415"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234684","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":"The Inner Nuclear Layer in Pediatric Multiple Sclerosis.","authors":"Hannah Hummel-Abmeier, Sabine Naxer, Ella Maria Kadas, Hanna Zimmermann, Bianca Knaack, Peter Huppke, Antonia Kowallick, Kolja Meier, Alexander Ulrich Brandt, Friedemann Paul, Michael Schittkowski, Frederike Cosima Oertel, Jutta Gärtner","doi":"10.1212/NXI.0000000000200424","DOIUrl":"10.1212/NXI.0000000000200424","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200424"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972159","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":"Acknowledgment to Reviewers.","authors":"Scott S Zamvil, Anne-Katrin Proebstel, Marinos C Dalakas, Josep O Dalmau, Romana Höftberger, Dennis L Kolson","doi":"10.1212/NXI.0000000000200441","DOIUrl":"10.1212/NXI.0000000000200441","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200441"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234681","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":"Identification of Distinct Biological Groups of Patients With Cryptogenic NORSE via Inflammatory Profiling.","authors":"Martin Guillemaud, Mario Chavez, Firas Kobeissy, Annamaria Vezzani, Anthony D Jimenez, Maysaa Merhi Basha, Ayush Batra, Sophie Demeret, Onome Eka, Krista Eschbach, Brandon Foreman, Nicolas Gaspard, Elizabeth E Gerard, Teneille Emma Gofton, Hiba A Haider, Stephen T Hantus, Charles L Howe, Amy Jongeling, Mariel Kalkach-Aparicio, Padmaja Kandula, Karnig Kazazian, Minjee Kim, Yi-Chen Lai, Clémence Marois, Andrew Mellor, Wazim Mohamed, Mikaela Morales, Cederic M Pimentel, Alexandra M Ramirez, Claude Steriade, Aaron F Struck, Olga Taraschenko, Nathan Torcida Sedano, Mark S Wainwright, Ji Yeoun Yoo, Kevin K W Wang, Vincent Navarro, Lawrence J Hirsch, Aurélie Hanin","doi":"10.1212/NXI.0000000000200403","DOIUrl":"10.1212/NXI.0000000000200403","url":null,"abstract":"<p><strong>Background and objectives: </strong>Emerging evidence suggests that immune dysregulation plays a pivotal role in triggering cryptogenic new-onset refractory status epilepticus (c-NORSE), prompting a consensus on early initiation of immunotherapy. However, despite similar timing of administration, responses to immunotherapies have been varied and unpredictable, suggesting the presence of heterogeneous underlying mechanisms<b>.</b> The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes.</p><p><strong>Methods: </strong>Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45).</p><p><strong>Results: </strong>Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies.</p><p><strong>Discussion: </strong>The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200403"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010110","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":"Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis.","authors":"Damiano Marastoni, Elisa Colato, Matteo Foschi, Agnese Tamanti, Stefano Ziccardi, Chiara Eccher, Francesco Crescenzo, Albulena Bajrami, Gian Marco Schiavi, Valentina Camera, Daniela Anni, Federica Virla, Maddalena Guandalini, Ermanna Turano, Francesca Benedetta Pizzini, Stefania Montemezzi, Bruno Bonetti, Owain Howell, Roberta Magliozzi, Richard S Nicholas, Antonio Scalfari, Cristina Granziera, Ludwig Kappos, Massimiliano Calabrese","doi":"10.1212/NXI.0000000000200399","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200399","url":null,"abstract":"<p><strong>Background and objectives: </strong>The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).</p><p><strong>Methods: </strong>This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.</p><p><strong>Results: </strong>During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, <i>p</i> = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, <i>p</i> < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], <i>p</i> = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], <i>p</i> = 0.005), and LIGHT (HR 1.79 [1.11-2.88], <i>p</i> = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], <i>p</i> = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], <i>p</i> = 0.028), and CLn (HR 1.15 [1.05-1.25], <i>p</i> = 0.003) were MRI predictors of PIRA.</p><p><strong>Discussion: </strong>A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200399"},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030495","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":"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":"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}