Epilepsy: Prognosis and TreatmentWilliam H Theodore MDChief, Clinical Epilepsy SectionNational Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesda, Maryland, USA

Prevalence and IncidenceThird most common neurologic disorderFirst seizure incidence: 20-70 / 100,000 Epilepsy incidence: 30-50 / 100, 000Prevalence: 5-10 / 1000Reported higher in some developing countriesCumulative adjusted lifetime risk: 1.3%3.3%Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences. New York, NY: Demos; 1991:1.

Annegers 1993Etiology of Symptomatic EpilepsyUSA

Annegers 1993

Epidemiology by Seizure TypesReproduced with permission from Hauser WA. Epilepsia. 1992;33(suppl 4):S10.Complex Partial (36%)Unclassified (3%)Myoclonic (3%)Absence (6%)Partial Unknown (7%)Other Generalized (8%)Simple Partial (14%)Generalized TC (23%)

Prognosis After a Single SeizureReported 30-70% recurrence over 3 yearssampling, etiology, seizure typesIncreased if underlying lesionDecreased if avoidable acute precipitantCBZ reduced recurrence in children (Camfield 1989)1/3 stopped drug due to side effects18% Rx vs 38% no RX in 2 years PHT, CBZ, VPA, PB (First Seizure Trial Group 1989)

AEDPeak Plasma concentrationProtein bindingclearanceT Drug interactionsTherapeutic level (mol/L)lamotrigine1-3h55%hepatic15-60AEDs10-60gabapentin2-3hdose0renal6-7h#minimal40-120tiagabine1-2h96CYP3A5-8hAEDs#vigabatrin1-2h05-7h##Topiramate2-4h15mixed18-23hLithium, OCs, some AEDs10-60Oxcarbazepine(MHD metabolite)1-2h40Non-CYP mediated10-12 hr(MHD metabolite)AEDsoral contraceptives50-140 (MHD)Felbamate2-6h22-25hepatic15-23hrAEDs200-400Phenobarbital1-4 h40-55hepatic80-130extensive50-130Phenytoin2-6 hr90Hepatic***extensive40-80CarbamazepineSlow, variable70-75hepatic18-55 hr*12 hr**extensive15-45 Levetiracetam1-2 h 0Renal6-10 hrminimal#Zonisamide3-4 h40-60CYP3A50-60 hrextensive35-200Valproic acid1-2 h90&Hepatic10-15 hrAEDs300-600Ethosuximide3-5 h0hepatic30-60 hrAEDs300-600

Table 2: AED Mechanisms and Clinical Efficacy

DrugSodium channelsCalcium channels GABA systemGlutamate receptorsClinical EfficacyLREPGESGEPhenytoin++YNNCarbamazepine++YNNOxcarbazepine++YNNLamotrigine+++YYYZonisamide+++YValproate+++YYYFelbamate++++YYTopiramate++++YYEthosuximide+++NYNGabapentin+++YLevetiracetam++YPhenobarbital+++Y

Epilepsy Therapy in 525 PatientsKwan and Brodie 2000

Veterans Administration Cooperative StudyReproduced with permission from Mattson RH, et al. N Engl J Med. 1985;313:145-151.Percent Continuinglllllllllllllslssssllphenobarbitalphenytoinprimidonecarbamazepine1008060402000369121518212427303336Months

Marsan et al 2007Time to 12 month remission% remaining on drugSANAD Study

Marsan et al 2007

Mattson et al 1985Reasons for AED FailureVA Cooperative Study

CBZN=101PHTN=101PBN=110PRMN=109AllN=421Toxicity1219183685Toxicity+ seizures30332925127Seizures341311Total45564874233

Mattson et al 1985

Callhagan et al 2008Prognosis of Drug-Refractory EpilepsyRe-evaluation of 246 patientsDrug 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 patientspersistent intractability: Duration > 10 years, mental retardation, status, > 6 AEDsNo drug seemed superior

Callhagan et al 2008

Some Emerging AEDs

AEDCPS (> placebo)PGESGEtoxicityBrivaracetam 22% 78% photosensitity GICarisbamate18-20%CNSEslicarbazepine ~ 20% CNS, GILacosamide 20-25%CNS, GI

Retigabine 20-25%CNSRufinamide 20% total 40% atonicCNS, GI

Why do AEDs Fail?About 30% of patients do not respond at allAbout 10% of patients with good initial AED response cease to respondPharmacokinetic Drug interactionsEnzyme inductionTolerance to non-BZP AEDs ?Receptor, channel response changesDrug efflux transporters PgP, MRPs,

AED ToleranceLoscher & Schmidt 2006Long-term BZPs: allosteric GABA-BZP site interactionsVGB tolerance in MES model: GAD due to GABA feedback inhibition

Altered NA+ Channel Responses?Remy et al 2003No MTSMTS

Multiple Drug Transporters (p-glycoproteins) Pump lipophilic drugs and other xenobiotics out of cellsRole in cancer chemotherapy resistanceMay be overexpressed in human epileptic tissue, especially TLEUnreplicated link between MDR gene polymorphisms and human AED resistance

