Autoimmune Epilepsy

Abstract

The field of autoimmune epilepsy has evolved substantially in the last few decades with discovery of several neural autoantibodies and improved mechanistic understanding of these immune-mediated syndromes. A considerable proportion of patients with epilepsy of unknown etiology have been demonstrated to have an autoimmune cause. The majority of the patients with autoimmune epilepsy usually present with new-onset refractory seizures along with subacute progressive cognitive decline and behavioral or psychiatric dysfunction. Neural specific antibodies commonly associated with autoimmune epilepsy include leucine-rich glioma-inactivated protein 1 (LGI1), N-methyl-D-aspartate receptor (NMDA-R), and glutamic acid decarboxylase 65 (GAD65) IgG. Diagnosis of these cases depends on the identification of the clinical syndrome and ancillary studies including autoantibody evaluation. Predictive models (Antibody Prevalence in Epilepsy and Encephalopathy [APE2] and Response to Immunotherapy in Epilepsy and Encephalopathy [RITE2] scores) based on clinical features and initial neurological assessment may be utilized for selection of cases for autoimmune epilepsy evaluation and management. In this article, we will review the recent advances in autoimmune epilepsy and provide diagnostic and therapeutic algorithms for epilepsies with suspected autoimmune etiology.

Keywords: Autoimmune limbic encephalitis; Diagnosis; Epilepsy; Immunotherapy.

Fig. 1

Timeline of neural specific antibody discovery

Fig. 2

Proposed autoimmune epilepsy diagnostic criteria stratifying patients based on APE2 score and immunotherapy trial into “definite,” “possible,” or “probable” autoimmune epilepsy. APE2 = Antibody Prevalence in Epilepsy and Encephalopathy; CSF = cerebrospinal fluid; MRI = magnetic resonance imaging. Superscript letter “a” indicates reasonable exclusion of alternative etiology (genetic, infectious encephalitis, neoplasm, neurodegenerative process, metabolic or toxic encephalopathy). Superscript letter “b” indicates rare patients with leucine-rich glioma-inactivated protein 1 antibody and mild presentation was found to have APE2 score < 4. Superscript letter “c” indicates neural specific antibodies clinically validated to have an association with autoimmune epilepsy (AMPA-R = amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, amphiphysin; AK5 = adenylate kinase 5; ANNA-1 = antineuronal nuclear antibody 1; ANNA-2 = antineuronal nuclear antibody 2; ANNA-3 = antineuronal nuclear antibody 3; DPPX = dipeptidyl-peptidase-like protein 6; CASPR-2 = contactin-associated protein 2; CRMP-5 = collapsin response mediator protein-5; GAD65 = glutamic acid decarboxylase 65 (serum > 20 nmol/L or CSF detected); GABABR = γ-aminobutyric acid B receptor; GABAAR = γ-aminobutyric acid A receptor; GFAPα = glial fibrillary acidic protein (CSF detected), IgLON5; LGI1 = leucine-rich glioma-inactivated protein 1, Ma-1/Ma-2; MOG = myelin oligodendrocyte glycoprotein; mGluR5 = metabotropic glutamate receptor 5, Neurexin-3α; NMDA-R = N-methyl-d-aspartate receptor (preferably CSF detected), PCA2 = Purkinje cell antibody type 2, PCA Tr) evaluated and confirmed by latest and validated techniques. Superscript letter “d” indicates standardized immunotherapy trials should be considered. 12-week IVMP trial: 1 g, intravenously once per day for 3 consecutive days, then once weekly for 5 weeks, followed by once every 2 weeks for 6 weeks, for total 12 weeks’ therapy; 6-week IVMP trial: 1 g, intravenously once per day for 3 consecutive days, then once weekly for 5 weeks; 12-week IVIG trial: 0.4 g/kg daily for 3 days followed by 0.4 g/kg every week for 6 weeks and then every 2 weeks for 6 weeks; 6-week IVIG trial: 0.4 g/kg daily for 3 days followed by 0.4 g/kg every week for 6 weeks. Superscript letter “d” indicates > 50% reduction in seizure frequency

Fig. 3

Extreme delta brush in a patient with NMDA-R encephalitis. Anterior–posterior bipolar montage. Sensitivity, 5 μV; high pass filter, 35 Hz

Fig. 4

(A–E) Patient 1 with LGI1 IgG limbic encephalitis. Brain MRI (FLAIR sequence) demonstrating bilateral medial temporal hyperintensities on axial (A) and sagittal (B) sections. Patient 2 with ANNA-1 IgG limbic encephalitis. Brain MRI (FLAIR sequence) demonstrating bilateral medial temporal hyperintensities on axial (C) and sagittal (D) sections. Patient 3 with Ma-2 IgG limbic encephalitis. Brain MRI (FLAIR sequence) demonstrating bilateral medial temporal (right greater than left) hyperintensities on axial (E) and sagittal (F) sections. ANNA-1 = antineuronal nuclear antibody-1; FLAIR = fluid-attenuated inversion recovery; LGI1 = leucine-rich glioma-inactivated protein 1

Fig. 5

Management algorithm for autoimmune epilepsy. Ab = antibody; APE2 = Antibody Prevalence in Epilepsy and Encephalopathy; CSF = cerebrospinal fluid; IVIG = intravenous immunoglobulin; IVMP = intravenous methyl prednisolone; PLEX = plasmapheresis