EpilepsyEpilepsySubspecialty seminarSubspecialty seminar

Oct 25, 2006Oct 25, 2006

defndefn

Two or more unprovoked seizures.Two or more unprovoked seizures. seizure is an abnormal electrical seizure is an abnormal electrical

activity of the brain due to hyper activity of the brain due to hyper synchronous firing of aggregates of synchronous firing of aggregates of neurons.neurons.

CONCON

• Normally there are highly differentiated Normally there are highly differentiated electrical signals with in the brain that electrical signals with in the brain that sustain the normal lifesustain the normal life

• ““Electrical rebellion” that results in to Electrical rebellion” that results in to monotonous discharge firing in synchrony monotonous discharge firing in synchrony across the brainacross the brain

• ‘‘Sacire’ to take possession of Sacire’ to take possession of

• Most prevalent of the neurological Most prevalent of the neurological disordersdisorders

Magnitude of the problemMagnitude of the problem

• World wide incidence 0.3-.0.5%World wide incidence 0.3-.0.5%

prevalence 5-10/1000prevalence 5-10/1000

• Ethiopia prevalence 5.2/1000 Ethiopia prevalence 5.2/1000

GTC 81%GTC 81%

Partial complex 13.9Partial complex 13.9

simple partial 5.7simple partial 5.7

The commonest of all neurological The commonest of all neurological problemsproblems

ClassificationClassification

• Partial and GeneralizedPartial and Generalized

• Partial when the seizure arises from Partial when the seizure arises from discreet area of the cortexdiscreet area of the cortex

• Generalized when there is clinical or EEGGeneralized when there is clinical or EEG

Manifestation of simultaneous i/v of both Manifestation of simultaneous i/v of both hemispheres .hemispheres .

• Partial sz are common ones in adultsPartial sz are common ones in adults– Temporal lobe epilepsy commonest of the Temporal lobe epilepsy commonest of the

partials szs partials szs

Classification of SeizuresClassification of Seizures

1. Partial seizures1. Partial seizuresa. Simple partial seizures (with motor, a. Simple partial seizures (with motor, sensory, autonomic, or psychic signs)sensory, autonomic, or psychic signs)b. Complex partial seizuresb. Complex partial seizuresc. Partial seizures with secondary c. Partial seizures with secondary generalizationgeneralization2. Primarily generalized seizures2. Primarily generalized seizuresa. Absence (petit mal)a. Absence (petit mal)b. Tonic-clonic (grand mal)b. Tonic-clonic (grand mal)c. Tonicc. Tonicd. Atonicd. Atonice. Myoclonice. Myoclonic3. Unclassified seizures3. Unclassified seizuresa. Neonatal seizuresa. Neonatal seizuresb. Infantile spasmsb. Infantile spasms

Partial szsPartial szs

• Simple partial no loss of consciousnessSimple partial no loss of consciousness area involved area involved →type of sz→type of sz Motor → convulsiveMotor → convulsive temporal →Auditory hallntemporal →Auditory halln → →behavioral abnbehavioral abn limbic → Psychiclimbic → PsychicPost ictal paralysis 13.5%Post ictal paralysis 13.5%Epilepsia partialis continuaEpilepsia partialis continuaJACKSONIAN marchJACKSONIAN march

•

Complex partial szComplex partial sz

• Ass with alteration in consciousnessAss with alteration in consciousness• Stereotypical auraStereotypical aura• AutomatismAutomatism• Post ictal confusionPost ictal confusion• AmnesiaAmnesia• Protean range of manifestationsProtean range of manifestations• Consider as DDx in any pt with Consider as DDx in any pt with

paroxysmal abnormal behavior esp if the paroxysmal abnormal behavior esp if the pt seems not to be fully aware of itpt seems not to be fully aware of it

concon

• Partial sz with sec generaliznPartial sz with sec generalizn Aura sterotyped clearAura sterotyped clear Generalized szsGeneralized szs--Absence szAbsence sz Common in childrenCommon in children difficult to dx difficult to dx easy to treateasy to treat transient lapses of consciousnesstransient lapses of consciousness Subtle motor manifestationsSubtle motor manifestations 70% remission rate70% remission rate classic EEG findingsclassic EEG findings

