Epilepsy: Challenges & Therapies

1. Epilepsy: Challenges & Therapies Orrin Devinsky, M.D. NYU Epilepsy Center

2. Diagnostic Challenges • Define epilepsy syndrome • Video-EEG monitoring • Understand the cause of epilepsy • High resolution MRI • Genetic studies (GEFS+, Chromosomal microarrays) • Define factors that provoke seizures • FAILURE • Identify long-term effects of epilepsy &s its treatment

3. Therapeutic Challenges • No seizures, no side effects • If patients had their choice: • No doctors, No Medicines • In general, would rather see doctor than take medication

4. Therapeutic Challenges • Ongoing assessment: consequences of seizures and therapy • How aggressive to pursue seizure control? • Do we treat interictal EEG? • ? Benign rolandic epilepsy • How to assess effects of long-term therapies?

5. Alternative Therapies for Epilepsy • Diverse group • Osteopathy, chiropractic, homeopathy, herbs, EEG feedback (neurotherapy), stress reduction, magnetic stimulation, carbon dioxide therapy, fatty acids • We need data!

6. Common Errors that Doctors Make • Misdiagnosis • Is it epilepsy? • Which epilepsy syndrome? • Not noticing change • Incorrect medication choice • AEDs can exacerbate seizures • Failure to reassess or consider VNS or surgery

7. Mistakes I’ve Made • Relying on prior diagnosis • Becoming “invested” in a course of action • Not listening to the information • Not challenging one’s own conclusion • Finding information that supports • Explaining information that doesn’t fit

8. Physician Issues in Selecting AED • AED relative efficacy:toxicity • Knowledge • Published studies • Randomized v. open-label • Dose range, methodology • Statistical v. clinical significance • Information from colleagues • Personal experience • Belief, Bias, & Comfort Zone

9. Quality of Life: The Traditional View • Medical Education - MD perspective • Medical literature, clinical experience • Disorders - signs & symptoms • Evaluation - history, PE, Lab • Therapy - studies of medical outcome

10. QOL: A Different View • QOL - Defined by patient not MD • Should patient’s perspective be filtered through “objective medical lens”? - NO • QOL is about listening, changing perspective, and using the patients’ view as the ultimate measure of outcome

11. QOL: Relevance to Epilepsy? • QOL issues most relevant to chronic disorders, problems beyond disease symptoms • Epilepsy is the paradigm of such a disorder • Seizures are infrequent,AED effects & psychosocial problems are chronic

12. A Case Study • 29 y.o. woman • monthly CPS, rare GTCs • Routine 6 mo. Checkup: complains of some tiredness, blurred vision, nausea • Exam - mild nystagmus, tremor • Labs - slightly elevated LFTs • MD’s perspective - doing great • Woman’s perspective - doing poorly; not driving, underemployed, fearful of seizures, troubled by AEs

13. Cognitive & Behavioral Changes in Epilepsy • Must diagnose to treat • Cognitive-behavioral disorders are often overlooked - “under appreciated” • Not spontaneously reported • Not asked about by MD/RN • Noted, but considered minor • Noted, but considered untreatable

14. Seizure Burden: The Great Lie • Are complex partial seizures bad? • Memory - long-term consequences • Personality changes • Affective changes • Psychosis • Are tonic-clonic seizures bad? • You bet!

15. PGE and Behavior:Absence Epilepsy (Wirrell et al, 1997) • 56 absence epilepsy v. 61 JRA patient • Pts with absence epilepsy had more academic, personal, and behavioral disorders (p<.001) • Those with ongoing seizures had worse outcomes

16. Epilepsy: Progressive Cognitive Decline • Tuberous Sclerosis (Gomez) • Relation of Seizure and MR • Of 140 pts with Szs - 89 MR • Of 19 pts w/o Szs - none MR • Age of seizure onset and MR related: • MR in 72/79 with seizures before age 1y • MR in 6/25 with seizures after age 4 y • ? Role of CNS pathology vs. Seizures • ? Younger brain protected or at risk

