Epilepsy: Prognosis and Treatment William H Theodore MD Chief, Clinical Epilepsy Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland, USA Prevalence and Incidence • • • • Third most common neurologic disorder First seizure incidence: 20-70 / 100,000 Epilepsy incidence: 30-50 / 100, 000 Prevalence: 5-10 / 1000 – Reported higher in some developing countries • Cumulative adjusted lifetime risk: 1.3%–3.3% Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences. New York, NY: Demos; 1991:1. Etiology of Symptomatic Epilepsy USA 80 70 60 devel infection trauma CVD tumor degen 50 40 30 20 10 0 <15 15-24 25-44 45-64 Annegers 1993 >65 Epidemiology by Seizure Types Generalized TC (23%) Complex Partial (36%) Simple Partial (14%) Unclassified (3%) Myoclonic (3%) Other Generalized Absence (6%) (8%) Partial Unknown (7%) Reproduced with permission from Hauser WA. Epilepsia. 1992;33(suppl 4):S10. Prognosis After a Single Seizure • Reported 30-70% recurrence over 3 years – sampling, etiology, seizure types – Increased if underlying lesion – Decreased if avoidable acute precipitant • CBZ reduced recurrence in children (Camfield 1989) – 1/3 stopped drug due to side effects • 18% Rx vs 38% no RX in 2 years – PHT, CBZ, VPA, PB (First Seizure Trial Group 1989) AED Peak Plasma concentration Protein binding clearance T½ Drug interactions Therapeutic level (μmol/L) lamotrigine 1-3h 55% hepatic 15-60 AEDs 10-60 gabapentin 2-3h dose 0 renal 6-7h# minimal 40-120 tiagabine 1-2h 96 CYP3A 5-8h AEDs # vigabatrin 1-2h 0 Topiramate 2-4h 15 mixed 18-23h Lithium, OCs, some AEDs 10-60 Oxcarbazepine (MHD metabolite) 1-2h 40 Non-CYP mediated 10-12 hr (MHD metabolite) AEDs oral contraceptives 50-140 (MHD) Felbamate 2-6h 22-25 hepatic 15-23hr AEDs 200-400 Phenobarbital 1-4 h 40-55 hepatic 80-130 extensive 50-130 Phenytoin 2-6 hr 90 Hepatic*** extensive 40-80 Carbamazepine Slow, variable 70-75 hepatic 18-55 hr* 12 hr** extensive 15-45 Levetiracetam 1-2 h 0 Renal 6-10 hr minimal # Zonisamide 3-4 h 40-60 CYP3A 50-60 hr extensive 35-200 Valproic acid 1-2 h 90& Hepatic 10-15 hr AEDs 300-600 Ethosuximide 3-5 h 0 hepatic 30-60 hr AEDs 300-600 5-7h# # Calcium channels GABA system Glutamate receptors Clinical Efficacy Drug Sodium channels Phenytoin ++ Y Carbamazepine ++ Oxcarbazepine ++ Lamotrigine ++ Zonisamide LRE PGE SGE N N Y N N Y N N + Y Y Y ++ + Y Valproate + + + Y Y Felbamate + + + + Y Y Topiramate + + + + Y Y Ethosuximide ++ + N Gabapentin ++ + Y Levetiracetam + + Y Phenobarbital + + Y + Y Y N Epilepsy Therapy in 525 Patients Kwan and Brodie 2000 Veterans Administration Cooperative Study Percent Continuing 100 sl sl l l s 80 s l l s l l s 60 s s l l s s l l s s ll s s 40 ll s s ll s s l l l l l l l l s s s s s s s s s s l l 20 s s l l phenobarbital phenytoin primidone carbamazepine 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Reproduced with permission from Mattson RH, et al. N Engl J Med. 1985;313:145-151. SANAD Study Time to 12 month remission % remaining on drug Marsan et al 2007 Reasons for AED Failure VA Cooperative Study CBZ PHT PB PRM All N=101 N=101 N=110 N=109 N=421 Toxicity 12 19 18 36 85 Toxicity+ seizures 30 33 29 25 127 Seizures 3 4 1 3 11 Total 45 56 48 74 233 Mattson et al 1985 Prognosis of ‘Drug-Refractory’ Epilepsy Re-evaluation of 246 patients • Drug failure before index date: – maximum tolerated dose in 54% – idiosyncratic reaction in 6.5% – intolerable side effect in 19% – unknown reasons in 21%. • 6-month terminal seizure remission: – 14% of AED-treated patients (about 5% per year of study) – 52% of surgery patients • persistent intractability: • Duration > 10 years, No drug seemed superior mental retardation, status, > 6 AEDs Callhagan et al 2008 Some Emerging AEDs AED CPS (> placebo) PGE Brivaracetam ↓ 22% 78% ↓ photosensitity Carisbamate ↓18-20% CNS Eslicarbazepine ↓ ~ 20% CNS, GI