Search

Two patients with large bilateral subdural haematomas with patterns of non-enhanced brain computed tomography (CT) falsely suggesting coexistent subarachnoid haemorrhage are presented. The CT images showed marked effacement of the [...]

OBJECTIVE: To describe novel neurological manifestations associated with glutamic acid decarboxylase (GAD65) autoimmunity. PATIENTS AND METHODS: This retrospective study (1987-2003) describes 62 patients Incidentally found to have a serum autoantibody that bound selectively to synapse-rich central nervous system tissues. The immunostaining pattern was determined to be GAD65-specific by radiolmmunoprecipitation assay. These cases were identified among samples submitted for paraneoplastic autoantibody evaluation using indirect immunofluorescence. In no case had GAD65 or any other islet cell antibody testing been requested. RESULTS: In most cases, the patients' presentations were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic). Median age at onset was 50 years, and 77% were women. Of the 44 patients seen at the Mayo Clinic, 23% were African American; in contrast, less than 10% of Mayo Clinic's neurology patients are African American. Median follow-up was 24 months. The radioimmunoprecipitation assay values for GAD65 antibody were extremely high (median, 1429 nmol/L; Interquartile range, 643-3078 nmol/L) and correlated significantly with immunofluorescence titers (median, 3840; interquartile range, 1920-15,360; r = 0.81; P < .001). Neurological manifestations were multifocal in 41 patients and included cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff-man phenomena (26%), extrapyramidal signs (16%), and myelopathy (8%). One third of the patients had type 1 diabetes mellitus, 53% had thyroid autoantibodies, and 16% had vitiligo. Eleven of 20 patients identified as African American had brainstem involvement. Some patients appeared to benefit from short-term immunosuppression (none received long-term therapy). CONCLUSIONS: The neurological spectrum of GAD65 autoimmunity includes brainstem, extrapyramidal, and spinal cord syndromes. In our experience, African American patients were disproportionately affected. A patient with a presumed neurodegenerative disorder of new onset, with high levels of GAD65 antibody (>20 nmol/L), merits consideration of immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS)-related tremor is classically attributed to infratentorial lesions., Objective: To characterize unilateral tremor associated with perirolandic lesions in MS., Methods: This retrospective study included Mayo Clinic patients diagnosed with MS who had: 1) Progressive unilateral tremor; and 2) Contralateral perirolandic juxtacortical T2-lesion. Medical records, neuroimaging and movement laboratory studies were evaluated., Results: Of 12 patients, 8 were female. Median age of tremor onset was 36.5 years (range, 23-49), with diagnosis of MS a median of 101 months (range, 5-238) after. Tremor was the first MS symptom in 10 and all had progression. Most had tremors (10/12) in the 4.5 - 7 Hz range, while 2 had Holmes tremors in 3 - 5 Hz range. The perirolandic lesions were often large and confluent. All 3 with acute/subacute MRIs (within 4 months of onset) had enhancement. There was lesional atrophy in 6/11 with follow-up imaging available. Detailed treatment outcomes are described., Conclusion: Progressive unilateral tremor with contralateral perirolandic lesion is a novel phenotype of progressive MS and the pathogenesis may reflect disruption of cerebello-thalamo-cortical circuitry., Competing Interests: Declaration of competing interest Dr. Banks was supported by Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. BTK, OHK, NN, MT, BMK and FA report no potential conflicts of interest. JHB receives research funding from Novartis Pharmaceuticals and Amylyx Pharmaceuticals; WOT reports receiving research funding from the National institutes of Health and Mallinckrodt Inc; SJP reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals, grants, personal fees, and non-financial support from Viela Bio/Horizon, grants from Adimune, grants, personal fees, and non-financial support from Genentech, Roche, personal fees for consulting UCB, Astellas and