..con..con

Tonic clonicTonic clonic

the sterotype sz in the public mindthe sterotype sz in the public mind• the commonest sz of the commonest sz of metabolic abnormalitiesmetabolic abnormalities• 10% of the general popn at one time during their life10% of the general popn at one time during their life• Cx by: Loss of consciousnessCx by: Loss of consciousness tonic stiffningtonic stiffning clonic phase clonic phase Post ictal confusionPost ictal confusion Headache/muscle pain Headache/muscle pain usually lasts for a minuteusually lasts for a minute

concon

Tonic /Clonic szsTonic /Clonic szsAtonicAtonic sudden loss of postural tone sudden loss of postural tone predisposes to traumapredisposes to trauma Consciousness briefly impairedConsciousness briefly impairedMyoclonicMyoclonic brief reigonal or generalized contraction of the brief reigonal or generalized contraction of the

musclesmuscles due to metabolic disturbancedue to metabolic disturbance Part of syndromesPart of syndromes

Epilepsy syndromesEpilepsy syndromes

Juvenile myoclonic epilepsyJuvenile myoclonic epilepsy adolescentsadolescents benignbenign ass with other szass with other szLennox Gastaut syd.Lennox Gastaut syd. multiple szmultiple sz Cognitive abnCognitive abn characterstic EEGcharacterstic EEGMTLE MTLE hippocampal sclerosishippocampal sclerosis partial complex szpartial complex sz most studiedmost studied

MechanismMechanism

• Imbalance b/n excitation and inhibition Imbalance b/n excitation and inhibition of the neuronof the neuron

endogenous factorendogenous factor

Epileptogenic PPtingEpileptogenic PPting

seizureseizure

……contdcontd

• Epileptogenic HI,stroke,malignanciesEpileptogenic HI,stroke,malignancies infections,drugs..infections,drugs..• Endogenous family HxEndogenous family Hx Genetic abnormalitiesGenetic abnormalities• PP factors sleep deprivationPP factors sleep deprivation photophoto mensesmensesEpileptogenesis refers to transformation of Epileptogenesis refers to transformation of

the normal neuronal network in to that of the normal neuronal network in to that of chronically hyperexcitable onechronically hyperexcitable one

..con..con

Structural abnormalitiesStructural abnormalities selective loss of neurones selective loss of neurones (inhibitory or excitatory )(inhibitory or excitatory )

sprouting and reorganizationsprouting and reorganization chronic hyperexcitable networkchronic hyperexcitable network

Con PartialCon Partial

• Inhibitory neuronal lossInhibitory neuronal loss exicitatory neurons that stimulate the exicitatory neurons that stimulate the

inhibitory pathways are also lostinhibitory pathways are also lost• Abnormal integration of neurons with Abnormal integration of neurons with reorganizationreorganization• New neuron differentiation with formation New neuron differentiation with formation

of new synapsesof new synapses• Alteration in the composition and Alteration in the composition and

expression of GABA receptors expression of GABA receptors

MTLEMTLE

……concon

• Neuronal lossNeuronal loss

• Reorganization gradually Reorganization gradually lowers lowers

• Neurogenesis sz thresholdNeurogenesis sz threshold

MechanismMechanism

AbsenceAbsence Alteration in the circuitry b/n the thalamus Alteration in the circuitry b/n the thalamus

and the cortex and the cortex Normally the rhythm of cortical stimulation is Normally the rhythm of cortical stimulation is

influenced by thalamusinfluenced by thalamusThe thalamocortical circuit underlies the The thalamocortical circuit underlies the

physiological cortical excitation including sleepphysiological cortical excitation including sleepEither fires in a burst form or in a tonic mannerEither fires in a burst form or in a tonic mannerIn turn it is influenced by the RASIn turn it is influenced by the RAS

