Seizures and EpilepsySeizures and EpilepsySeizures and EpilepsySeizures and Epilepsy

Dr. Khalid El-SalemDr. Khalid El-SalemAmerican Board of NeurologyAmerican Board of Neurology

American Board of Clinical American Board of Clinical NeurophysiologyNeurophysiology

Assistant Prof of NeurologyAssistant Prof of Neurology

JUSTJUST

ConceptsConceptsConceptsConcepts

Seizure: sudden temporary Seizure: sudden temporary change in brain function change in brain function caused by an abnormal caused by an abnormal rhythmic excessive rhythmic excessive electrical dischargeelectrical discharge

Epilepsy: a state of Epilepsy: a state of recurrent seizures recurrent seizures

Epidemiology of Epidemiology of EpilepsyEpilepsy

Epidemiology of Epidemiology of EpilepsyEpilepsy

Lifetime risk of developing Lifetime risk of developing epilepsy is 3.2%epilepsy is 3.2%

10% of population 10% of population experience at least one experience at least one seizure before the age of seizure before the age of 80 years80 years

Higher prevalence at the Higher prevalence at the extremes of ageextremes of age

Seizure Type Versus Seizure Type Versus Epileptic SyndromeEpileptic Syndrome

A seizure typeA seizure type is determined is determined by the patient’s behavior and by the patient’s behavior and EEG pattern during the ictal EEG pattern during the ictal eventevent

An epileptic syndromeAn epileptic syndrome is is defined bydefined by- Seizure type(s)Seizure type(s)- Natural historyNatural history- EEG (ictal and interictal)EEG (ictal and interictal)- Response to AEDsResponse to AEDs- EtiologyEtiology

Classification of Classification of SeizuresSeizures

Partial seizuresPartial seizures- Simple partial seizuresSimple partial seizures- Complex partial seizuresComplex partial seizures

Impaired consciousness at outsetImpaired consciousness at outset

Simple partial evolving to lost Simple partial evolving to lost consciousnessconsciousness

- Partial seizures evolving to Partial seizures evolving to general general tonic-clonic seizures (GTCS)tonic-clonic seizures (GTCS)

Classification of Classification of Seizures Seizures (cont.)(cont.)

Generalized seizuresGeneralized seizures- Absence seizuresAbsence seizures- Tonic-clonic seizuresTonic-clonic seizures- Myoclonic seizuresMyoclonic seizures- Tonic seizuresTonic seizures- Clonic seizuresClonic seizures- Atonic seizuresAtonic seizures

Classification of Classification of EpilepsiesEpilepsies

Classification of Classification of EpilepsiesEpilepsies

Partial Epilepsy SyndromesPartial Epilepsy Syndromes

- SymptomaticSymptomatic

•Lesional epilepsyLesional epilepsy

•Medial Temporal SclerosisMedial Temporal Sclerosis

•Neocortical EpilepsyNeocortical Epilepsy

- Idiopathic(Genetic)Idiopathic(Genetic)

•Benign Rolandic EpilepsyBenign Rolandic Epilepsy

•Benign occipital EpilepsyBenign occipital Epilepsy

Generalized Epilepsy Generalized Epilepsy

SyndromesSyndromes

- SymptomaticSymptomatic

•Lennox-Gastaut SyndromeLennox-Gastaut Syndrome

•West’s SyndromeWest’s Syndrome

•Progressive Myoclonic Progressive Myoclonic

EpilepsyEpilepsy

- Idiopathic(Genetic)Idiopathic(Genetic)

•Juvenile myoclonic Juvenile myoclonic

epilepsyepilepsy

•Generalized tonic clonic Generalized tonic clonic

seizures upon awakeningseizures upon awakening

Absence SeizureAbsence SeizureAbsence SeizureAbsence Seizure

Simple: abrupt onset and Simple: abrupt onset and cessation of motionless stare, cessation of motionless stare, with unresponsiveness and no with unresponsiveness and no post ictal state ( few-30 sec)post ictal state ( few-30 sec)

Complex: Complex: typical+clonic/myoclonic typical+clonic/myoclonic activity or automatismactivity or automatism