Arialys; AZ reports research funding from Roche; EPF received research support from UCB, he has received speaker honoraria from Pharmacy Times, he received royalties from UpToDate, he has received funding from the NIH (R01NS113828)., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high-titer serum/CSF GAD65 antibodies (radioimmunoassay)., Methods: A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high-titer GAD65 antibodies (≥ 20 nmol/L in serum [equivalent to > 10,000 IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5 years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG., Results: We identified 12 patients with high-titer GAD65 IgG and motor neuronopathy, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness as compared to ALS patients. On further analysis, a subgroup of these patients with neurogenic changes on EMG, had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from the ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography; significantly lesser worsening in mRS and mortality on long-term follow-up., Discussion: An upper motor neuron predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, which could yield favorable results., Competing Interests: Declarations. Conflicts of interest: N K Paramasivan, P Sarker and NP Staff report no conflicts interest. A.Zekeridou has patents submitted for Tenascin-R-IgG, PDE10A-IgG, and DACH1-IgG as biomarkers of paraneoplastic neurological autoimmunity. She's received research funding from Roche that was used for neurofilament analysis in this work. She's consulted, without personal compensation, for Alexion Pharmaceuticals. CJ Klein has received personal compensation for his service as a consultant in Takeda, Faze Medicine and Sangamo Therapeutics. A.McKeon. is funded by grants from NIH (RO1NS126227, U01NS120901), and has consulted for Janssen and Roche Pharmaceuticals without personal compensation. Dr. McKeon has patents for Septin-5-IgG and Septin-7-IgG licensed to Euroimmun, a patent for GFAP-IgG issued, a patent for MAP1B-IgG with royalties paid to himself and licensed to Ravo Diagnostika, and patents for CAMKV-IgG, KLCHL11-IgG and PDE10A-IgG pending. S.J. Pittock reports receiving grants, personal fees paid to Mayo Clinic, and nonfinancial support from Alexion Pharmaceuticals, Inc. and MedImmune, Inc./Viela Bio; receiving personal fees from Genentech/Roche, UCB, and Astellas, outside the submitted work; holding patent 8,889,102 (application 12-678350) issued and patent 9,891,219B2 (application 12-573942) issued. D. Dubey has consulted for UCB, Immunovant, Argenx, Arialys and Astellas pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He is a named inventor on filed patent that relates to KLHL11 as marker of autoimmunity and germ cell tumor. He has patents pending for LUZP4-IgG, cavin-4-IgG and SKOR2-IgG as markers of neurological autoimmunity. He has received funding from the DOD (CA210208 & PR220430), David J. Tomassoni ALS Research Grant Program and UCB. Ethical approval: All patients provided consent for participation in this study. The study was approved by the Mayo Clinic Institutional Review Board., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Cavin-4 was identified as a potential autoantigen for immune-mediated rippling muscle disease (iRMD). To validate this, we developed and tested various immunoassays, including a cell-based assay (CBA), cavin-4 recombinant protein ELISA, and multi-peptide ELISA. Among 19 iRMD patients, all exhibited muscle rippling, and 13 had percussion-induced mounding. All immunoassays demonstrated clinical and analytical specificities greater than 95%. The protein ELISA had the highest sensitivity (94.7%) and specificity (99.9%), outperforming CBA (sensitivity 89.5%, specificity 99.6%) and the multi-peptide ELISA (sensitivity 79.0%, specificity 97.2%). Our results suggest that the cavin-4 protein ELISA is a promising tool for high-throughput clinical testing in iRMD., (© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cases of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) co-occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77-4.81; P < 0.001) when compared to the age- and country-adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare., (© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care., Competing