Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"A 73-Year-Old Woman With Confusion, Visual Field Disturbances, and Edematous White Matter Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.","authors":"Zachery Rohm, Myla D Goldman, Claire Riley, Scott S Zamvil, Siddharama Pawate","doi":"10.1212/NXI.0000000000200300","DOIUrl":"10.1212/NXI.0000000000200300","url":null,"abstract":"<p><p>We describe the case of a 73-year-old woman presenting with headaches, confusion, and vision disturbances. Brain MRI showed a large T2-hyperintense lesion in the right temporo-occipital region with vasogenic edema and leptomeningeal enhancement. A leptomeningeal biopsy was performed, which led to a definitive diagnosis.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200300"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982916","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":"CD19-Directed CAR T-Cells in a Patient With Refractory MOGAD: Clinical and Immunologic Follow-Up for 1 Year.","authors":"Jose Maria Cabrera-Maqueda, Maria Sepulveda, Raquel Ruiz García, Guillermo Muñoz-Sánchez, Nuria Martínez-Cibrian, Valentín Ortíz-Maldonado, Daniel Lorca-Arce, Mar Guasp, Sara Llufriu, Eugenia Martinez-Hernandez, Thais Armangue, Elianet G Fonseca, María Teresa Alba-Isasi, Julio Delgado, Josep Dalmau, Manel Juan, Albert Saiz, Yolanda Blanco","doi":"10.1212/NXI.0000000000200292","DOIUrl":"10.1212/NXI.0000000000200292","url":null,"abstract":"<p><strong>Objectives: </strong>In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells.</p><p><strong>Methods: </strong>CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen.</p><p><strong>Results: </strong>A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19⁺ B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year.</p><p><strong>Discussion: </strong>This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD.</p><p><strong>Classification of evidence: </strong>This provides Class IV evidence. It is a single observational study without controls.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200292"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897936","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":"Should We Measure CSF Complement Levels in Patients With MOGAD?","authors":"Carson E Moseley, Scott S Zamvil","doi":"10.1212/NXI.0000000000200302","DOIUrl":"10.1212/NXI.0000000000200302","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200302"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971546","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":"High NEDA and No PIRA in Natalizumab-Treated Patients With Pediatric-Onset Multiple Sclerosis.","authors":"Marco Puthenparampil, Marta Gaggiola, Marta Ponzano, Giovanni Zanotelli, Alessandro Miscioscia, Margherita Nosadini, Alessandro Di Paola, Stefano Sartori, Paola Perini, Francesca Rinaldi, Francesca Bovis, Paolo Gallo","doi":"10.1212/NXI.0000000000200303","DOIUrl":"10.1212/NXI.0000000000200303","url":null,"abstract":"<p><strong>Background and objectives: </strong>Although pediatric-onset multiple sclerosis (POMS) is characterized by a more rapid accumulation of CNS inflammation than adult-onset MS (AOMS), the therapeutic algorithms applied in POMS are usually based on AOMS therapeutic outcomes. To define a high-efficacy treatment (HET)-based strategy to treat POMS, we designed an observational retrospective study aimed at evaluating the efficacy and safety of natalizumab (NTZ) in naïve POMS and AOMS.</p><p><strong>Methods: </strong>Starting from 160 patients, we applied a 2:1 (adult:pediatric) matching on propensity scores and obtained 32 patients with NTZ-treated POMS and 64 with AOMS, estimated from a multivariable logistic regression model. All patients were clinically and radiologically followed up every 6 months for a mean period of 46.0 ± 26.9 months.</p><p><strong>Results: </strong>Following re-baseline at month 6, no difference (log-rank test: <i>p</i> = 0.924) in new and enlarging T2 white matter lesions, postcontrast T1 lesions, and relapse rate were observed between POMS and AOMS throughout the study. Progression independent of relapse activity (PIRA) was never observed in POMS, while 9 of 64 patients with AOMS (12.5%) had PIRA events during the follow-up (40.0 ± 25.9 months; log-rank <i>p</i> value 0.0156). JCV seroconversion rate during NTZ infusion did not differ between POMS and AOMS (log-rank test <i>p</i> = 0.3231). Finally, no serious adverse event was observed in both POMS and AOMS.