Autoimmune epilepsies:

Transcription

1 Autoimmune epilepsies: Syndromes and Immunotherapies Sarosh R Irani Associate Professor, Wellcome Trust Intermediate Fellow and Honorary Consultant Neurologist Nuffield Department of Clinical Neurosciences, University of Oxford

2 Immune causes of epilepsy STRUCTUAL GENETIC INFECTIOUS METABOLIC IMMUNE Rasmussens encephalitis FIRES / NORSE Status epilepticus T2 / FLAIR changes on imaging OTHERS

3 What are Autoimmune epilepsies? Any contribution of immune system? Role of cytokines / complement? Potential primary contribution pathogenic?

4 Antibodies with pathogenic potential: The simple rules IgG autoantibodies which target extracellular aspect of native neuronal membrane protein Antigen-EGFPexpressing HEK cells Patient IgG Rat brain sections bound by patient IgG Hippocampal neurons bound by patient IgG

5 Common autoantibodies in epilepsies and encephalopathies Neuronal surface LGI1 / CASPR2 NMDAR Others GABA B R, GABA A R, AMPAR Intracellular GAD Other VGKC-complex

6 LGI1-antibody limbic encephalitis Later years Subacute onset Amnesia, disorientation Seizures +/- Psychiatric features Dysautonomia Sleep disturbances <10% neoplasms Hyponatraemia Normal CSF Vincent et al 2004; Thieben et al 2004

7 Faciobrachial dystonic seizures (FBDS) Adult-onset Arm and Face Frequent Brief Dystonic Stereotyped LGI1-antibodies Number of Patients Age (years) 100 Irani et al Ann Neurol; Thompson et al in submission

8 FBDS often precede Limbic Encephalitis Days FBDS precede Cognitive Impairment Cognitive Impairment precedes FBDS -200

9 Prevention of cognitive disability and late-onset epilepsies? LIMBIC ENCEPHALITIS HIPPOCAMPAL SCLEROSIS Bien et al Neurology

10 One major caveat: Voltage-gated potassium channel (VGKC) complex antibodies More CNS: Limbic Encephalitis Faciobrachial dystonic Szs >Morvan s LGI1 DTX VGKC C A S P R 2 More PNS: Morvan s Neuromyotonia >Limbic Encephalitis C O N T A C T I N 2 PATHOGENIC Extracellular

11 The caveat in the VGKC-complex UNPERMEABILISED LIVE CELL BASED ASSAY VGKC-complex VGKC-complex antibodies: (pm) in solution LGI1 (N=64) CASPR2 (N=20) Antigen (N=13) Clinic cohort (N=13) Epilepsy (N=582) Autonomic (N=95) LEMS (N=45) LGI1 CASPR2 antigen Hu (N=78) Healthy Smokers (N=38) Cut-off HC (N=75) Anti-Kv1.1 Patient 1 Kv1.1/1.2/ 1.6 & EGFP Patient IgG Merge Kv1.1/1.2/ 1.6 & EGFP Anti-Kv1.1e Merge PERMEABILISED FIXED CELL BASED ASSAY HEK-Kv1.1 HEK-Kv1.2 HEK-Kv1.6

12 Number (total = 27) 10 What did these patients with intracellular antibodies have? * * * Autoimmune Epilepsy: Symptomatic / IGE Neurodegenerative Epilepsy: Cryptogenic Pain Encephalopathy Dysautonomia Amnesia HS VGKC-complex and Kv1.2-HEK RIA antibodies (pm) VGKC-complex and Kv1.2-HEK RIA antibodies (pm) AEDs AEDs Days from onset ST Days from onset Seizures / year Seizures / year Clinical Features NMT with EMG confirmation NMT with EMG confirmation Limbic encephalitis with radiological confirmation NMT plus SCLC LEMS plus Hu-antibody related sensory neuropathy and SCLC Myelitis plus progressive cognitive decline Cryptogenic TLE with prominent amnesia / depression Cryptogenic probable frontal lobe epilepsy Isolated amnesia Cryptogenic TLE Cryptogenic TLE Widespread neuropathic pain Widespread neuropathic pain and depression Cryptogenic focal motor SZs with prominent anxiety/amnesia Cryptogenic TLE Cryptogenic epilepsy Cryptogenic epilepsy Cryptogenic epilepsy Dysautonomia Idiopathic generalised epilepsy Alzheimer s disease and a single SZ Parkinson s disease dementia Healthy smoker. No neurological symptoms TLE related to left hippocampal sclerosis TLE related to left hippocampal sclerosis Epilepsy after childhood meningitis TLE secondary to cerebrovascular accident Disease aetiology Autoimmune Autoimmune Autoimmune Paraneoplastic Paraneoplastic Genetic Degenerative Degenerative Healthy Structural Structural Structural Structural

13 Limbic Encephalitis & Faciobrachial dystonic Szs; NMT DTX Few immune-mediated Chronic epilepsy, some pain syndromes, CJD, other non-immune

14 Antibodies against the NMDA-R Initially described in young females with ovarian teratomata Immunotherapy-responsive condition Characteristic clinical features: psychiatric, movement disorder, dysautonomia, hypoventilation Dalmau et al Ann Neurol

15 Shift in demographics N=44 from UK/Europe Similar clinical features but differing demographics Age at disease onset Female PNP Male PNP Female NPNP Male NPNP Children NPNP = non-paraneoplastic PNP = paraneoplastic

16 Sequential Seizure and Movement disorder in the same limb Movement disorder with normal EEG Myoclonic / clonic activity at 3.5Hz with hemispheric spread Recurrence of movement disorder with normal EEG

17 Effects of immunotherapies in NMDAR-antibody encephalitis All 1 st line responders mrs 6 = Death mrs 3 = Requires some help, but able to walk unassisted. 1 st line non-responders 1 st line plus 2 nd line mrs 1 = N ADLs, despite some symptoms 1 st line = Steroids, IVIG, PLEX 2 nd line= Cyclophosphamide, Rituximab Titulaer et al Lancet Neurol

18 Immunotherapy-response of patients with autoimmune epilepsies LGI1 / CASPR2 Toledano et al Neurology

19 IVMP / IVIG responsive epilepsies Mostly LGI1+ 60% received >1 AED Followed by prospectivelyassessed IT course Follow up at 6-12 weeks

20 Natural history of the commonest syndromes Severity of symptoms NMDAR GAD LGI1/CASPR2 1 5 Years Varley, Vincent and Irani 2015 J Neurol

21 Autoantibodies to GAD (glutamic acid decaroxylase) Highly refractory to all interventions Either: Nihilism to IT Offer patients low improvement rate Think about novel therapies Malter et al 2010 Ann Neurol

22 Novel options Tociluzimab (IL-6R blockade) Bortezomib

23 Conclusions Autoantibody associated epilepsies benefit from IT Principles Treat early Escalate if refractory Antigenic target determined strength and duration Continue for variable periods Novel immunotherapies hold hope for the future