Interests: Declaration of interests S.R.I. has received honoraria/research support from UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, ADC therapeutics, BioHaven therapeutics, CSL Behring, and ONO Pharma and licensed royalties on patent application WO/2010/046716 entitled “Neurological autoimmune disorders” and has filed two other patents entitled “Diagnostic method and therapy” (WO2019211633 and US app 17/051,930; PCT application WO202189788A1) and “Biomarkers” (WO202189788A1, US App 18/279,624; PCT/GB2022/050614). S.J.P. is a named inventor on patent #9,891,219B2, application #12-573,942, methods for treating neuromyelitis optica (NMO) by administration of Eculizumab to an individual that is AQP4-IgG positive, which has been issued and for which he had received royalties. S.J.P. has received grants or research support from Alexion/Astra Zeneca Rare, Horizon/Amgen, F. Hoffmann-La Roche AG, UCB, and Adimune. Since receiving research funding, S.J.P. has received no personal compensation from these companies. In the event of consultation, all compensation for consulting activities is paid directly to Mayo Clinic as per Mayo Clinic policy. S.J.P. has received personal compensation for consultation for Arialys. C.L.H. and B.D.S.C. have received research support from Adimune., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To assess the real-world performance of a live (LCBA) versus a fixed (FCBA) cell-based assay for the detection of serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG-IgG) and aquaporin-4 (AQP4-IgG)., Methods: This was a retrospective study of patients evaluated at a single tertiary academic referral center, with serum testing performed clinically for AQP4-IgG and/or MOG-IgG by FCBA and LCBA on the same day. Additionally, frozen banked sera from the same day for patients tested only by one assay were retrieved and tested by the other assay. FCBA was performed by the Johns Hopkins Immunology Laboratory using Euroimmun kits with detection by indirect immunofluorescence (FCBA-IF), whereas LCBA was performed by the Mayo Clinic Neuroimmunology Laboratory with detection by flow cytometry (LCBA-FACS)., Results: Of 594 specimens with paired MOG-IgG testing, 500 were negative by both assays, 33 were positive by both assays, 56 were positive exclusively by LCBA-FACS, and 5 were only positive by FCBA-IF. Overall, MOG-IgG LCBA-FACS exhibited 95.1% sensitivity and 97.7% specificity, whereas MOG-IgG FCBA-IF had 45.7% sensitivity and 99.8% specificity. Of 577 specimens with paired AQP4-IgG testing, 503 were negative by both assays, 51 were positive by both assays, 21 were positive exclusively by LCBA-FACS, and 2 were only positive by FCBA-IF. Overall, AQP4-IgG LCBA-FACS exhibited 97.3% sensitivity and 100% specificity, whereas AQP4-IgG FCBA-IF had 71.6% sensitivity and 100% specificity., Interpretation: LCBA-FACS for both MOG-IgG and AQP4-IgG had markedly better sensitivity than FCBA-IF, with similar specificity. The use of FCBA-IF may result in underrecognition of both MOG antibody-associated disease (MOGAD) and AQP4-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD)., (© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To describe the phenotypes, oncological associations, biomarker profiles, and outcomes across different age groups in patients with ANNA1 (anti-Hu) autoimmunity., Methods: A retrospective review of patients with ANNA1-IgG in serum/CSF between January 1, 2001, and December 31,2019 was performed. Patients were classified into three groups based on the age of symptom onset. Phage immunoprecipitation sequencing (PhIP-Seq) and neurofilament light chain (NfL) measurements were done in patient sera/CSF with archived samples., Results: Of 122 patients, 81 (66%), 20 (16%), and 21 (17%) patients belonged to older adults, young adults, and pediatric groups, respectively. Lung cancer and neuromuscular presentations were more common in older adults (p < 0.001), while limbic encephalitis and neuroblastoma were more common in pediatric patients (p < 0.005). Most young adults (75%) did not have cancer identified. Proportions of patients with a favorable response to immunotherapy were 20%, 30%, and 52% among