Lacosamide ↓ 20-25% CNS, GI Retigabine ↓ 20-25% CNS Rufinamide SGE toxicity GI ↓ 20% total ↓ 40% atonic CNS, GI Why do AEDs Fail? • About 30% of patients do not respond at all • About 10% of patients with good initial AED response cease to respond • Pharmacokinetic – Drug interactions – Enzyme induction • Tolerance to non-BZP AEDs ? – Receptor, channel response changes • Drug efflux transporters – ⁭ PgP, MRPs, AED Tolerance • Long-term BZPs: ↓ allosteric GABA-BZP site interactions • VGB tolerance in MES model: ↓ GAD due to GABA feedback inhibition Loscher & Schmidt 2006 Altered NA+ Channel Responses? No MTS MTS Remy et al 2003 Multiple Drug Transporters (p-glycoproteins) • Pump lipophilic drugs and other xenobiotics out of cells – Role in cancer chemotherapy resistance • May be overexpressed in human epileptic tissue, especially TLE • Unreplicated link between MDR gene polymorphisms and human AED resistance Loscher 2007 PgP Affects Brain Phenytoin Levels Loscher 2007 Possible Therapeutic Maneuvers • Manage with drug holidays, dose adjustments? – Alternate AEDs? • Lower starting doses? • Cross-tolerance ? – Choose drugs with different mechanisms? • PgP inhibition – verapamil – tariquidar – Bromides since 1857 – PB available since 1912 Charles Locock • Natural history of untreated epilepsy unknown Alfred Hauptman Natural History of Epilepsy Natural History of Epilepsy • Natural history of untreated epilepsy unknown. – Course may ‘fluctuate.’ • No difference in seizure-free rate if treatment begun after 1st or 2d seizure • In ‘resource poor’ countries, spontaneous remission rate ~ 30% – prognosis not related to pretreatment GTCS # Hauser et al 1998 Early onset LRE may not become clearly intractable for many years • 7 centers: 333 patients evaluated for resective surgery for localization-related epilepsy prospectively identified at initial evaluation • Latency from epilepsy onset to 2 AED failure 9.1 years • 26% reported at least 1 yr remission • 8.5% 5 year remission Berg et al 2003 Intractable Epilepsy: Comparison of Diagnostic Criteria Berg et al Epilepsia 2006 ILAE Epilepsy Outcome Categories Seizure Control Side Effects Outcome Seizure-free* No 1A Yes 1B undetermined 1C No 2A Yes 2B undetermined 2C No 3A Yes 3B undetermined 3C Treatment failure Undetermined *at least 12 months AND three times the longest interseizure interval in 12 months prior to new intervention Kwan et al Epilepsia 2009 Drug Resistant Epilepsy ILAE 2009 • Failure of informative trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Kwan et al Epilepsia 2009 Data Needed to Determine if a Therapeutic Intervention is “Informative” • Mode of application (e.g., formulation, dose, dosing interval) • Compliance • Duration of exposure • Was there was effort to optimize dose? • Reason(s) for discontinuation – Unsatisfactory seizure control – Adverse effects – Psychosocial reasons, for example, planning for pregnancy – Administrative reasons, for example, lost to follow up – Financial issues, for example, cannot afford drug – Other reasons Kwan et al Epilepsia 2009 Early onset LRE may not become clearly intractable for many years • 7 centers: 333 patients evaluated for resective surgery for localization-related epilepsy prospectively identified at initial evaluation • Latency from epilepsy onset to 2 AED failure 9.1 years • 26% reported at least 1 yr remission • 8.5% 5 year remission Berg et al 2003 Predicting Intractable Epilepsy • Epilepsy ‘Pattern:’ • Remittent – KCNQ2 or KCNQ3 benign familial convulsions – Some absence • Non-remittent ‘drug responsive’ – JME • Non drug-responsive but treatable – Localization-related • Poorly responsive – LGS • Clinical Features at Onset: • Early age of onset • presentation in status epilepticus ? • abnormal neurological exam • partial seizures at diagnosis • mixed seizure types ~ developmental delay • multiple seizures prior to treatment • seizure clustering, ‘density’ • Structural lesion New onset TLE in Children: MRI and Prognosis Spooner et al 2006 Prospective Study of Finnish Children 1964-1992 90 80 70 % 60 50 40 30 20 10 0 IdioPE IGE remission SympPE no remission Sillanpaa et al 1999 dead SecGE Drug Therapy: Prognosis by Seizure Type (n=1102) 60 50 40 VA118-12 VA118-24 VA264-12 VA264-24 30 20 10 0 GTC Mixed Mattson et al 1996 CPS What is Intractable Epilepsy? (modified after DC Taylor) • The Lesion or Disease: – mesial temporal sclerosis, malformation • The Illness: – intermittent seizures • The Predicament: – social – psychological – economic • AEDs treat the illness, not the disease – Is that important? Progression of Epilepsy • “The interparoxysmal mental state of epileptics often presents grave deterioration.” • “Each fit apparently leaves a change in the nerve centers, facilitating the occurrence of other fits.” – Gowers 1890 • “Mental deterioration follows relentlessly.’’ – Cecil’s Textbook of Medicine 1929 Edwin G Zabriskie Associate Professor of Neurology, Columbia University Physician to the Neurological Institute Neuropsychological and functional Prognosis in TLE • Surgery accelerates decline if unsuccessful • Stops or reverses it if successful • In Finnish pediatric study, adverse socioeconomic effects even in patients who entered adult life in remission off AEDs Silanpaa et al 1998; Jokeit et al 2000; Helmstaedter et al 2003 Depression and Epilepsy • Depression in Population > 18 survey data – 36.5% epilepsy – 27.8% asthma – 11.8% control – Adults ever told of epilepsy: RR 2.5 – Adults with active epilepsy: RR 3.0 • Reduced quality of life • Increased medical resource use Cramer et al 2003, Ettinger et al 2004, 2005, Kobau et al 2006 Quality of Life • Seizure control usually considered most important measure • Complete seizure-freedom usually has a much greater effect on HRQOL measures than simply reduced frequency • Depression has greater adverse impact than seizure frequency itself in some studies • Drug side effects and unemployment – Issue of when to withdraw drugs after successful surgery Seizure Control, Depression, and Anxiety • Several studies suggest seizure frequency predicts anxiety and depression symptoms • Multicenter surgery study 25 20 15 10 5 – ↓ depression ~ seizure 0 control % depressed – 6.1% new depression preop in non-seizure free Devinsky et al Neurology 2005; patients Baker Neurology 2006 % anxious NSF SF Death • Standardized mortality ratio is increased in epilepsy, even if no underlying illness • Marked increase in sudden unexplained death – SUDEP related to: – GTCS – > 2 AEDs • Death after TLE – SMR for patients with recurrent seizures 4.69 – seizure free patients: no difference vs age- and sexmatched population of the United States • Persistent seizures ~ death in Finnish pediatric study • Death is due to uncontrolled epilepsy Silanpaa et al 1998; Sperling et al 1999 Approaches to Intractable Epilepsy • Surgery – Focal resection – hemispherectomy – Callosotomy (palliative) • Ketogenic Diet • Experimental Drugs • Brain Stimulation ‘Intractable’ TLE: Comparison of Medical and Surgical Outcome Helmstaedter et al 2003 Non-randomized Clinical Series Wiebe et al 2001 Controlled Temporal Lobectomy Trial 70 Seizure-free 60 50 40 30 20 10 0 surgical 2-10 years medical One year The Ketogenic Diet 20% Protein 10% Protein 5% Carbs 30% Fat 85% Fat 50% Carbs Potential Mechanisms of Action • • • • • • • • • • • • Ketosis Acetone Aspartate, GABA Polyunsaturated fatty acids Mitochondrial uncoupling Glucose modulation Enhanced glutamate transport Opening KATP channels Acidosis Caloric restriction Decreased IL-1ß Neurosteroids Ketogenic Diet • Traditionally started gradually in the hospital after a 24-48 hour fast – Families