</p><p><strong>Discussion: </strong>The favorable outcomes observed on clinical, especially in PIRA, and radiologic parameters strongly support the use of NTZ as a first-choice HET in POMS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200303"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982917","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":"Young-Onset Alzheimer Dementia Due to a Novel Pathogenic <i>Presenilin 1</i> Variant Initially Misdiagnosed as Autoimmune Encephalitis.","authors":"Nathalia Rossoni Ronchi, Matheus A Castro, Artur M Coutinho, Leandro T Lucato, Guilherme Diogo Silva, Sonia M Brucki, Fernando Kok, Eduardo Sturzeneker Trés, Paulo Ribeiro Nóbrega, Fernando Freua, Ricardo Nitrini, Mateus Mistieri Simabukuro","doi":"10.1212/NXI.0000000000200280","DOIUrl":"10.1212/NXI.0000000000200280","url":null,"abstract":"<p><strong>Objectives: </strong>Pathogenic variants in presenilin 1 <i>(PSEN1)</i> are related to early-onset Alzheimer disease (AD) and may occur as de novo variants. In comparison with sporadic forms, it can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders and because these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked. Our aim was to demonstrate the challenge in diagnosing young patients with neurodegenerative diseases that simulate AE.</p><p><strong>Methods: </strong>We describe a case of a young patient with insidious progressive dementia, myoclonus, seizures, and aphasia, with no family history of dementia, along with signs suggestive of neuroinflammation on brain MRI and CSF examination.</p><p><strong>Results: </strong>She was initially misdiagnosed as having AE. Further investigation was performed, leading to the discovery of a novel and de novo pathogenic variant in PSEN1.</p><p><strong>Discussion: </strong>This case demonstrates the importance of considering PSEN1 in young patients with insidious progressive dementia with atypical clinical and neuroimaging features, even in patients without a family history of neurologic disorders. Not adhering to published criteria of possible and probable AE and overinterpretation of subtle inflammatory findings in CSF and MRI contribute to misdiagnosis.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200280"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724044","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":"Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness <i>z</i> Scores.","authors":"Ting-Yi Lin, Seyedamirhosein Motamedi, Susanna Asseyer, Claudia Chien, Shiv Saidha, Peter A Calabresi, Kathryn C Fitzgerald, Sara Samadzadeh, Pablo Villoslada, Sara Llufriu, Ari J Green, Jana Lizrova Preiningerova, Axel Petzold, Letizia Leocani, Elena Garcia-Martin, Celia Oreja-Guevara, Olivier Outteryck, Patrick Vermersch, Laura J Balcer, Rachel Kenney, Philipp Albrecht, Orhan Aktas, Fiona Costello, Jette Frederiksen, Antonio Uccelli, Maria Cellerino, Elliot M Frohman, Teresa C Frohman, Judith Bellmann-Strobl, Tanja Schmitz-Hübsch, Klemens Ruprecht, Alexander U Brandt, Hanna G Zimmermann, Friedemann Paul","doi":"10.1212/NXI.0000000000200269","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200269","url":null,"abstract":"<p><strong>Background and objectives: </strong>Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted <i>z</i> scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS).</p><p><strong>Methods: </strong>We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted <i>z</i> scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests.</p><p><strong>Results: </strong>In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], <i>p =</i> 3.82e^-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], <i>p</i> = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], <i>p</i> = 0.04). Compared with raw values with arbitrary cutoffs, applying the <i>z</i> score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score).</p><p><strong>Discussion: </strong>In conclusion, our work demonstrated reference cohort-based <i>z</i> scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200269"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469747","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":"Retinal Changes in Double-Antibody Seronegative Neuromyelitis Optica Spectrum Disorders.","authors":"Frederike C Oertel, Hanna G Zimmermann, Seyedamirhosein Motamedi, Charlotte Bereuter, Luca Magdalena Manthey, Fereshteh Ashtari, Rahele Kafieh, Alireza Dehghani, Mohsen Pourazizi, Lekha Pandit, Anitha D'Cunha, Orhan Aktas, Philipp Albrecht, Marius Ringelstein, Elena H Martinez-Lapiscina, Bernardo F Sanchez Dalmau, Pablo Villoslada, Nasrin Asgari, Romain Marignier, Alvaro Cobo-Calvo, Letizia Leocani, Marco Pisa, Marta Radaelli, Jacqueline Palace, Adriana Roca-Fernandez, Maria Isabel S Leite, Srilakshmi Sharma, Jerome De Seze, Thomas Senger, Michael R Yeaman, Terry J Smith, Lawrence J Cook, Alexander U Brandt, Friedemann Paul","doi":"10.1212/NXI.0000000000200273","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200273","url":null,"abstract":"<p><strong>Background and objectives: </strong>To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement.</p><p><strong>Methods: </strong>Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL).</p><p><strong>Results: </strong>This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL (<i>p</i> < 0.001) and GCIPL (<i>p</i> = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL (<i>p</i> = 0.027) and GCIPL (<i>p</i> = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses.</p><p><strong>Discussion: </strong>DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200273"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469748","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":"MOG CNS Autoimmunity and MOGAD.","authors":"Carson E Moseley, Akash Virupakshaiah, Thomas G Forsthuber, Lawrence Steinman, Emmanuelle Waubant, Scott S Zamvil","doi":"10.1212/NXI.0000000000200275","DOIUrl":"10.1212/NXI.0000000000200275","url":null,"abstract":"<p><p>At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200275"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601069","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":"Erdheim-Chester Disease Masquerading as CLIPPERS.","authors":"Samir Alkabie, Eli L Diamond","doi":"10.1212/NXI.0000000000200294","DOIUrl":"10.1212/NXI.0000000000200294","url":null,"abstract":"<p><strong>Objectives: </strong>To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).</p><p><strong>Methods: </strong>Case series.</p><p><strong>Results: </strong>Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as \"hairy kidney\" appearance and metadiaphyseal osteosclerosis on ¹⁸F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS.</p><p><strong>Discussion: </strong>ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200294"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760100","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":"LGI1 Autoantibodies Enhance Synaptic Transmission by Presynaptic K_v1 Loss and Increased Action Potential Broadening.","authors":"Andreas Ritzau-Jost, Felix Gsell, Josefine Sell, Stefan Sachs, Jacqueline Montanaro, Toni Kirmann, Sebastian Maaß, Sarosh R Irani, Christian Werner, Christian Geis, Markus Sauer, Ryuichi Shigemoto, Stefan Hallermann","doi":"10.1212/NXI.0000000000200284","DOIUrl":"10.1212/NXI.0000000000200284","url":null,"abstract":"<p><strong>Background and objectives: </strong>Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune encephalitis with predominant involvement of the limbic system, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening.</p><p><strong>Methods: </strong>We studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies.</p><p><strong>Results: </strong>LGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels because presynaptic Ca_v2.1 channel density, calcium current amplitude, and calcium channel gating were unaffected by LGI1 autoantibodies. By contrast, application of LGI1 autoantibodies homogeneously reduced K_v1.1 and K_v1.2 channel density on the surface of presynaptic boutons. Direct presynaptic patch-clamp recordings revealed that LGI1 autoantibodies cause a pronounced broadening of the presynaptic action potential. Domain-specific effects of LGI1 autoantibodies were analyzed at the neuronal soma. Somatic action potential broadening was induced by polyclonal LGI1 autoantibodies and patient-derived monoclonal autoantibodies targeting the epitempin domain, but not the leucin-rich repeat domain.</p><p><strong>Discussion: </strong>Our results indicate that LGI1 autoantibodies reduce the density of both K_v1.1 and K_v1.2 on presynaptic boutons, without actions on calcium channel density or function, thereby broadening the presynaptic action potential and increasing neurotransmitter release. This study provides a molecular explanation for the neuronal hyperactivity observed in patients with LGI1 autoantibodies.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"11 5","pages":"e200284"},"PeriodicalIF":7.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982918","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}