Objective To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.
Methods We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003–2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).
Results On review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5–83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.
Interpretation High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.
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Contributors AB designed/conceptualised the study, acquired/analysed the data, drafted the manuscript and composed the tables/figures. ES, EPF, DD, AZ, SSS, AG, EN and AM acquired/analysed the data, and revised the manuscript for intellectual content. SJP and NLZ designed/conceptualised the study, acquired/analyzed the data, revised the manuscript for intellectual content and supervised the study.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests AB has no disclosures to report. ES has no disclosures to report. EPF is a site principal investigator in a randomised placebo-controlled clinical trial of Inebilizumab (A CD19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio. He receives no personal compensation and just receives reimbursement for the research activities related to the trial. DD has a patent pending for Kelch-like protein 11 as a marker of neurological autoimmunity and has received research support from Grifols, Translational Research Innovation and Test Development Office and, Center for Clinical and Translational Science. DD has consulted for UCB and Astellas. All compensation for consulting activities is paid directly to Mayo Clinic. AZ has a patent pending for PDE10A-IgG as a biomarker of neurological autoimmunity. SS has no disclosures to report. AG has a patent pending for MAP1B IgG as a biomarker of neurological autoimmunity and small-cell lung cancer. EN has no disclosures to report. AM reports grants from Alexion, grants from Grifols, grants from Euroimmun, outside the submitted work; in addition, AM has a patent for Septin-5-IgG pending, a patent for PDE10A-IgG pending, a patent for MAP1B-IgG pending, and a patent for GFAP-IgG pending. SJP reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants from Grifols, Autoimmune Encephalitis Alliance; grants, personal fees, non-financial support and other from MedImmune; SJP has a patent (patent #8889102) (application#12-678350) on neuromyelitis optica autoantibodies as a marker for neoplasia, and also a patent (patent #9891219B2) (application#12-573942) on methods for treating neuromyelitis optica (NMO) by administration of eculizumab to an individual that is aquaporin-4 (AQP4)-IgG autoantibody positive; SJP also has patents pending for the following IgGs as biomarkers of autoimmune neurological disorders (septin-5, Kelch-like protein 11, GFAP, PDE10A and MAP1B). NLZ has no disclosures to report.
Patient consent for publication Not required.
Ethics approval This study was approved by the institutional review board of the Mayo Clinic, Rochester, Minnesota.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Deidentified participant data will be made available to any qualified investigator on reasonable request directed to the corresponding author (NLZ).
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