Thalamo cortical circuitThalamo cortical circuit

MechanismMechanism

• Developmental influencesDevelopmental influences• Cortical malformationsCortical malformations proliferationproliferation migrationmigration cortical organizationcortical organizationBeing identified using high resoln neuroimagingBeing identified using high resoln neuroimaging• Change in the neuronal microenvironment Change in the neuronal microenvironment key buffering functionkey buffering function• ChannelopathiesChannelopathies

concon

Focal Discreet lisions with Focal Discreet lisions with disruption of the balance disruption of the balance

Generalized Network abnormalitiesGeneralized Network abnormalities

Intrinsic neuronal Intrinsic neuronal abnormalitiesabnormalities

EvaluationEvaluation

Is it a seizure?Is it a seizure? DDx for SzDDx for SzDoes it have any reversible cause?Does it have any reversible cause?Is medication worth initiating?Is medication worth initiating?HX preictal, ictal post ,ictal ,frequencyHX preictal, ictal post ,ictal ,frequency family hxfamily hx drugsdrugs systemic illnessessystemic illnesses•

……ConCon

• pptin factorspptin factors• P/E look for atherosclerotic MarkersP/E look for atherosclerotic Markers signs of traumasigns of trauma skin abnormalitiesskin abnormalities neurological abnneurological abnLAB CBC,U/A, OFTsLAB CBC,U/A, OFTs electrolyteselectrolytes LPLP EEGEEG

……CONCON

• Neuroimaging MRI/CTNeuroimaging MRI/CT

• functional studiesfunctional studies

evaluationevaluation

TreatmentTreatment

• Treat the underlying causeTreat the underlying cause

• Treat the ppting factorTreat the ppting factor

• Prevent recurrence Prevent recurrence

• Address psychosocial issuesAddress psychosocial issues

General principlesGeneral principles

• The lower possible doseThe lower possible dose

• Single drugSingle drug

• Appropraite for the typeAppropraite for the type

• Start low and go slowStart low and go slow

• depends on the frequency of the szdepends on the frequency of the sz

• Side effect profile Side effect profile

• Drug interactionDrug interaction

• Clinical monitoringClinical monitoring

……concon

• Serum drug levelsSerum drug levels

• Switch to another class of drug if not Switch to another class of drug if not controlled by onecontrolled by one

• Use two drugs if single therapy of Use two drugs if single therapy of two different classes failtwo different classes fail

• Follow up acc the control of szFollow up acc the control of sz

• Issue of discontinuationIssue of discontinuation

Antiepileptic drugsAntiepileptic drugs

mode of action ion mode of action ion channels/N.transmitterschannels/N.transmitters

act on Na channels act on Na channels phenytoin,carbamaphenytoin,carbama

lamotrigine,topiramatelamotrigine,topiramate Ca channel phenytoinCa channel phenytoin GABA potentiation BarbituratesGABA potentiation Barbiturates Glutamate uptake LamotrigineGlutamate uptake Lamotrigine

Primary Primary generalizgeneralizeded

PartialPartial AbsenceAbsence Atypical Atypical absence, absence, myoclonimyoclonic,c,

atonicatonic

First lineFirst line Valproic acidValproic acid

LamotrigineLamotrigineCarbamazepineCarbamazepine

PhenytoinPhenytoin

LamotrigineLamotrigine

Valproic acidValproic acid

Valproic acidValproic acid

EthosuxamideEthosuxamideValproic acidValproic acid

AlternatiAlternativeve

PhenytoinPhenytoin

CarbamazepineCarbamazepine

TopiramateTopiramate

ZonisamideZonisamide

FelbamateFelbamate

PrimidonePrimidone

PhenobarbitalPhenobarbital

TopiramateTopiramate

LevitracetamLevitracetam

TiagabineTiagabine

ZonisamideZonisamide

GabapentineGabapentine

PrimidonePrimidone

PhenobarbitalPhenobarbital

Lamotrigine Lamotrigine ClonazepamClonazepam

LamotrigineLamotrigine

TopiramateTopiramate

ClonazepamClonazepam

FelbamateFelbamate

New vs old drugsNew vs old drugs

• The new ones are found to be The new ones are found to be as effective as those of the oldas effective as those of the old expensiveexpensive not time testednot time tested

