Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights

Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) ‘Perspective’ article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activity in vitro and in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3B peptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have ‘frenetic character’- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different ‘faces’ in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.

Limbic autoimmune encephalitis with antibodies to glutamate decarboxylase (GAD)

Limbic encephalitis (LE) is a rare neurological syndrome, in most cases has a paraneoplastic nature, but recently there has been a large number of observations of idiopathic autoimmune LE associated with antibodies to neuronal membrane proteins. A clinical case of a disease in a 13-year-old patient with the detection of antibodies to glutamate decarboxylase (GAD) is described. The debut of the disease is marked by a decrease in memory for current events after the first convulsive attack during 2 months.

NR2 antibodies as diagnostic and prognostic stroke biomarker

Given the high percentage of disability and mortality resulting from a stroke, search of new ways to improve early diagnosis and optimize therapeutic approaches is highly relevant. The article reviews the studies of NR2 antibodies to glutamate N-methyl-D-aspartate (NMDA) receptors as a biomarker in acute stroke. The review shows that this biomarker is suitable for determining the presence of ischemic process in the brain and the degree of destruction of brain tissue, both in the first hours of stroke and at follow-up. In addition, the analysis of NR2 antibodies can be informative to predict the worsening, the increase in the locus size, which can contribute to the timely correction of treatment and will improve the effectiveness of the therapy. The prognostic potential of NR2 antibodies can be used for personalized therapeutic approach. However, currently the lack of studies of NR2 antibodies in acute stroke requires further study of this biomarker.