older adults, young adults, and pediatric groups, respectively. PhIP-Seq demonstrated significant enrichment for ELAVL4 peptides especially for amino acids 240-289, in the majority of samples evaluated (36/67, 54%). ZIC and SOX2 peptides were significantly enriched in those with central nervous system presentations. Serum NfL levels were elevated in patients with cancer and those with poor long-term outcomes., Interpretation: Young adults with ANNA1 autoimmunity phenotypically resembled older adults but rarely had an underlying cancer. Pediatric patients frequently presented with limbic encephalitis and neuroblastoma and often responded favorably to immunotherapy. Distinct antigenic signatures may underlie differences in clinical presentations. Serum NfL levels may be a biomarker of poor long-term outcomes in ANNA1 autoimmunity., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Defining the CSF cytokine/chemokine and injury biomarker signature of glial fibrillary acidic protein (GFAP) autoimmunity can inform immunopathogenesis. CSF GFAP-IgG-positive samples (N = 98) were tested for 17 cytokines/chemokines, neurofilament light chain (NfL), and GFAP (ELLA, Bio-Techne). Controls included non-inflammatory (N = 42), AQP4-IgG-positive (N = 83), CNS infections (N = 13), and neurosarcoidosis (N = 32). IL5, IL6, IL10, IL8/CXCL8, CXCL9, CXCL10, CXCL13, BAFF, GM-CSF, IFN-gamma, and TNF-alpha concentrations were higher compared to non-inflammatory controls (P < 0.01). GFAP concentrations were similar to those of AQP4-IgG-positive patients; NfL was higher (P < 0.001) and correlated with MRI changes and outcomes. CSF cytokine/chemokine findings in GFAP autoimmunity correlate with histopathology; GFAP and NfL hold promise as disease biomarkers., (© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Data regarding long-term recovery from autoimmune encephalitis (AE) remain limited., Methods: This retrospective observational study investigated outcomes in 182 patients who met the 2016 criteria for definite AE. Recovery data were available in 172 patients. Follow-up data at ≥24 months post-attack were available for 119. Recovery trajectory, residual symptoms, outcome predictors and causes of post-AE death were assessed., Results: Of 172 patients, 138 (80%) achieved good recovery (modified Rankin Scale (mRS) ≤2) with a median recovery time of 4 months (95% CI: 2 to 6 months). Recovery varied by associated neural antibody, with the best recovery observed in leucine-rich glioma-inactivated 1 (97% good recovery, median recovery time 0 (0 to 2) months). Paraneoplastic AE (p=0.007), severe attacks (eg, mRS ≥4 at attack, p=0.007) and cerebrospinal fluid pleocytosis (p=0.005) were associated with a lower likelihood of good recovery, while seizure presentation (p=0.026) was associated with better recovery. Despite good recovery, several residual symptoms persisted ≥24 months post-AE, including cognitive deficits (53%), seizures (26%), depression (23%), sleep disorders (25%), brainstem/cerebellar symptoms (13%), other movement disorders (14%) and autonomic symptoms (12%). Predictors of long-term sequelae included disabling cognitive deficit at onset and delayed immunotherapy for post AE-dementia, and medial temporal atrophy as well as escalation to cyclophosphamide therapy for both drug-resistant epilepsy and chronic depression. Of 182 patients, 20 (11%) died; the most common cause of death was progression of AE (6/20 (30%))., Conclusion: While the majority of patients achieved functional independence after AE, several residual symptoms persisted. Several clinical and paraclinical features were associated with long-term sequelae., Competing Interests: Competing interests: ST reports no disclosure relevant to this study. MG has a patent pending for CAMKV-IgG. EO reports no disclosure relevant to this study. JWB has an inventor agreement with Seer Medical. DD reports a patent for KLHL11 pending, a patent for LUZP4 pending, and a patent for CAVIN4 pending, has consulted for UCB, Astellas, Argenx, Immunovant and Arialys pharmaceuticals (all compensation paid directly to Mayo Clinic), and has participated in advisory boards for UCB who has upcoming treatment trial in LGI IgG autoimmune encephalitis; and Mayo Clinic Laboratories