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Epilepsy: Challenges & Therapies Orrin Devinsky, M.D. NYU Epilepsy Center Diagnostic Challenges Define epilepsy syndrome Understand the cause of epilepsy High resolution MRI Genetic studies (GEFS+, Chromosomal microarrays) Define factors that provoke seizures Video-EEG monitoring FAILURE Identify long-term effects of epilepsy &s its treatment 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 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? 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! Common Errors that Doctors Make Misdiagnosis Is it epilepsy? Which epilepsy syndrome? Not noticing change Incorrect AEDs medication choice can exacerbate seizures Failure to reassess or consider VNS or surgery 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 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 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 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 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 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 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 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! 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 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 Issues with AED Safety Idiosyncratic AE’s Dose-related AE’s Cognitive Behavioral Quality of life Chronic AE’s Teratogenic AE’s Drug interactions 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 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 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; Treatment bone densitomety - Vit D/Ca, sun, alendrodate, estrogen supp after menopause Rapist Roosters Grandin - 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 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 Depression Common Underdiagnosed Undertreated Doctors and patients are at fault Major factor in reducing quality of life Polycystic ovarian syndrome 100 70 80 60 Total QOLIE-89 QOLIE-89 Total Score Depression and QOL in Epilepsy 60 Gilliam et al., 2002 40 50 Johnson et al., 2004 40 30 20 20 0 -5 0 5 10 15 20 25 30 35 30 40 40 50 60 70 80 90 Depression (SCL-90-R) Beck Depression Inventory Score 100 100 90 Cramer et al, 2003 Quality of Life (QOLIE-31) QOLIE-31 80 60 40 20 80 70 Boylan et al., 2004 60 50 40 30 20 10 0 0 0 10 20 30 40 50 60 70 -5 0 5 10 15 2 0 25 30 Depression (BDI) 35 40 45 50 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 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) 0 25 50 75 100 125 150 Annual incidence per 10,000 population 175 200 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 New Therapies in Epilepsy: AED Pipeline Novel mechanisms New Relatives of known drugs Potassium channels - retigabine, Functionalized amino acid (glycine; NMDA antagonist) lacosamide GABAA receptor modifiers - neuroctive steroid (ganaxalone) 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 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