A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis

• Authors: Raymond Dingledine, Emory University; Olga Taraschenko, University of Nebraska Medical Center; Howard S. Fox, University of Nebraska Medical Center; Sean J. Pittock, Mayo Clinic; Anastasia Zekeridou, Mayo Clinic; Maftuna Gafurova, University of Nebraska Omaha; Ember Eldridge, University of Nebraska Medical Center; Jinxu Liu, Creighton University; Shashank M. Dravid, Creighton University
• Journal Title: Epilepsia
• Volume: Volume 60, Number 3
• Publisher: Wiley | 2019-03-01, Pages 452-463
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/epi.14662
• Subjects: Health Sciences, Immunology; Biology, Neuroscience; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Neurosciences & Neurology; animal model; anti-NMDAR antibodies; autoantibodies; autoimmune seizures; refractory seizures; NMDA receptor; Cerebrospinal fluid; Status epilepticus; Functional anatomy; Follow up; Diagnosis; Memory; Mice; Suppression; Mechanisms

Abstract

Objective: Seizures develop in 80% of patients with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. Methods: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. Results: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. Significance: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.