Side effects of AEDSSide effects of AEDS

Current recommendationCurrent recommendation(American Academy Of (American Academy Of Neurology)Neurology)Patients with newly diagnosed epilepsyPatients with newly diagnosed epilepsy Who require treatment can be initiated on Who require treatment can be initiated on

standard AEDs such as carbamazepine, standard AEDs such as carbamazepine, valproic acid,phenobarbitalvalproic acid,phenobarbital ORORThe new AEDs The new AEDs

lamotrigine,gabapentin,oxcarbazine,or lamotrigine,gabapentin,oxcarbazine,or topiramatetopiramate

(evidence level A/B)(evidence level A/B)

Status epilepticusStatus epilepticus

• Continues or repititive discreet szs Continues or repititive discreet szs without regaining consciousness in without regaining consciousness in between which lasts 5 or more minutesbetween which lasts 5 or more minutes

• Medical emergencyMedical emergency• As many statuses as epilepsiesAs many statuses as epilepsies• Ass with mortality rate of 20%Ass with mortality rate of 20%• The mechanism which normally aborts The mechanism which normally aborts

a sz is losta sz is lost

EtiologyEtiology

• Drug discontinuation or incomplianceDrug discontinuation or incompliance

• Acute structural injuriesAcute structural injuries

• Remote >> abnormalitiesRemote >> abnormalities

• Metabolic abnormalitiesMetabolic abnormalities

• Drugs intoxicationsDrugs intoxications

……concon

• Status is Cx byStatus is Cx by1.1. self sustenanceself sustenance2.2. Pharmaco-resistancePharmaco-resistance3.3. Neuronal damageNeuronal damageWhich tends to worsen as time passes Which tends to worsen as time passes

withoutwithoutBeing controlledBeing controlled

PathophysiologyPathophysiology

• Milliseconds to secsMilliseconds to secs ionchannel opening/closingionchannel opening/closing Neurotransmitter modulationNeurotransmitter modulation• Secs to minutes Secs to minutes Receptor trafficingReceptor trafficing• Minutes to HrsMinutes to Hrs Plastic changesPlastic changes in neuropeptide modulators in neuropeptide modulators• Hrs to days change in Hrs to days change in gene expressiongene expression partly explains how sz becomes self sustaining and partly explains how sz becomes self sustaining and Pharmaco resistantPharmaco resistant

complicationscomplications

• HyperthermiaHyperthermia

• AspirationAspiration

• RahbdomyolysisRahbdomyolysis

• Lactic acidosisLactic acidosis

• Brain injuryBrain injury

• Pulmonary edemaPulmonary edema

TreatmentTreatment

• SupportiveSupportive

AirwaysAirways

BPBP

Fast neurological examnFast neurological examn

Draw blood/secure iv lineDraw blood/secure iv line

• Ideal situations this should take <4’Ideal situations this should take <4’

• INITIATE Rx as fast as possible INITIATE Rx as fast as possible

RxRx

……concon

Diazepam/LorazepmDiazepam/Lorazepm

IV statIV stat

Repeat another doseRepeat another dose

Secure 2Secure 2ndnd iv line iv line

Phenytoin 20mg/kg 50mg/minPhenytoin 20mg/kg 50mg/min

10mg/kg10mg/kg

..cont...cont.

Phenobarb 20mg/kg 50mg/minPhenobarb 20mg/kg 50mg/min

Repeat 10mg/kgRepeat 10mg/kg

If controlled taper for 24 hrs but If controlled taper for 24 hrs but maintain higher serum levelsmaintain higher serum levels

G/A PropofolG/A Propofol

When the bp is low consider When the bp is low consider midazolam drip .midazolam drip .

ReferencesReferences

Harrisons 16Harrisons 16thth edt edtUptudate 14.1Uptudate 14.1Lancet (vol 5 march 2006)Lancet (vol 5 march 2006)Nejm(349;13 sep 25,2003)Nejm(349;13 sep 25,2003)Nejm(2005,Tales of temporal lobeNejm(2005,Tales of temporal lobewww.neurology.comwww.neurology.com