educated daily • Ratio (fat: carbs and protein) – 4:1 more strict – 3:1 for infants, adolescents • Calories 60-100% • Fluids 85-100% • Solid foods and/or formula • Requires dietician support • Strong family committment Side Effects • • • • • • • • Constipation Slowed weight gain Acidosis when ill Vitamin deficiency (if unsupplemented) Renal stones Impaired height and weight Dyslipidemia Gastrointestinal upset Ketogenic Diet Randomized Controlled Study 10/65 who stopped diet not included in analysis Neal et al Lancet Neurology 2008 Brain Stimulation for Epilepsy • Vagal Nerve Stimulation • Transcranial Magnetic stimulation • Intracranial stimulation – Surface electrodes (‘responsive’) – Deep Brain Stimulation • Hippocampus • Thalamus • Cerebellum Torpedo fuscomaculata VNS 0 • Requires surgery, but extracranial -5 -10 % reduction versus -15 baseline -20 • Effects broadly comparable to new AED trials • 30-40% ≥ 50% seizure frequency reduction • In open label extension effect sustained ≥ 12 months • Very rare patients seizurefree • Only consider when no chance for resective surgery high low -25 -30 EO3 (p<.05) EO5 (p<.001) Refractory Generalized Epilepsy Nei et al Epilepsia 2006 Transcranial Magnetic Stimulation TMS in Epilepsy • TLE: – Case reports and open trials: • 30-70% seizure decreases reported – Blinded controlled trial • 16% reduction > placebo (0.05<p<0.10) • Effect lasted 2-4 weeks • Cortical Dysplasia – significantly decreased the seizures in active compared with sham rTMS group ~4 cm Thalamic Stimulation • Centromedian – Uncontrolled studies reported improvement – Small controlled study: no effect • Anterior – Recent controlled study showed seizure ↓ • 14.5% in the control group • 40.4% in the stimulated group • Subthalamic – Improvement in uncontrolled studies Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy • Long-term follow-up (mean, 5 years) – 6 patients with anterior (AN) – 2 centromedian thalamic deep brain stimulation • Five patients (all AN) had 50% seizure reduction – benefit was delayed in two until years 5 to 6 – after changes in antiepileptic drugs. • Seizure reduction 1 to 3 months before active stimulation – Possibility of a beneficial microthalamotomy effect. Andrade et al Neurology 2006 Hippocampal Stimulation • Reduced CPS frequency reported in several uncontrolled studies • One small controlled study: • Four patients with refractory MTLE – Risk to memory contraindicated temporal lobe resection • Double-blind stimulation randomly turned ON 1 month and OFF 1 month for 6 months • Median reduction in seizures of 15% – Effects seemed to carry over into the OFF period – Possible implantation effect. • No adverse effects. • One patient treated for 4 years has substantial long-term improvement. Tellez-Zenteno et al NEUROLOGY 2006;66:1490–1494 Seizure Prediction Energy level (red) decision threshold (blue) prediction output (green) seizure onset (black) Positive outputs (high level in green curve) observed ~ 2 h before seizures. Esteller et al Clin Neurophysiol 2005 RNS™ Placement Courtesy of Martha Morrell Anterior Lead (A) Posterior Lead (P) Parahippocampal Longitudinal Strip (not connected) Courtesy of Martha Morrell Preliminary RNS Efficacy (n=65) Initial 84 days Most recent 84 days Seizuretype % with 50% ↓ Overall % ↓ % with 50% ↓ Overall % ↓ CPS 32 27 40 34 GTCS 63 59 55 66 Total Disabling 26 29 41 35 Barkley et al AES 2006 Risks of Brain Stimulation • TMS – Rare seizures at high (>10hz) frequency • Epilepsy therapy trials are at ≤ 1 hz – Mild headache, scalp discomfort • VNS – Cough, Hoarseness when stimulator on – dyspnea, pain, paresthesia, and headaches – respond to alteration of stimulation settings – Very rare vocal cord paralysis, bradycardia during implant • DBS – – – – Bleeding infarction intracranial infection All less likely with surface RNS