Immune-mediated epilepsy: Which Patients Should Be Tested? December 04, 2012

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1 : Which Patients Should Be Tested? December 04, 2012 Christian G. Bien, Epilepsy Center Bethel, Germany American Epilepsy Society Annual Meeting

2 Disclosure Service on scientific advisory boards of UCB, Eisai. Industry-funded travel with support of Eisai, UCB and Desitin. Honoraria for educational speaking engagements from Eisai, UCB, GlaxoSmithKline, Desitin, Grifols. Dr. Bien s employer, Krankenhaus Mara, runs a laboratory for the detection of anti-neural autoantibodies. American Epilepsy Society Annual Meeting 2012

3 Learning Objectives By the end of this lesson, you should be able to identify epilepsy patients in which testing for antineural autoantibodies is promising (i.e., has a favorable balance between positive and negative results). American Epilepsy Society Annual Meeting 2012

4 - Tentative definition - Brain disorder with recurrent seizures 1, directly 2 or indirectly 3 caused by elements of the adaptive immune-system (antibodies, T cells). Immunotherapy may improve the condition. 1 Seizures are not necessarily the only symptom. 2 E.g., antibodies modify synaptic transmission in an epileptogenic manner 3 E.g., cytotoxic T cells destroy brain cells; the resulting scar gives rise to seizures

5 - Antibodies and potential targets - Vincent, Bien, Irani, Waters, Lancet Neurology 2011

6 Antibody testing Antibody lab, Bethel Epilepsy Centre, Bielefeld, Germany. Biochip assays by Euroimmun, Lübeck. > Antikörperlabor

7 - When should antibody testing be done? - Syndrome : Limbic encephalitis Faciobrachial dystonic seizures Encephalopathy Patient and history: Young females Other autoimmune conditions Seizure types and patterns: Unexplained new onset epilepsy in adult life Onset with status or very high seizure frequency Pilomotor seizures Paraclinical findings: EEG: extreme delta brush CSF: cell count or unmatched oligoclonal bands MRI: encephalitic lesions Histopathology: chronic encephalitis

8 - Case 1: G., H. 66 yrs: Limbic encephalitis - Slide Unavailable

9 Case 1: G., H. 66 yrs: MRI: Limbic encephalitis LGI1 antibodies, titer 1:250 (serum)

10 - Case 2: O., N. 24 yrs: Encephalopathy - Disease onset: Within one week Seizures (tonic-clonic? frontal lobe?) Apraxia Disorientation Aphasia Aggression Compulsory treatment in psychiatric hospital

11 - Case 2: O., N. 24 yrs: Encephalopathy - Slide Unavailable NMDAR antibodies 1:4000 (serum), 1:250 (CSF)

12 Case 3, 24 y : Faciobrachial dystonic seizures LGI1 antibodies, 1:500 (serum), 1:12 (CSF) Original description: Irani SR et al., Ann Neurol 2011;69:892. Here: Patient of Dr. Frank Bösebeck, Rotenburg/W., Germany

13 - Conceptual - Clinical suspicion Onco Ab NSAb Onco/NSAb-negativ Tu +/- Tu +/- Tu - Tu + GAD or neuropil abs or clinical supportive evidence* Immuno-tx successful Immuno-tx unsuccessful Immuno-tx successful Immuno-tx unsuccessful Definite PNS Definite Immune Probable Immune Possible Immune Def/poss PNS PNS=paraneoplastic neurological syndrome; NSAb= novel surface antibody ; *Other ab mediated disease or organ-specific autoimmunity or preceding infectious/febrile disease Modified from: Graus et al., JNNP 2004; Zuliani et al., JNNP Succesful Immuno-Tx =improvement by >1 mrs

14 Impact on Clinical Care and Practice Limbic encephalitis, seizures in the context of encephalopathy, faciobrachial dystonic seizures, and other features suggest autoimmune epilepsy. They should prompt antibody testing and immunotherapy.

15 - Overview of autoantigens - Intracellular antigen Surface antigen Neuropil antibodies Onconeural VGKC complex Hu Ma other? GAD mglur1 LGI1 CASPR2? NMDAR AMPAR GABA B R mglur5 DPPX? 2001/ Description 1980/90s Published patients > >200 > Tumor >90% <10% 100% 0%/<25% 40% 50% 60% 100% 0%

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