1. Drug Resistant Epilepsy: Diagnostic and Treatment Options Mark A. Granner, MD Medical Director, Epilepsy Monitoring Unit Co-Director, Iowa Comprehensive Epilepsy Program Professor and Vice Chair for Clinical Programs Department of Neurology University of Iowa

2. Overview Definitions and statistics Treatment options for drug resistant epilepsy – AEDs, diet, VNS Introduction to epilepsy surgery The multidisciplinary approach to epilepsy care The Iowa Comprehensive Epilepsy Program Iowa Comprehensive Epilepsy Program

3. Definitions Seizure – An episode of altered behavior or awareness – Associated with too much excitation of a population of nerve cells (neurons) Epilepsy – The tendency to have recurrent, unprovoked seizures (brain makes seizures happen) Acute symptomatic (provoked) seizure – A seizure occurring in the setting of some systemic provoking factor (normal brain, body makes seizures happen) Iowa Comprehensive Epilepsy Program

4. Definitions Acute repetitive seizures (“cluster”) – A period of increased severity or frequency of seizures in an epilepsy patient Status epilepticus – A single prolonged seizure (> 5-10 min) – Repeated seizures without recovery to baseline SUDEP – Sudden unexpected death in epilepsy patients 1-6 per 1000 patients per year Probably under recognized, under reported Needs further study Iowa Comprehensive Epilepsy Program

5. Definitions Drug resistant epilepsy – Failure of at least TWO seizure medications to completely control seizures Appropriately chosen for seizure type Taken as prescribed Well tolerated (not failed due to side effects) Iowa Comprehensive Epilepsy Program

6. Drug Resistant Epilepsy 470 patients with previously untreated epilepsy –Seizure-free to 1 st medication 47% –Seizure-free to 2 nd medication 13% –Seizure-free to 3 rd medication or beyond 4% 36% of epilepsy patients are drug resistant! The new generation of medications are generally safer (fewer side effects), but are not significantly more effective. Kwan P, Brodie M. NEJM 2000; 342(5) Iowa Comprehensive Epilepsy Program

7. Epidemiology of Seizures & Epilepsy In the U.S. – 10% lifetime risk of a seizure – 4% lifetime risk of recurrent seizures – 3% lifetime risk of epilepsy – 0.6% prevalence of epilepsy 2,000,000 Americans $15,500,000,000 U.S. annual cos t Higher in developing countries Iowa Comprehensive Epilepsy Program

8. Epidemiology of Epilepsy Iowa Comprehensive Epilepsy Program

9. Epidemiology of Epilepsy 2,000,000 with epilepsy 600,000 with DRE 1500 surgeries a year Iowa Comprehensive Epilepsy Program 120,000 surgery candidates

10. Options in Drug Resistant Epilepsy Medication – New, study drugs Diet – Ketogenic, Atkins Vagus Nerve Stimulator Epilepsy Surgery Gamma knife Brain stimulation Iowa Comprehensive Epilepsy Program

11. U.S. Epilepsy Drug Development 185719121937195419601974197519781993199519972000200520082009 Bromide salts Clonazepam Ethosuximide Primidone Phenytoin PhenobarbitalLamotrigine Felbamate Gabapentin Valproate Carbamazepine Oxcarbazepine Zonisamide Levetiracetam Topiramate Tiagabine Rufinamide Pregabalin 1999 Lacosamide 2012 Ezogabine Iowa Comprehensive Epilepsy Program

12. Diets in Adults With Epilepsy Ketogenic diet – Effective (40% seizure reduction) – Compliance challenging (about 50% don’t follow or stop) – Minimal short term side effects – Long term consequences not known Modified Atkin’s diet may be as effective and better tolerated

13. Vagus Nerve Stimulator Effectiveness – Average seizure reduction (24.5%) – 50% responder rate (31%) – Seizure free (0%) Side Effects – Hoarseness/voice change (37.2%) All patients should undergo video-EEG prior to VNS – Rule-out non-epileptic events – Screen for surgery VNS Study Group. Neurology 1995 Arain, et al. Epilepsy & Behavior 2011 Iowa Comprehensive Epilepsy Program

14. UIHC VNS Experience > 100 patients currently followed 21 implant surgeries in 2012 Seizure-free about 5-10% Seizure reduction about 50% Patient satisfaction high Iowa Comprehensive Epilepsy Program

15. Indications for Epilepsy Surgery Drug resistant epilepsy Localized seizures Which can safely and effectively be resected Informed and willing patient Referral to surgical epilepsy center – Epilepsy duration before referral 18 (2-58) years – 61% sent by neurologist – 39% self-referred, never advised of surgery – 14% advised by neurologist not to have surgery – 83% seizure free Iowa Comprehensive Epilepsy Program Benbadis et al. Seizure 2003.

