Management of Difficult to Management of Difficult to Treat Epilepsy in ChildrenTreat Epilepsy in Children

Northeast Regional Epilepsy GroupNortheast Regional Epilepsy Group

Advances in the Diagnosis and Advances in the Diagnosis and Treatment of Epilepsy Treatment of Epilepsy

Marcelo E. Lancman, M.D.Marcelo E. Lancman, M.D.Director, Epilepsy ProgramDirector, Epilepsy Program

Northeast Regional Epilepsy GroupNortheast Regional Epilepsy Group

Advances in the Diagnosis Advances in the Diagnosis and Treatment of Epilepsy and Treatment of Epilepsy Epilepsy conceptsEpilepsy concepts Diagnosing EpilepsyDiagnosing Epilepsy What causes EpilepsyWhat causes Epilepsy Treating EpilepsyTreating Epilepsy New developmentsNew developments

Epilepsy ConceptsEpilepsy Concepts

What is epilepsy?What is epilepsy?

What is a seizure?What is a seizure?

IncidenceIncidence

EpilepsyEpilepsy

0.5-1% 0.5-1%

SeizuresSeizures

5-10%5-10%

Classification of SeizuresClassification of Seizures

PartialPartialSimpleSimpleComplexComplexSecondary GeneralizedSecondary Generalized

GeneralizedGeneralizedAbsenceAbsenceAtonicAtonicClonicClonicTonicTonicTonic-clonicTonic-clonicMyoclonicMyoclonic

Classification of EpilepsyClassification of Epilepsy

By LocalizationBy Localization– PartialPartial– GeneralizedGeneralized

By CauseBy Cause– Idiopathic (unknown)Idiopathic (unknown)– SymptomaticSymptomatic

Classification of EpilepsyClassification of Epilepsy

Idiopathic Partial EpilepsyIdiopathic Partial Epilepsy Symptomatic Partial EpilepsySymptomatic Partial Epilepsy Idiopathic Generalized EpilepsyIdiopathic Generalized Epilepsy Symptomatic Generalized EpilepsySymptomatic Generalized Epilepsy

Idiopathic Generalized Idiopathic Generalized EpilepsyEpilepsy Benign Neonatal Familial EpilepsyBenign Neonatal Familial Epilepsy Benign Myoclonic Epilepsy of InfancyBenign Myoclonic Epilepsy of Infancy Generalized epilepsy with febrile seizures plusGeneralized epilepsy with febrile seizures plus Epilepsy with myoclonic absenceEpilepsy with myoclonic absence Epilepsy with myoclonic-astatic seizuresEpilepsy with myoclonic-astatic seizures Childhood absence epilepsyChildhood absence epilepsy Juvenile absence epilepsyJuvenile absence epilepsy Epilepsy with GTCS onlyEpilepsy with GTCS only

Idiopathic Partial EpilepsyIdiopathic Partial Epilepsy

Benign Rolandic EpilepsyBenign Rolandic Epilepsy Benign Occipital EpilepsyBenign Occipital Epilepsy

Symptomatic Generalized Symptomatic Generalized EpilepsyEpilepsy Infantile spasms (West syndrome)Infantile spasms (West syndrome) Dravet syndromeDravet syndrome Lennox-Gastaut syndromeLennox-Gastaut syndrome

Symptomatic Partial EpilepsySymptomatic Partial Epilepsy

Temporal Lobe EpilepsyTemporal Lobe Epilepsy Frontal Lobe EpilepsyFrontal Lobe Epilepsy Parietal Lobe EpilepsyParietal Lobe Epilepsy Occipital Lobe EpilepsyOccipital Lobe Epilepsy (Tuberous Sclerosis Complex, (Tuberous Sclerosis Complex,

Neurofibromatosis)Neurofibromatosis)

Special types of EpilepsySpecial types of Epilepsy

Neonatal seizuresNeonatal seizures Landau-Kleffner syndromeLandau-Kleffner syndrome ESES (electrical status epilepticus ESES (electrical status epilepticus

during sleep)during sleep) Reflex EpilepsyReflex Epilepsy

Type of EpilepsyType of Epilepsy

The importance of knowingThe importance of knowing

Diagnosis of EpilepsyDiagnosis of Epilepsy

Medical HistoryMedical History Physical examPhysical exam

TestingTesting

Testing Testing – EEG, AEEG, VEEGEEG, AEEG, VEEG– LabsLabs– GeneticsGenetics

ImagingImaging– CT, MRI (high CT, MRI (high

definition)definition)

Diagnosis Diagnosis

Diagnosis is clear: treatment is initiatedDiagnosis is clear: treatment is initiated

Diagnosis unclear: Video-EEGDiagnosis unclear: Video-EEG

Video-EEG MonitoringVideo-EEG Monitoring

Continuous EEG monitoring along with Continuous EEG monitoring along with continuous audio-video recordingcontinuous audio-video recording