Activated by hyperventilation Activated by hyperventilation

Generalized Tonic Clonic Generalized Tonic Clonic SeizureSeizure

Generalized Tonic Clonic Generalized Tonic Clonic SeizureSeizure

Prodrome: apathy, fatigueProdrome: apathy, fatigue No auraNo aura Tonic phase: 10-15 sec, jaw snap shut, Tonic phase: 10-15 sec, jaw snap shut,

spasm, cyanosisspasm, cyanosis Clonic phase: 1-2 min, rhythmic Clonic phase: 1-2 min, rhythmic

generalized muscle contractions apnea, generalized muscle contractions apnea, increased BPincreased BP

Terminal phase: coma, pupils react, Terminal phase: coma, pupils react, breathing resumebreathing resume

Post-ictal phase: confusion, Post-ictal phase: confusion, somnolencesomnolence

Complex Partial Complex Partial SeizuresSeizures

Complex Partial Complex Partial SeizuresSeizures

Prodrome: LethargyProdrome: Lethargy Aura: commonAura: common Oral or motor automatism, Oral or motor automatism,

alteration of consciousness, head alteration of consciousness, head and eye deviation, contralateral and eye deviation, contralateral twitching or clonic movements, twitching or clonic movements, posturingposturing

Rt temporal often hypermobileRt temporal often hypermobile Lt temporal often behaviour arrestLt temporal often behaviour arrest

Frontal lobe seizures Frontal lobe seizures are partial seizures are partial seizures that can be easily that can be easily

confused with confused with psychiatric diseasepsychiatric disease

Frontal lobe seizures Frontal lobe seizures are partial seizures are partial seizures that can be easily that can be easily

confused with confused with psychiatric diseasepsychiatric disease

Acquired EpilepsyAcquired Epilepsy

TraumaTrauma InfectionInfectionVascular diseaseVascular diseaseMetabolic changesMetabolic changesTumorTumorAge effects on brainAge effects on brain

Epilepsy Risk Epilepsy Risk FactorsFactors

Epilepsy Risk Epilepsy Risk FactorsFactors

Structural brain lesionsStructural brain lesions Degenerative diseasesDegenerative diseases Head traumaHead trauma CNS infectionsCNS infections Perinatal insultsPerinatal insults Alcohol/drugsAlcohol/drugs HIEHIE Febrile seizuresFebrile seizures Genetic factorsGenetic factors

Diagnosing EpilepsyDiagnosing EpilepsyDiagnosing EpilepsyDiagnosing Epilepsy

History of recurrent seizuresHistory of recurrent seizures- Differentiate epileptic from non-Differentiate epileptic from non-

epileptic fitsepileptic fits- Classify seizure typeClassify seizure type- Determine etiologyDetermine etiology

Associated clinical featuresAssociated clinical features

Diagnostic testingDiagnostic testing• EEGEEG• MRIMRI

Epileptiform Epileptiform DischargesDischarges

Epileptiform Epileptiform DischargesDischarges

Focal DischargesFocal DischargesFocal DischargesFocal Discharges

Generalized Generalized DischargesDischargesGeneralized Generalized DischargesDischarges

PhenytoinPhenytoinPhenytoinPhenytoin

For partial and generalized For partial and generalized SzSz

^ Pt. bound, hepatic inducer^ Pt. bound, hepatic inducerSide effectsSide effects

- Dose related: ataxia, Dose related: ataxia, dysarthria, nystagmusdysarthria, nystagmus

- Idiosyncratic: hirsutism, Idiosyncratic: hirsutism, gingival hypertrophy, acne, gingival hypertrophy, acne, coarsening facial features coarsening facial features

Valproic AcidValproic AcidValproic AcidValproic AcidStrong metabolic inhibitorStrong metabolic inhibitorFor partial and generalized For partial and generalized

SzSzStrongly Teratogenic: spina Strongly Teratogenic: spina

bifidabifidaSide effects:Side effects:

- somnolence, wt gain, tremor, somnolence, wt gain, tremor, hair losshair loss

- Pancreatitis, hepatotoxicity, Pancreatitis, hepatotoxicity, blood dyscrasiasblood dyscrasias

CarbamazepineCarbamazepineCarbamazepineCarbamazepine

Potent enzyme inducerPotent enzyme inducerMainly for partial seizuresMainly for partial seizuresSide effects:Side effects:

- somnolence, dizziness, somnolence, dizziness, blurred vision, diplopia’ blurred vision, diplopia’ nystagmusnystagmus

- skin rash, hepatotxicity, skin rash, hepatotxicity, blood dyscrasiasblood dyscrasias

