Cerebellar Ataxia With Anti-DNER Antibodies: Outcomes and Immunologic Features
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Lippincott Williams and Wilkins
Abstract
Background and Objective s There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies. Methods Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface. Results Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro. Discussion DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments. © American Academy of Neurology.
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Adult, Aged, Aged, 80 and over, Cerebellar ataxia, Female, Humans, Immunoglobulin g, Male, Middle aged, Nerve tissue proteins, Proteomics, Receptors, cell surface, Retrospective studies, Young adult, Bleomycin, Brentuximab vedotin, Corticosteroid, Cyclophosphamide, Dacarbazine, Doxorubicin, Epidermal growth factor, Gadolinium, Immunoglobulin, Immunoglobulin g1, Immunoglobulin g3, Leukocyte antigen, Oligoclonal band, Pembrolizumab, Rituximab, Vinblastine, Cell surface receptor, Nerve protein, Acute confusion, Anaplastic large cell lymphoma, Animal experiment, Animal model, Article, Ataxia, Ataxic gait, B lymphocyte, Bone marrow donor, Brain membrane, Cancer chemotherapy, Cancer patient, Cell membrane, Cell surface, Cerebellar slice, Cerebellum, Cerebellum atrophy, Cerebrospinal fluid, Clinical feature, Cognitive defect, Controlled study, Cytosolic fraction, Disabled person, Disease severity, Dysarthria, Ex vivo study, Follow up, Fractionation, Gene overexpression, Gray matter, Gray matter volume, Hematologic malignancy, Hla system, Hodgkin disease, Human, Human cell, In vitro study, Leukocyte, Long term care, Neurologic disease, Neuropathy, Nonhuman, Nuclear magnetic resonance imaging, Nystagmus, Outcome assessment, Plasmapheresis, Protein expression, Protein expression level, Purkinje cell, Rankin scale, Rat, T1 weighted imaging, Temporal lobe epilepsy, Tonic clonic seizure, Metabolism, Retrospective study, Very elderly