16. Epilepsy Surgery Evaluation Drug Resistant Epilepsy Phase 1 (Non-invasive) Phase 2 (Invasive) Concordant Discordant Not a candidate Not a candidate Phase 3 - Wada test - Surgery Phase 3 - Wada test - Surgery Case Conference Iowa Comprehensive Epilepsy Program

17. Epilepsy Surgery Evaluation Phase 1 (Non-invasive) MRI (3T, sz protocol) Ictal video-EEG Neuropsychology PET, SPECT MEG Phase 2 (Invasive) Intracranial video-EEG Indications: – Phase 1 data not agreeing – Phase 1 data not localizing – Concern of left vs. right side – Concern of middle vs. surface temporal lobe – Onset outside temporal lobe Iowa Comprehensive Epilepsy Program

18. Types of Surgery Lobectomy (removal of all or most of lobe) – Temporal >> frontal Corticectomy (removal of area of cortex) Hemispherectomy (removal/disconnection of hemisphere) Corpus callosotomy (disconnection) Multiple subpial transection Iowa Comprehensive Epilepsy Program

19. Outcome Measures Seizure freedom – Anterior temporal lobectomy 60-80% – Extratemporal resection 25-50% – Better if lesion on MRI – Worse if widespread or multifocal seizure onset Complications – Major < 2% (stroke, hemorrhage) – Infection – Vision loss (temporal lobectomy) – Memory or mood change Iowa Comprehensive Epilepsy Program

20. Seizure Outcome After Anterior Temporal Lobectomy Iowa Comprehensive Epilepsy Program Wiebe, et al. NEJM 2001

21. Other Outcomes Mean Seizure Severity Score Mean Global Quality of Life Employed or Attending School Iowa Comprehensive Epilepsy Program Wiebe, et al. NEJM 2001

22. Seizure Outcome at UIHC: Anterior Temporal Lobectomy Engel Score Percent 2007 Surgical Outcome Survey Iowa Comprehensive Epilepsy Program Grade 1 – Seizure free Grade 2 – Rare seizures Grade 3 – Significant reduction Grade 4 – No improvement n=88 Iowa Comprehensive Epilepsy Program

23. Sudden, unexpected death in epilepsy (SUDEP) Leading cause of premature death in epilepsy patients Sudden death 20 times greater than in general population Risks – Generalized tonic clonic (“grand mal”) seizures – Male gender – Long duration of epilepsy – Seizure medicine polytherapy Possible mechanisms – Respiratory depression – Cardiac arrhythmia – Autonomic dysfunction Iowa Comprehensive Epilepsy Program Shorvon, Tomsen. Lancet, 2011.

24. Incidence of SUDEP Shorvon, Tomsen. Lancet, 2011. Iowa Comprehensive Epilepsy Program

25. Research at the Iowa Comprehensive Epilepsy Program Human brain physiology – Auditory physiology – Microdialysis Respiratory mechanisms – SUDEP, SIDS – Study of respiratory monitoring on EMU Human-computer interface Iowa Comprehensive Epilepsy Program

26. Services Offered: Iowa Comprehensive Epilepsy Program Consultation – Episodes of unknown nature – New onset seizures – Drug resistant epilepsy – Special populations (pregnancy, elderly) Epilepsy monitoring unit – 9 beds adult / 5 beds pediatric – Specialty nursing staff – Epilepsy fellowship trained physicians – Safety protocols – 24-hour monitor observation Diagnostic tests – Electroencephalography (routine, prolonged outpatient, inpatient) – Imaging (MRI, fMRI, PET, SPECT) – Neuropsychology Multidisciplinary team – Neurosurgery – Psychiatry – Neuropsychology – Pharmacy – Social services – Physical, occupational therapy Iowa Comprehensive Epilepsy Program

27. Multidisciplinary Epilepsy Clinic Joint effort of Neurology, Neurosurgery, Psychiatry Launching later in 2013 New clinic space on Pomerantz Lower Level Coordinated visits with more than one care provider in same day Coordinated tests (EEG, MRI, Neuropsychology) Drug resistant or surgical epilepsy – Maybe expand to other patient populations

28. Emergency Department Emergency Department Primary Care Neurologist Epilepsy Center First seizure Epilepsy Management Iowa Comprehensive Epilepsy Program Seizures controlled Seizures not controlled/diagnosis in question Initial consultation Seizures not controlled/diagnosis in question Medication withdrawal 0 0 0-1 12 3 3 36+ Month Seizures controlled Modified from: National Association of Epilepsy Centers, 2010