offer commercial testing for LGI1-IgG, but none of the authors receive financial compensation for this. EPF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. EPF was a site primary investigator in a randomised clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EPF has received funding from the NIH (R01NS113828). EPF is a member of the medical advisory board of the MOG project. EPF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. ASL-C has received personal compensation for participating in scientific advisory boards for Genentech and Horizon. KS is a site primary investigator for a study funded by UCB Pharmaceuticals. CV-S reports no disclosure relevant to this study. NLZ reports no disclosure relevant to this study. AZ has received research funding from Roche and the Mayo Clinic Center for MS and Autoimmune Neurology relevant to this work. Roche funded this project. SJP reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants, personal fees and non-financial support from Amgen (previously MedImmune /Viela Bio/Horizon); grants, personal fees and non-financial support from Genentech, Roche; grants from Adimune, and personal fees for consulting from UCB, Astellas and Arialys and Sage Therapeutics. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive) for which he has received royalties. He also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A and MAP1B. He works at Mayo Clinic, which offers commercial MOG-IgG and AQP4-IgG testing. He receives no royalties from the sale of tests done at the neuroimmunology Laboratory at Mayo Clinic. AM reports research funding from National Institutes of Health (NIH: RO1NS126227, U01NS120901), patents issued for GFAP and MAP1B-IgGs and patents pending for CAMKV, PDE10A, Septin-5 and Septin-7 and KLHL11-IgGs, and has consulted for Janssen and Roche pharmaceuticals, without personal compensation., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: To report myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) epidemiology in two American regions using 2023 diagnostic criteria., Patients and Methods: We compared age- and sex-adjusted incidence and prevalence of MOGAD per 2023 diagnostic criteria in Olmsted County (Minnesota [USA]) and Martinique (Caribbean [FR]) (01/01/2003-12/31/2018, prevalence day) using Poisson regression. Archived sera in 68-85% were available for MOG-IgG testing by live cell-based assay at Mayo Clinic., Results: Of 21 patients with MOG-IgG positivity identified, 16 fulfilled MOGAD criteria (38% female; median age of 27 years, interquartile-range [IQR 23-42]) and five with low-positive MOG-IgG did not (optic neuritis lacking supportive criteria, 2; alternative diagnosis of multiple sclerosis, 3). MOGAD prevalence was similar in Olmsted County (3.70/100,000, 95% confidence interval [CI] 0.74-6.66]) and Martinique (2.61/100,000; 95% CI 0.85-4.37, P = 0.46). MOGAD incidence was 3.00/million-person-years (95% CI 0.78-5.22) in Olmsted County and 1.18/million-person-years (95% CI 0.30-2.07) in Martinique (P = 0.08). Children represented 29% of MOGAD in Olmsted County and 11% in Martinique. During their disease course the attacks included: optic neuritis (13/16 [81%]); myelitis (6/16 [38%]); and acute disseminated encephalomyelitis (2/16 [13%]). The proportion of MOGAD among incident CNS demyelinating diseases was greater in children (13-14%) than adults (2-4%; P = 0.005). At last follow-up (median, 5 years, IQR 2-9), the median EDSS was 1.0 (IQR 0.5-2.75) with 1/16 (6%) blind in one eye and 9/16 (56%) had relapsing MOGAD., Conclusions: This study provides estimates of incidence and prevalence of MOGAD in the USA and Martinique and shows that, although children are predisposed, the disease is spread broadly across the age spectrum and population-based outcomes are favorable., Competing Interests: Declarations. Conflicts of interest: Laura Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS, Celgene, and Sanofi and travel support for conferences from Merck-Serono. She serves as Review Editor for Brain Health and Clinical Neuroscience (section of Frontiers in Human Neuroscience) and Clinical Neuroimaging (section of Frontiers in Neuroimaging). Elia Sechi received speaker honoraria and/or support for attending