Classic Versus Newer Classic Versus Newer AnticonvulsantsAnticonvulsants

Classic AEDsClassic AEDs PhenobarbitalPhenobarbital Phenytoin Phenytoin

(Dilantin(Dilantin®®)) Primidone Primidone

(Mysoline(Mysoline®®)) Carbamazepine Carbamazepine

(Tegretol(Tegretol®®)) Valproate Valproate

(Depakote(Depakote®®/ / DepaconDepacon®®))

Ethosuximide Ethosuximide (Zarontin(Zarontin®®))

Newer AEDsNewer AEDs Felbamate Felbamate

(Felbatol(Felbatol®®)) Gabapentin Gabapentin

(Neurontin(Neurontin®®)) Lamotrigine Lamotrigine

(Lamictal(Lamictal®®)) Levetiracetam Levetiracetam

(Keppra(Keppra®®) ) Oxcarbazepine Oxcarbazepine

(Trileptal(Trileptal®®)) Tiagabine (GabitrilTiagabine (Gabitril®®)) Topiramate Topiramate

(Topamax(Topamax®®)) Vigabitrin (SabrilVigabitrin (Sabril®®)) Zonisamide Zonisamide

(Zonegran(Zonegran®®))

Applications of New AEDs in Applications of New AEDs in EpilepsyEpilepsy

Applications of New AEDs in Applications of New AEDs in EpilepsyEpilepsy

MedicationMedication Application in EpilepsyApplication in Epilepsy

FelbamateFelbamate Some efficacy in all seizure types Some efficacy in all seizure types

GabapentinGabapentin Partial and sec generalized tonic clonic seizures Partial and sec generalized tonic clonic seizures onlyonly

LamotrigineLamotrigine Some efficacy in all seizure typesSome efficacy in all seizure types

LevetiracetamLevetiracetam Partial and sec generalized tonic clonic seizures Partial and sec generalized tonic clonic seizures

OxcarbazepineOxcarbazepine Partial and sec generalized tonic clonic seizures Partial and sec generalized tonic clonic seizures

TiagabineTiagabine Partial and sec generalized tonic clonic seizures Partial and sec generalized tonic clonic seizures onlyonly

TopiramateTopiramate Some efficacy in all seizure typesSome efficacy in all seizure types

VigabatrinVigabatrin Infantile spasms, Partial seizuresInfantile spasms, Partial seizures

ZonisamideZonisamide Some efficacy in all seizure typesSome efficacy in all seizure types

GeneralizedPartial

Choice and Use of Choice and Use of DrugsDrugs

Tonic-clonic

Tonic Myoclonic AtonicInfantileSpasms Absence

PHT, CBZ, PB, GBP, TGB, LVT, OCBZ

ACTHTPM?TGB?VGB?

ESX

VPA, LTG, TPM, ZNSFBM

SimpleComplex

Secondarygeneralized

Newer ADE Mechanisms of Newer ADE Mechanisms of ActionAction

Newer ADE Mechanisms of Newer ADE Mechanisms of ActionAction

MedicatioMedicationn

Na ChannelNa Channel GABA R GABA R ChannelChannel

NMDA NMDA ChannelChannel

T Calcium T Calcium ChannelChannel

FelbamateFelbamate + / ?+ / ? + / ?+ / ? + / ?+ / ? ??

GabapentinGabapentin + / ?+ / ? + / ?+ / ? + / ?+ / ? ??

LamotrigineLamotrigine ++++ - / ?- / ? + / ?+ / ? - / ?- / ?

LevetiracetaLevetiracetamm

-- -- -- --

OxcarbazepiOxcarbazepinene

+ / ?+ / ? ?? -- --

TiagabineTiagabine -- ++++ -- --

TopiramateTopiramate + / ?+ / ? ?? ?? ??