Loscher 2007

Loscher 2007PgP 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 inhibitionverapamiltariquidar

Natural History of EpilepsyNatural history of untreated epilepsy unknownBromides since 1857PB available since 1912Alfred HauptmanCharles Locock

Natural History of EpilepsyNatural history of untreated epilepsy unknown.Course may fluctuate. No difference in seizure-free rate if treatment begun after 1st or 2d seizureIn resource poor countries, spontaneous remission rate ~ 30%prognosis not related to pretreatment GTCS #

Hauser et al 1998

Berg et al 2003Early 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 evaluationLatency from epilepsy onset to 2 AED failure 9.1 years26% reported at least 1 yr remission8.5% 5 year remission

Berg et al 2003

Intractable Epilepsy:Comparison of Diagnostic Criteria Berg et al Epilepsia 2006

Kwan et al Epilepsia 2009ILAE Epilepsy Outcome Categories

*at least 12 months AND three times the longest interseizure interval in 12 months prior to new intervention

Seizure ControlSide EffectsOutcomeSeizure-free*No1AYes1Bundetermined1CTreatment failureNo2AYes2Bundetermined2CUndeterminedNo3AYes3Bundetermined3C

Kwan et al Epilepsia 2009Drug Resistant EpilepsyILAE 2009Failure 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 2009Data Needed to Determine if a Therapeutic Intervention is InformativeMode of application (e.g., formulation, dose, dosing interval)ComplianceDuration of exposureWas there was effort to optimize dose?Reason(s) for discontinuationUnsatisfactory seizure controlAdverse effectsPsychosocial reasons, for example, planning for pregnancyAdministrative reasons, for example, lost to follow upFinancial issues, for example, cannot afford drugOther reasons

Berg et al 2003Early 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 evaluationLatency from epilepsy onset to 2 AED failure 9.1 years26% reported at least 1 yr remission8.5% 5 year remission

Predicting Intractable EpilepsyEpilepsy Pattern:RemittentKCNQ2 or KCNQ3 benign familial convulsions Some absenceNon-remittent drug responsiveJMENon drug-responsive but treatableLocalization-relatedPoorly responsiveLGSClinical Features at Onset:Early age of onsetpresentation in status epilepticus ?abnormal neurological exampartial seizures at diagnosismixed seizure types ~ developmental delaymultiple seizures prior to treatmentseizure clustering, densityStructural lesion

Spooner et al 2006New onset TLE in Children: MRI and Prognosis

Spooner et al 2006

Sillanpaa et al 1999Prospective Study of Finnish Children1964-1992

Sillanpaa et al 1999

Drug Therapy: Prognosis by Seizure Type (n=1102)Mattson et al 1996

What is Intractable Epilepsy?(modified after DC Taylor)The Lesion or Disease:mesial temporal sclerosis, malformationThe Illness:intermittent seizuresThe Predicament:socialpsychologicaleconomicAEDs treat the illness, not the diseaseIs that important?

Progression of EpilepsyThe 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 1890Mental deterioration follows relentlessly.Cecils Textbook of Medicine 1929 Edwin G Zabriskie Associate Professor of Neurology, Columbia University Physician to the Neurological Institute

Silanpaa et al 1998; Jokeit et al 2000; Helmstaedter et al 2003Neuropsychological and functional Prognosis in TLESurgery accelerates decline if unsuccessfulStops or reverses it if successfulIn Finnish pediatric study, adverse socio-economic effects even in patients who entered adult life in remission off AEDs

Silanpaa et al 1998; Jokeit et al 2000; Helmstaedter et al 2003

Cramer et al 2003, Ettinger et al 2004, 2005, Kobau et al 2006Depression and EpilepsyDepression in Population > 18 survey data36.5% epilepsy27.8% asthma11.8% controlAdults ever told of epilepsy: RR 2.5 Adults with active epilepsy: RR 3.0Reduced quality of lifeIncreased medical resource use

Cramer et al 2003, Ettinger et al 2004, 2005, Kobau et al 2006

Quality of LifeSeizure control usually considered most important measureComplete seizure-freedom usually has a much greater effect on HRQOL measures than simply reduced frequencyDepression has greater adverse impact than seizure frequency itself in some studiesDrug side effects and unemploymentIssue of when to withdraw drugs after successful surgery

Devinsky et al Neurology 2005; Baker Neurology 2006Seizure Control, Depression, and AnxietySeveral studies suggest seizure frequency predicts anxiety and depression symptomsMulticenter surgery study depression ~ seizure control6.1% new depression in non-seizure free patients