scientific meetings from Alexion, Horizon, Novartis, Roche and UCB. He serves as an editorial board member for BMC Neurology and Frontiers in Neurology. Dr. Sechi is a member of the medical advisory board of the MOG project. Isabelle Komla-Soukha reports no disclosures. John J. Chen reports payment for consultation from UCB and Horizon. Carin Y. Smith reports no disclosures. Sarah M. Jenkins reports no disclosures. Kai Guo reports no disclosures. Vyanka Redenbaugh reports no disclosures. James P. Fryer reports no disclosures. Jan-Mendelt Tillema is Associate Editor for Journal of Child Neurology. Nisa Vorasoot reports no disclosures. Nanthaya Tisavipat reports no disclosures. Smathorn Thakolwiboon reports no disclosures. Divyanshu Dubey has consulted for UCB, Immunovant, Argenx, Arialys, and Astellas pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He has patents pending for KLHL11, LUZP4-IgG, SKOR2-IgG, and cavin-4-IgG as markers of neurologic autoimmunity. Dr. Dubey has received funding from the DOD (CA210208, PR220430). Anastasia Zekeridou has patents submitted for DACH1-IgG, PDE0A-IgG, CAMKV-IgG and Tenascin-R-IgG as biomarkers of paraneoplastic neurological autoimmunity; receives research funding from Roche not relevant to this manuscript and consulted for Alexion Pharmaceuticals without personal compensation. Andrew McKeon reported grants from the NIH (Grants RO1NS126227 and U01NS120901) during the conduct of the study; consulting fees from Janssen and Roche (all paid to Mayo Clinic) outside the submitted work; and had a patent for MAP1B antibody issued, a patent for Septins 5, 7, GFAP, PDE10A, KLHL11 antibodies pending, a patent for Septin antibodies and MAP1B antibodies with royalties paid. W. Oliver Tobin has received grants from the National Institutes of Health, and book royalties from the publication of Mayo Clinic Cases in Neuroimmunology (Mayo Clinic Scientific Press) 2022. Orhun H. Kantarci reports no disclosures. B. Mark Keegan served as a consultant to EMD Serono, is a member of the Center for Multiple Sclerosis and Autoimmune Research Mayo Clinic, receives publishing royalties for Common Pitfalls in Multiple Sclerosis and CNS Demyelinating Diseases, and is an Editorial Board member of Multiple Sclerosis and Related Disorders. Deena A. Tajfirouz reports no disclosures. Kevin D. Chodnicki reports no disclosures. Jay Mandrekar reports no disclosures. Claudia F. Lucchinetti accrue revenue for a patent (no. 7101679) regarding aquaporin-4-associated antibodies for diagnosis of neuromyelitis optica and receives research support from the National MS Society, Biogen, and NIH. Sebastian A. Lopez-Chiriboga has served on advisory boards for Genentech and Horizon Therapeutics. Nabeela Nathoo reports no disclosures. Nycole K. Joseph reports no disclosures. Michelle F. Devine reports no disclosures. Jessica A. Sagen reports no disclosures. Sean J. Pittock has received personal compensation for serving as a consultant for Roche/Genentech, Sage Therapeutics, Arialys and Astellas. He has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-LaRoche AG, Genentech, Arialys and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion, and Viela Bio/MedImmune. All compensation is paid to Mayo Clinic. He has received research support from Alexion, Viela Bio/MedImmune, Roche/Genentech and Adimmune. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)-issued and from which he has received royalties and a patent for GFAP-IgG; Septin-5-IgG; MAP1B-IgG; Kelch-like protein 11; PDE10A pending. He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service. The Mayo Clinic Neuroimmunology Laboratory commercially offers MOG-IgG testing, but revenue accrued does not contribute to salary, research support, or personal income. Philippe Cabre reports no disclosures. Eoin P. Flanagan has served on advisory boards for Alexion, Genentech and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. Dr Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. Dr Flanagan has received funding from the NIH (R01NS113828). Dr Flanagan is a member of the medical advisory board of the MOG project. Dr Flanagan is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. Ethics approval: This study has been approved by the appropriate