VigabatrinVigabatrin ++ -- -- --

ZonisamideZonisamide ++ -- -- ++

New AEDs DosingNew AEDs DosingNew AEDs DosingNew AEDs Dosing

MedicationMedication Starting Starting dose mgdose mg

Incrementation Incrementation mgmg

Maintenance dose Maintenance dose mg mg

FelbamateFelbamate 600 tid600 tid 600-1200 / wk600-1200 / wk 1200-1600 tid1200-1600 tid

GabapentinGabapentin 300-400 qd300-400 qd 300-400 / day300-400 / day 600-1200 tid600-1200 tid

LamotrigineLamotrigine 50 qd50 qd 100 / wk100 / wk 100-300 bid100-300 bid

LevetiracetaLevetiracetamm

500 bid500 bid 500 bid / 2 wks500 bid / 2 wks 500-1000 bid500-1000 bid

OxcarbazepinOxcarbazepinee

300 bid300 bid 300 bid / wk300 bid / wk 600-1200 bid600-1200 bid

TiagabineTiagabine 4 qd4 qd 4-8 qd / wk4-8 qd / wk 32-56 in 2-4 doses32-56 in 2-4 doses

TopiramateTopiramate 50 qd50 qd 50 / wk50 / wk 100-200 bid100-200 bid

VigabatrinVigabatrin 40/kg/d40/kg/d 80-150 /kg/d80-150 /kg/d

ZonisamideZonisamide 100 qd-bid100 qd-bid 100 / wk100 / wk 100-300 bid100-300 bid

Elimination of classic Elimination of classic AEDsAEDs

Elimination of classic Elimination of classic AEDsAEDs

0 20 40 60 80 100

Phenobarb

Ethosux

Valproate

Hepatic

Renal

Elimination of Newer Elimination of Newer AEDsAEDs

Elimination of Newer Elimination of Newer AEDsAEDs

0 20 40 60 80 100

Gabapentin

Vigabatrin

Topiramate

Felbamate

Lamotrigine

Tiagabine

Oxcarbazepine

Levitiracetam

Zonisamide

hepatic

Renal

Hepatic Enzyme Effects Of AEDsHepatic Enzyme Effects Of AEDsHepatic Enzyme Effects Of AEDsHepatic Enzyme Effects Of AEDs

InducersInducers InhibitorsInhibitors No or MinNo or Min

PhenytoinPhenytoinPhenobarbitalPhenobarbital

PrimidonePrimidoneCarbamazepineCarbamazepine

ValproateValproateFelbamateFelbamate

GabapentinGabapentinLamotrigineLamotrigineTopiramateTopiramateTiagabineTiagabine

OxcarbazepineOxcarbazepineLevitiracetamLevitiracetam

ZonisamideZonisamide

Drug-Drug Interaction Drug-Drug Interaction Potential of AEDsPotential of AEDs

Drug-Drug Interaction Drug-Drug Interaction Potential of AEDsPotential of AEDs

HighHigh IntermediateIntermediate Minimal-NoneMinimal-None

PhenytoinPhenytoinCarbamazepinCarbamazepin

eeValproateValproate

PhenobarbitalPhenobarbitalPrimidonePrimidoneFelbamateFelbamate

TopiramateTopiramateLamotrigineLamotrigine

TiagabineTiagabineOxcarbazepineOxcarbazepine

ZonisamideZonisamide

GabapentinGabapentinEthosuximideEthosuximideLevitiracetamLevitiracetam

VigabatrilVigabatril

Main Inhibitory Interactions Main Inhibitory Interactions of AED’sof AED’s

Main Inhibitory Interactions Main Inhibitory Interactions of AED’sof AED’s

Effect of Inducer AED’s Effect of Inducer AED’s on Other AED’son Other AED’s

Effect of Inducer AED’s Effect of Inducer AED’s on Other AED’son Other AED’s

Serious Side EffectsSerious Side EffectsSerious Side EffectsSerious Side Effects

MedicationMedication Serious side effectsSerious side effects

FelbamateFelbamate Aplastic anemia, Liver failure Aplastic anemia, Liver failure

GabapentinGabapentin NoneNone

LamotrigineLamotrigine Stevens Johnson SyndromeStevens Johnson Syndrome

LevetiracetamLevetiracetam NoneNone

OxcarbazepineOxcarbazepine HyponatremiaHyponatremia

TiagabineTiagabine StuporStupor

TopiramateTopiramate Nephrolithiasis, glucomaNephrolithiasis, glucoma

VigabatrinVigabatrin Optic nerve demyelinationOptic nerve demyelination

ZonisamideZonisamide Renal calculiRenal calculi

Cognetive Effects of AEDsCognetive Effects of AEDsCognetive Effects of AEDsCognetive Effects of AEDs