Mostly requires inpatient admissionMostly requires inpatient admission

Goals of Video-EEG Goals of Video-EEG MonitoringMonitoring Epilepsy vs. non-Epilepsy vs. non-

epileptic eventsepileptic events

Characterize epilepsy Characterize epilepsy typetype

Pre-surgical Pre-surgical evaluation evaluation

Non-Epileptic Events Non-Epileptic Events

20 to 30% of patients referred with 20 to 30% of patients referred with diagnosis of intractable epilepsydiagnosis of intractable epilepsy

Events that do not have electrical source in Events that do not have electrical source in brainbrain

May have physical or psychological May have physical or psychological causes that are not epilepsycauses that are not epilepsy

But CAN also occur in patients who have But CAN also occur in patients who have epilepsyepilepsy

Non-epileptic eventsNon-epileptic events

Physiologic (other medical conditions)Physiologic (other medical conditions)– Fainting, low sugar, changes in electrolytes, Fainting, low sugar, changes in electrolytes,

toxins, fever.toxins, fever. Psychological Psychological

– Referred to psychiatry and neuropsychologist Referred to psychiatry and neuropsychologist who work with this type of stress-seizurewho work with this type of stress-seizure

– Psychiatric medication, psychotherapy, Psychiatric medication, psychotherapy, educationeducation

Non-epileptic eventsNon-epileptic events

Conditions that may look like seizures:Conditions that may look like seizures:– TIAs, complicated migraines, movement TIAs, complicated migraines, movement

disorders, sleep disorders, anxiety/panic disorders, sleep disorders, anxiety/panic disorder, vertigo, cardiac disorders, rage disorder, vertigo, cardiac disorders, rage attacks, breath-holding spells, attacks, breath-holding spells,

Diagnostic AdvancesDiagnostic Advances

MagnetoencefalographyMagnetoencefalography

What causes of Epilepsy?What causes of Epilepsy?

The seizure thresholdThe seizure threshold Causes:Causes:

– Genetics, head injury, stroke, tumors, Genetics, head injury, stroke, tumors, infections, malformations, metabolic infections, malformations, metabolic disorders (diabetes, thyroid, parathyroid, disorders (diabetes, thyroid, parathyroid, adrenal), degenerative disorders, perinatal adrenal), degenerative disorders, perinatal factors and other less common (cardiac, GI, factors and other less common (cardiac, GI, blood, inflammatory, poisons, etc)blood, inflammatory, poisons, etc)

Seizure TriggersSeizure Triggers

Alcohol, stress, environmental Alcohol, stress, environmental temperature, lights, fever/illness, temperature, lights, fever/illness, hormonal changes, hyperventilation, sleep hormonal changes, hyperventilation, sleep deprivation, medications and supplements, deprivation, medications and supplements, missing medication doses and travel missing medication doses and travel across time zonesacross time zones

Treating EpilepsyTreating Epilepsy

What is intractable epilepsy?What is intractable epilepsy?

Despite medical management, patient Despite medical management, patient continues to have frequent, debilitating continues to have frequent, debilitating seizuresseizures

Seizure ControlSeizure Control

Options for the Intractable Options for the Intractable Seizure PatientSeizure Patient

Medications (combinations)Medications (combinations) DietsDiets Surgical proceduresSurgical procedures

– StimulatorsStimulators– ResectionsResections

MedicationsMedications Choices based on epilepsy type, patient profile, side Choices based on epilepsy type, patient profile, side

effect profile, costeffect profile, cost

Best to have patient on single antiepileptic drug (AED)Best to have patient on single antiepileptic drug (AED)

May need polytherapy (combination of medications)May need polytherapy (combination of medications)

Adding meds requires going up slowly with the new Adding meds requires going up slowly with the new agent before discontinuing previous drugagent before discontinuing previous drug

Polytherapy requires deep knowledge of interactionsPolytherapy requires deep knowledge of interactions

How to use polytherapy How to use polytherapy rationallyrationally Pharmacodynamics Pharmacodynamics

(what the medication does to the body)(what the medication does to the body)

Pharmacokinetics Pharmacokinetics (what the body does to the (what the body does to the

medications)medications)– AbsorptionAbsorption– Distribution Distribution – EliminationElimination

Half lifeHalf life LiverLiver KidneysKidneys

How to use polytherapy How to use polytherapy rationallyrationally Side effectsSide effects

– Dose-related Dose-related

– Idiosyncratic (each Idiosyncratic (each person is different)person is different)

Older MedicationsOlder Medications

Carbamazepine Carbamazepine (Tegretol)(Tegretol)

PhenobarbitalPhenobarbital

Ethosuximide (Zarontin)Ethosuximide (Zarontin)

Phenytoin Phenytoin (Dilantin/Cerebyx)(Dilantin/Cerebyx)

Valproic acid (Depakote)Valproic acid (Depakote)

Primidone (Mysoline)Primidone (Mysoline)

Newer AED’sNewer AED’s

Gabapentin (Neurontin)Gabapentin (Neurontin)

Lamotrigine (Lamictal)Lamotrigine (Lamictal)

Topiramate (Topamax)Topiramate (Topamax)

Felbamate (Felbatol)Felbamate (Felbatol)

Diastat (Diazepam)Diastat (Diazepam)

Vigabatrin (Sabril)Vigabatrin (Sabril)