ethics committee and have therefore has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We describe neurologic phenotype, clinical associations, and outcomes in autoimmune brainstem encephalitis., Methods: Medical records of neural-IgG positive autoimmune brainstem encephalitis patients diagnosed at Mayo Clinic (January 1, 2006-December 31, 2022) were reviewed., Results: Ninety-eight patients (57 male) were included. Median age of symptom onset was 51 years (range, 8 months-85 years). Frequent presenting features were ≥1: diplopia (80%), ataxia (78%), dysarthria (68%), vestibulocochlear symptoms (67%), dysphagia (61%), nausea/vomiting (42%), and facial weakness (32%). Altered mental status (11%) was uncommon. Neural antibodies detected were as follows: KLHL-11 (26 patients), GAD65 (high titer, 12), ANNA-1 (anti-Hu, 8), ANNA-2 (anti-Ri, 8), Ma2 (7), IgLON-5 (6), AQP4 (6), MOG (4), glycine receptor (4), GQ1B (4), PCA-1 (anti-Yo, 4), DPPX (2), neurochondrin (2), neurofilament (2), NMDA-R (2), AGNA-1 (SOX-1, 1), ANNA-3 (DACH1, 1), amphiphysin (1), CRMP-5 (1), ITPR-1 (1), PCA-Tr (DNER, 1), and PDE10A (1). Cancer was identified in 55 patients: germ cell (23 patients; 3 extra-testicular), ductal breast adenocarcinoma (8), small cell carcinoma (6, lung 4), adenocarcinomas (6), neuroendocrine carcinoma (3), hematologic (2), squamous cell (2), and other (7). Median modified Ranking score (mRS) at last follow-up was 3 (range, 0-6). Factors associated with poor outcome included abnormal brain MRI, bulbar symptoms, and elevated CSF IgG index. Kaplan-Meier analysis revealed faster progression to wheelchair in patients who were immunotherapy refractory and with elevated CSF IgG index. Diagnostic criteria for autoimmune brainstem encephalitis (definite and probable) are proposed., Interpretation: Autoimmune brainstem encephalitis is a distinct clinical subphenotype of autoimmune encephalitis. Abnormal brain MRI, bulbar symptoms, and elevated CSF-IgG index associate with poor outcome., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To characterize the frequency and clinicoradiologic phenotype of cerebellar involvement in attacks of aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) which are incompletely captured in current diagnostic criteria., Methods: Brain MRI scans from patients with AQP4+NMOSD in the Mayo Clinic database were reviewed, and those with cerebellar T2-hyperintense lesions ≤30 days from attack onset were included for clinical and radiologic characterization., Results: From 432 patients with AQP4+NMOSD, we identified 17 (4%) with cerebellar attacks. The median age at attack onset was 47 years (range, 7-74). Cerebellar symptoms and signs were noted in 16 (94%) of 17 and the remaining patient was intubated preventing a detailed cerebellar exam. The median Expanded Disability Status Scale score at nadir was 5 (range, 2-9.5). Sixteen (94%) had other regions involved during the attack, most frequently with brainstem or area postrema involvement. Cerebellar MRI T2-lesions (8 single; 11 contiguous with the brainstem; 6/15 [35%] enhancing) were located in cerebellar peduncles, 15 (inferior, 5; middle, 10; superior, 10), and cerebellar parenchyma, 8 (dentate, 4; medial, 2; lateral, 4). T2-lesions persisted in 9 (82%) of 11 beyond 6 months., Discussion: Cerebellar involvement during attacks of AQP4+NMOSD is rare but the associated neurologic deficits tend to be severe. Cerebellar peduncle or dentate nucleus T2-lesions are frequent MRI accompaniments. Clinical features and MRI lesion patterns of cerebellar involvement could be incorporated into future iterations of AQP4+NMOSD criteria.

