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

• Type of Material: Article
• 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
• Language: English
• Date: 2019-03-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Wiley Periodicals, Inc. © 2019 International League Against Epilepsy
• Final Published Version (URL): http://dx.doi.org/10.1111/epi.14662
• Title of Journal or Parent Work: Epilepsia
• Volume: 60
• Issue: 3
• Start Page: 452
• End Page: 463
• Grant/Funding Information: OT received salary support from the UNMC College of Medicine Physician-Scientist Award, and funds for the experiments from the Department of Neurological Sciences, UNMC.; Additional support was provided by NINDS grant 1R01NS097776 (RD), NIMH grant 3P30MH062261 (HSF) as well as NSF grants NS104705 (SMD) and NSF1456818 (SMD).
• Keywords: Diagnosis; animal model; Mechanisms; NMDA receptor; Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; anti-NMDAR antibodies; autoantibodies; Suppression; Follow up; Neurosciences & Neurology; Functional anatomy; Status epilepticus; refractory seizures; Cerebrospinal fluid; Memory; Mice; autoimmune seizures
• Research Categories: Health Sciences, Immunology; Health Sciences, Pharmacology; Biology, Neuroscience

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.