Minimal-Minimal-NoneNone

somesome SignificantSignificant

GabapentinGabapentinTiagabineTiagabine

LamotrigineLamotrigineOxcarbazepinOxcarbazepin

eeLevitiracetaLevitiraceta

mm

PhenytoinPhenytoinCarbamazepinCarbamazepin

eeValproateValproate

ZonisamideZonisamide

PhenobarbitalPhenobarbitalPrimidonePrimidone

TopiramateTopiramate

Therapeutic Drug Monitoring Therapeutic Drug Monitoring for Newer AEDsfor Newer AEDs

Therapeutic Drug Monitoring Therapeutic Drug Monitoring for Newer AEDsfor Newer AEDs

• Not widely practiced Not widely practiced • No generally accepted No generally accepted

target rangestarget ranges• A wide range is associated A wide range is associated

with clinical efficacy. with clinical efficacy. • Considerable overlap in Considerable overlap in

drug concentrations related drug concentrations related to toxicity and non to toxicity and non response.response.

Tentative Target Tentative Target Concentration RangesConcentration Ranges

Tentative Target Tentative Target Concentration RangesConcentration Ranges

MedicationMedication RangeRangeFelbamateFelbamate 40-100 mic g/ml40-100 mic g/ml

GabapentinGabapentin >2 mic g/ml>2 mic g/ml

LamotrigineLamotrigine 1-4 mic g/ml1-4 mic g/ml

LevetiracetamLevetiracetam 35-120 mic m/L35-120 mic m/L

OxcarbazepineOxcarbazepine 4-12 mic g/ ml4-12 mic g/ ml

TiagabineTiagabine 50-250 nmol/L50-250 nmol/L

TopiramateTopiramate 2-4 mic g/ml2-4 mic g/ml

VigabatrinVigabatrin 6-278 mic m/L6-278 mic m/L

ZonisamideZonisamide 10-30 mic g/ml10-30 mic g/ml

AAN Evidence Based GuidelinesAAN Evidence Based GuidelinesLevel A or B RecommendationsLevel A or B Recommendations

Newly Diagnosed EpilepsyNewly Diagnosed Epilepsy

AAN Evidence Based GuidelinesAAN Evidence Based GuidelinesLevel A or B RecommendationsLevel A or B Recommendations

Newly Diagnosed EpilepsyNewly Diagnosed Epilepsy

MedicationMedication Monotherapy for newly Monotherapy for newly diagnosed partial/mixeddiagnosed partial/mixed

Newly diagnosed Newly diagnosed absenceabsence

FelbamateFelbamate

GabapentinGabapentin YesYes NoNo

LamotrigineLamotrigine YesYes YesYes

LevetiracetaLevetiracetamm

NoNo NoNo

OxcarbazepinOxcarbazepinee

YesYes NoNo

TiagabineTiagabine NoNo NoNo

TopiramateTopiramate YesYes NoNo

VigabatrinVigabatrin

ZonisamideZonisamide NoNo NoNo

AAN Evidence Based GuidelinesAAN Evidence Based GuidelinesLevel A or B RecommendationsLevel A or B Recommendations

Refractory EpilepsyRefractory Epilepsy

AAN Evidence Based GuidelinesAAN Evidence Based GuidelinesLevel A or B RecommendationsLevel A or B Recommendations

Refractory EpilepsyRefractory Epilepsy

MedicatioMedicationn

PartialPartial

Add Add on/adulton/adult

PartialPartial

MonotheraMonotherapypy

PrimaryPrimary

GeneralizeGeneralizedd

SymptomaSymptomatictic

GeneralizeGeneralizedd

PedsPeds

PartialPartial

FelbamateFelbamate

GabapentinGabapentin YesYes NoNo NoNo NoNo YesYes

LamotrigineLamotrigine YesYes YesYes NoNo YesYes YesYes

LevetiracetaLevetiracetamm

YesYes NoNo NoNo NoNo NoNo

OxcarbazepiOxcarbazepinene

YesYes YesYes NoNo NoNo YesYes

TiagabineTiagabine YesYes NoNo NoNo NoNo NoNo

TopiramateTopiramate YesYes YesYes YesYes YesYes YesYes

VigabatrinVigabatrin

ZonisamideZonisamide YesYes NoNo NoNo NoNo NoNo

ConclusionsConclusionsConclusionsConclusions

New AED’s are not more New AED’s are not more effective than classical effective than classical onesones

Classical AEDs remain first Classical AEDs remain first line of treatmentline of treatment

Pharmacokinetics and Pharmacokinetics and dynamics are more dynamics are more determinent than efficacy.determinent than efficacy.