Background and Objective: Despite constituting one-third of suspected autoimmune encephalitis (AE) patients, antibody-negative cases without typical AE features are understudied. We aim to characterize the clinical phenotypes and long-term outcomes of "possible only" and "probable" AE cases., Methods: We conducted a retrospective analysis of adult patients evaluated at Mayo Clinic's Autoimmune Neurology Clinic (01/01/2006-12/31/2020), meeting diagnostic criteria for "possible only" or "probable but antibody-negative" AE, with ≥ 1 year of follow-up. All patients underwent neural antibody testing., Results: Among fifty-one patients, six had a change in diagnosis (non-autoimmune, 2) and were excluded from further analysis. Forty-five patients were analyzed [median age, 61 years (range 20-88); female, 21 (47%); median follow-up, 36 months (range 12-174)]. A nadir modified Rankin Scale (mRS) ≥ 3 was recorded in 41/45 (91%). CSF was inflammatory in 20/44 (45%) and MRI had encephalitic changes in 21/45 (47%). Unclassified neural-specific IgG staining on tissue-based assay was detected in five (11%). Two patients (4%) had paraneoplastic causation. Relapses (> 3 months from onset) were noted in 14 (31%). Memory dysfunction (69%), attention deficits (38%), and gait instability (29%) were the most frequent at the last follow-up. Most patients (76%) were independent at the last follow-up and only two required an assistive device to ambulate; 11 patients (24%) had poor neurological outcome (mRS ≥ 3). Higher mRS score and gait assistance requirement at 3 months were predictive of poor outcome (P ≤ 0.01)., Discussion: Despite significant disability at initial disease stages, most antibody-negative AE patients regain independent functioning. Early functional status and gait assistance requirements may predict long-term prognosis., Competing Interests: Declarations. Conflict of interest: Georgios Mangioris and Emma Orozco report no disclosures. Divyanshu Dubey has consulted for UCB, Immunovant, Argenx, Arialys and Astellas pharmaceuticals. All compensations for consulting activities are paid directly to Mayo Clinic. He is a named inventor on filed patent that relates to KLHL11 as marker of autoimmunity and germ cell tumor. He has patents pending for LUZP4-IgG, cavin-4-IgG and SKOR2 IgG as markers of neurological autoimmunity. He has received funding from the DOD (CA210208 & PR220430), David J. Tomassoni ALS Research Grant Program and UCB. Eoin P. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. He is a site principal investigator in a randomized clinical trial of Rozanolixizumab for relapsing myelin oligodendrocyte glycoprotein antibody-associated disease run by UCB. He is a site principal investigator and a member of the steering committee for a clinical trial of satralizumab for relapsing myelin oligodendrocyte glycoprotein antibody-associated disease run by Roche/Genentech. He has received funding from the NIH (R01NS113828). He is a member of the medical advisory board of the MOG project. He is an editorial board member of Neurology, Neuroimmunology and Neuroinflammation, The Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. Sean J. Pittock has received personal compensation for serving as a consultant for F. Hoffman-LaRoche AG, Genentech, Sage Therapeutics, Astellas and Arialis. He’s received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-LaRoche AG, Genentech, and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion/Astra Zeneca Rare Diseases, and Horizon/Amgen. All compensation is paid to Mayo Clinic. He has received research support from Alexion/Astra Zeneca Rare Diseases, Horizon/Amgen, F. Hoffman-LaRoche AG, Genentech and Adimmune. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)-issued and from which he has received royalties. He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service. He has patents issued for a variety of target antigens including MAP1B-IgGs, KLCHL11, SKOR2, and LUZP4 IgGs. Anastasia Zekeridou has patents submitted for Tenascin-R-IgG, PDE10A-IgG, CAMKV-IgG, and DACH1-IgG as biomarkers of paraneoplastic neurological autoimmunity. She has received research funding from Roche not relevant to this work and the Mayo Clinic Center for MS and Autoimmune Neurology. She’s consulted, without personal compensation, for Alexion Pharmaceuticals. Andrew McKeon reports research funding from National Institutes of Health (NIH: RO1NS126227, U01NS120901), patents issued for GFAP and MAP1B-IgGs and patents pending for CAMKV, PDE10A, Septins-5 and -7, and KLCHL11-IgGs, and has consulted for Janssen and Roche pharmaceuticals, without personal compensation. Ethical approval: This retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB, 21-001297). Medical records of patients who consented to research review were included., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)