Devinsky et al Neurology 2005; Baker Neurology 2006

Silanpaa et al 1998; Sperling et al 1999DeathStandardized mortality ratio is increased in epilepsy, even if no underlying illnessMarked increase in sudden unexplained deathSUDEP related to: GTCS > 2 AEDsDeath after TLE SMR for patients with recurrent seizures 4.69seizure free patients: no difference vs age- and sex-matched population of the United StatesPersistent seizures ~ death in Finnish pediatric studyDeath is due to uncontrolled epilepsy

Silanpaa et al 1998; Sperling et al 1999

Approaches to Intractable Epilepsy

SurgeryFocal resectionhemispherectomyCallosotomy (palliative)Ketogenic DietExperimental DrugsBrain Stimulation

Wiebe et al 2001One year2-10 yearsHelmstaedter et al 2003Controlled Temporal Lobectomy Trial Intractable TLE:Comparison of Medical and Surgical Outcome Non-randomized Clinical Series

The Ketogenic Diet30% Fat50% Carbs20% Protein85% Fat5% Carbs10% Protein

Potential Mechanisms of ActionKetosisAcetoneAspartate, GABAPolyunsaturated fatty acids Mitochondrial uncouplingGlucose modulation Enhanced glutamate transportOpening KATP channelsAcidosisCaloric restrictionDecreased IL-1Neurosteroids

Ketogenic DietTraditionally started gradually in the hospital after a 24-48 hour fastFamilies educated dailyRatio (fat: carbs and protein)4:1 more strict3:1 for infants, adolescentsCalories 60-100% Fluids 85-100%Solid foods and/or formulaRequires dietician supportStrong family committment

Side EffectsConstipationSlowed weight gainAcidosis when illVitamin deficiency (if unsupplemented) Renal stones Impaired height and weightDyslipidemia Gastrointestinal upset

Ketogenic Diet Randomized Controlled StudyNeal et al Lancet Neurology 200810/65 who stopped diet not included in analysis

Brain Stimulation for EpilepsyVagal Nerve StimulationTranscranial Magnetic stimulationIntracranial stimulationSurface electrodes (responsive) Deep Brain StimulationHippocampusThalamusCerebellum

Torpedo fuscomaculata

VNSRequires surgery, but extracranialEffects broadly comparable to new AED trials30-40% 50% seizure frequency reductionIn open label extension effect sustained 12 monthsVery rare patients seizure-freeOnly consider when no chance for resective surgeryRefractory Generalized EpilepsyNei et al Epilepsia 2006

Transcranial Magnetic Stimulation

TMS in Epilepsy

TLE: Case reports and open trials:30-70% seizure decreases reportedBlinded controlled trial 16% reduction > placebo (0.05

Thalamic StimulationCentromedianUncontrolled studies reported improvementSmall controlled study: no effectAnteriorRecent controlled study showed seizure 14.5% in the control group40.4% in the stimulated group SubthalamicImprovement in uncontrolled studies

Long-term follow-up of patients with thalamic deep brain stimulation for epilepsyLong-term follow-up (mean, 5 years) 6 patients with anterior (AN)2 centromedian thalamic deep brain stimulation Five patients (all AN) had 50% seizure reductionbenefit was delayed in two until years 5 to 6after changes in antiepileptic drugs. Seizure reduction 1 to 3 months before active stimulationPossibility of a beneficial microthalamotomy effect.

Andrade et al Neurology 2006

Hippocampal StimulationReduced CPS frequency reported in several uncontrolled studiesOne small controlled study: Four patients with refractory MTLERisk to memory contraindicated temporal lobe resectionDouble-blind stimulation randomly turned ON 1 month and OFF 1 month for 6 monthsMedian reduction in seizures of 15%Effects seemed to carry over into the OFF periodPossible implantation effect. No adverse effects. One patient treated for 4 years has substantial long-term improvement.

Tellez-Zenteno et al NEUROLOGY 2006;66:14901494

Seizure PredictionEnergy level (red)decision threshold (blue)prediction output (green)seizure onset (black)Positive outputs (high level in green curve) observed ~ 2h before seizures.Esteller et al Clin Neurophysiol 2005

RNS PlacementCourtesy of Martha Morrell

Courtesy of Martha Morrell

Preliminary RNS Efficacy (n=65)Barkley et al AES 2006

Initial 84 daysMost recent 84 daysSeizure-type% with 50% Overall % % with 50% Overall % CPS32274034GTCS63595566Total Disabling26294135

Risks of Brain StimulationTMSRare seizures at high (>10hz) frequencyEpilepsy therapy trials are at 1 hzMild headache, scalp discomfortVNSCough, Hoarseness when stimulator ondyspnea, pain, paresthesia, and headachesrespond to alteration of stimulation settingsVery rare vocal cord paralysis, bradycardia during implantDBSBleedinginfarctionintracranial infectionAll less likely with surface RNS

**Hasnt changed much in years. No more than 4 children the first Monday of the month. Watch the dextrosticks. There has been a significantAmount of research, perhaps the hottest topic outside JHH in the past 2 years, is to discuss if this is the ideal protocol*Helped by alkalinization of the urine (polycitra), no proof it works 6.2%*