17. Issues with AED Safety • Idiosyncratic AE’s • Dose-related AE’s • Cognitive • Behavioral • Quality of life • Chronic AE’s • Teratogenic AE’s • Drug interactions

18. Uncommon Side Effects • Increased frequency of urination - lamotrigine • High blood pressure, migraines - carbamazepine • Aggressiveness - phenobarb, ethosuximide, levetiracetam • Severe sedation, coma - valproic acid • Movement disorders - phenytoin, carbamazepine • Kidney stones - topiramate, zonisamide, acetazolamide

19. Getting Off AEDs • Everyone’s goal • Must balance risk - benefit • Lifestyle factors such as driving • Potential side effects • How long do you wait for seizure freedom • Do you ever try when EEG has spikes or sharp waves, or if auras/minor seizures persist • Middle road is often reasonable - gradual taper over months or often years

20. Chronic Adverse Effects: Bone Disorders • Decrease Ca/Vit D levels • CBZ (?OXC), PRM, PB, PHT, VPA • New AEDs appear safer, but ? • Risk factors • Dose, polytherapy, & duration • Diagnosis • Suspicion; bone densitomety • Treatment - Vit D/Ca, sun, alendrodate, estrogen supp after menopause

21. Rapist RoostersGrandin - Animals in Translation • Observed chicken pecked to death • Chicken farmer - we see this; roosters rape and murder, lots of them • Breeding for single traits • Large breasts & rapid growth • Roosters lost their mating dance • We get used to abnormal, and think its normal

22. Long Term Side Effects: ? Drugs v. Disease v. Person • After several years, hard to determine if something really exists - ? personality/person versus disease process versus AED • Can be impossible to determine • Reducing or changing drugs may be only way to answer, but may be dangerous • Young woman, PB, and memory

23. Depression • Common • Underdiagnosed • Undertreated • Doctors and patients are at fault • Major factor in reducing quality of life • Polycystic ovarian syndrome

24. Quality of Life (QOLIE-31) 100 90 80 70 60 50 40 30 20 10 0 20 10 15 25 30 35 40 45 50 0 5 -5 Depression (BDI) Depression and QOL in Epilepsy Johnson et al., 2004 Gilliam et al., 2002 Boylan et al., 2004 Cramer et al, 2003

25. Sudden Unexplained Death in Epilepsy (SUDEP) • SUDEP incidence increases with epilepsy severity • Community sample -- 0.35/1000 pt-yrs • 24X general populate rate • Epilepsy centers -- 1.0/1000 pt-yrs • AED/VNS trials -- 3.75/1000 pt-yrs

26. Sudden Unexplained Death in Epilepsy (SUDEP) General population (2–3) Epilepsy incidence population (5) Epilepsy prevalence population (7) Patients in clinical trials (30–50) Patients undergoing vagus nerve stimulation (41) Patients referred to epilepsy centers (50–60) Surgical candidates (90) Surgical failures (150)

27. Developmental Disabilities & Epilepsy • Never lose sight of the person behind the frail frame or cognitive impairment • Put yourself in their shoes • We relate to those like us • Teachers favor good looking students, what of doctors? • Lower expectations • Don’t tolerate side effects, seizures, lower QOL • Neurologic disorders close doors of normality, but open new ones

28. New Therapies in Epilepsy:AED Pipeline • Novel mechanisms • Potassium channels - retigabine, • Functionalized amino acid (glycine; NMDA antagonist) - lacosamide • GABAA receptor modifiers - neuroctive steroid (ganaxalone) • New Relatives of known drugs • Synaptic vesical 2A ligands (levetericetam relatives) • Sodium channel - oxcarbazepine relative • Valproate relatives - valrocamide, isovaleramide • Felbamate relative - flourofelbamate • Nasal midazolam - new rescue medication! • More rapid onset, quicker offset than rectal diazepam

29. Closing Thoughts • Health care is a partnership • Knowldege is power • Communication is essential • QOL is yours • Never accept seizures and side effects • The future has never been better