Ezogabine (Potiga)Ezogabine (Potiga)

Oxcarbazepine (Trileptal)Oxcarbazepine (Trileptal)

Pregabalin (Lyrica)Pregabalin (Lyrica)

Zonisamide (Zonegran)Zonisamide (Zonegran)

Levetiracetam (Keppra)Levetiracetam (Keppra)

Lacosamide (Vimpat)Lacosamide (Vimpat)

Rufinamide (Banzel)Rufinamide (Banzel)

Clobazam (Onfi)Clobazam (Onfi)

Medication choices based on Medication choices based on epilepsy type…epilepsy type…

AED’s for Partial EpilepsyAED’s for Partial Epilepsy

All but Zarontin and BanzelAll but Zarontin and Banzel

Best AED’s for Generalized Best AED’s for Generalized EpilepsyEpilepsy DepakoteDepakote KeppraKeppra LamictalLamictal Topamax Topamax ZonegranZonegran BanzelBanzel

Future MedicationsFuture Medications

– BrivaracetamBrivaracetam– CarisbamateCarisbamate– EslicarbazepineEslicarbazepine– GanaxaloneGanaxalone– LosigamoneLosigamone– Nitrfazepam Nitrfazepam – PerampanelPerampanel– PiracetamPiracetam– ProgabideProgabide– RemacemideRemacemide– RetigabineRetigabine– SeletracetamSeletracetam– StiripentolStiripentol

What Are Some What Are Some Promising New Medical Promising New Medical Treatments?Treatments? Maintenance Maintenance

TreatmentTreatment

– Ezogabine Ezogabine (Potiga)(Potiga)

– PerampanelPerampanel

– VertexVertex

Emergency Emergency TreatmentTreatment

– Intranasal Intranasal MidazolamMidazolam

PotigaPotiga Potassium Potassium

Channel OpenerChannel Opener

Partial SeizuresPartial Seizures

Rare but serious Rare but serious side effectsside effects

PeramapanelPeramapanel Glutamate BlockerGlutamate Blocker

Effective in trials Effective in trials for partial seizuresfor partial seizures

Side effects: Side effects: Dizziness, Dizziness, SleepinessSleepiness

Approved in Approved in EuropeEurope

Under study in US Under study in US for Generalized for Generalized Seizure typesSeizure types

Under FDA review Under FDA review for Partial Seizuresfor Partial Seizures

Vx-765 for Partial Vx-765 for Partial EpilepsyEpilepsy New approach to New approach to

Epilepsy RxEpilepsy Rx

– Anti-InflammatoryAnti-Inflammatory

– Short Duration of Short Duration of therapy (weeks therapy (weeks instead of years)instead of years)

– Oral MedicineOral Medicine

Early Clinical Trials Early Clinical Trials CompletedCompleted

– Early results Early results encouraging but encouraging but longer treatment longer treatment duration to be studiedduration to be studied

– Headache, dizziness, Headache, dizziness, GI most common side GI most common side effectseffects

Emergency TreatmentEmergency Treatment Rectal DiastatRectal Diastat

– Clinically provenClinically proven

– Hard to giveHard to give

– Adults don’t likeAdults don’t like

– Can’t self Can’t self administeradminister

Intranasal MidazolamIntranasal Midazolam Easy to giveEasy to give

Preferred routePreferred route

Can be self-Can be self-administered or administered or given by caretakergiven by caretaker

Under studyUnder study

For patients that do not For patients that do not respond to medicationrespond to medication Ketogenic dietKetogenic diet SurgeriesSurgeries

Epilepsy SurgeryEpilepsy Surgery

http://www.rch.unimelb.edu.au/cep/Media/brain/mri6.jpg http://www.fleni.org.ar/files/servicio_193_8

Rates of Surgical Rates of Surgical Success*Success*

Temporal Lobectomy 70-80%Temporal Lobectomy 70-80%

““Lesion” Resection 70-80%Lesion” Resection 70-80%

““Non-Lesional” Resection 30-50%Non-Lesional” Resection 30-50%

Medical Management 5%Medical Management 5%

* Absence of Disabling Seizures

VisualaseVisualase

•Laser Treatment

•Evaluation is same asfor epilepsy surgery

No need for open brainoperation

VisualaseVisualase

Neuromodulatory Neuromodulatory TreatmentsTreatments Device implanted to alter instead of Device implanted to alter instead of

destroy brain tissuedestroy brain tissue

Range of treatment possible: Range of treatment possible: Electrical, Cooling, local medicationsElectrical, Cooling, local medications– Limit body/brain side effectsLimit body/brain side effects

Improve brain function?Improve brain function?

NeuroPaceNeuroPace

Deep Brain Stimulation (DBS)Deep Brain Stimulation (DBS)

What will Epilepsy Care What will Epilepsy Care Look Like in Future?Look Like in Future? Personalized Medical Personalized Medical

Choices based on Choices based on geneticsgenetics

Truly Truly Anti-epilepticAnti-epileptic therapytherapy

Treatment directed Treatment directed right at the seizure right at the seizure focusfocus