EPILEPSYEPILEPSY

ITS LONG AND MULTIDISCIPLINARY MULTIDISCIPLINARY

APPROACH

DR.WITJAHYAKARTA SPS

DefinitionsDefinitions

S i h   i   l li i l Seizure – the transient electroclinical manifestation of an abnormal paroxysmal l i l di h   f   i   h  b ielectrical discharge of neurons in the brain

Epilepsy – any disorder characterized by recurrent epileptic seizures.p p

KTBPG, October 2006

EpidemiologyEpidemiology

I id   /   l ti /  Incidence: 44/100,000 population/year (Hauser et al)Excluding convulsions complicating febrile and other intercurrent illnesses or injuriesj

2/3 of all epileptic seizures begin in childhood (most in first year of life)

1% of persons in the USA will have epilepsy by 20 years of age (Hauser & Annegers)

Incidence increases again after age 60y

KTBPG, October 2006

Prevalence of Epilepsy in IndonesiaPrevalence of Epilepsy in Indonesia

– The prevalence of epilepsy in Indonesia around

p p yp p y

0.5% until 4%.

That’s mean if total population in IndonesiaThat s mean if total population in Indonesia

± 220 million so number of epilepsy patients is

approximately 1 1 8 8 millionapproximately 1.1 – 8.8 million

based on data :

Guideline in Treatment of Epilepsy, 3rd Ed. 2008 – POKDI PERDOSSI

Epilepsy incidence by age Epilepsy incidence by age

1000

p p y y gp p y y g0

,00

0

All epilepsy types

100

ce p

er 1

0In

cide

nc

100 10 20 30 40 50 60 70 80

Age (years)

Hauser WA et al. Epilepsia 1991;32:429–45

EtiologyEtiologyIdiopathic  

presumed to be genetic in originp g gepilepsy with no underlying structural lesion or other neurologic signs and symptomsage‐dependent: onset usually between 5‐20 years, but 

  t t l t  i  lifmay start later in life

Symptomatic  the cause of the seizures is identified with one or more the cause of the seizures is identified with one or more identifiable structural lesions in brainmost likely cause is related to age at onset

Probably symptomatic or cryptogenica symptomatic etiology is suspected but cannot be identified

KTBPG, October 2006

Causes of Symptomatic Epilepsies

perinatal anoxia or injuryp j y

congenital abnormalities or cortical malformations

trauma

drug or alcohol toxicity or withdrawal

metabolic disorders ie uremia, hypoglycemia

infectious disease

tumors and other space occupying lesions

vascular disease ie stroke, venous thrombosis

degenerative disease ie AD

KTBPG, October 2006

TREATMENT OF Antiepileptic drugs

TREATMENT OF EPILEPSY

Basic Principles of pTreatment

Try to use only one drug, gradually increasing the dose until seizures stop or side effects appearIf the first drug does not work  try another drug If the first drug does not work, try another drug with a different mode of action.If the second drug does not work  you may try If the second drug does not work, you may try another drug or try polypharmacyConsider the side effects of each AED you are yusing, and try not to combine drugs with the same adverse effects.

KTBPG, October 2006

Response to Treatment: ( )Kwan P, Brodie MJ, N Engl J Med. 2000. N=525 (age 9 to 93 years)

6 %  i  f       i l   t t d 63% seizure free among 470 previously untreated patients

47% seizure free on 1st AEDSubsequent seizure free rates depend on reason for failure of 1st AED: 11% if lack of efficacy, 41% if intolerable side effects, 55% if idiosyncratic reaction

14% seizure free with 2nd or 3rd AED% i f3% seizure free on 2 AEDs

67% seizure free with single established AED vs. 7 g69% with single new AED 

KTBPG, October 2006

Kwan P, Brodie MJ, N Engl J Med. 2000.

Considerations in AED Selection: EFFICACY can vary depending on seizure  

type or syndrome 

Partial

Simple

Generalized

SimpleComplexSecondarily generalized

Tonic-clonic

Tonic Myoclonic Atonic Infantile spasms

Absence

ACTH, VGB

ESX, VPA, LTG, TPX, LEV, ZNS

CBZ, OXC, PHT, GBP, TGB, PB, VPA, LTG, TPM, ZNS, LEV

VPA, ZNS, TPX, LEV

VPA, LTG, TPM, ZNS, LEV, (FBM)

KTBPG, October 2006*Narrow spectrum drugs

Considerations in AED Selection

Side effects & SafetyCognitive

b l

Special populationsChildren

MetabolicHematologicObstetric

Pregnant WomenRenal or Hepatic ImpairmentObstetric

BoneWeight

ImpairmentElderlyOther comorbidities

Teratogenic

KTBPG, October 2006

AEDs: Cognitive Profiles

Best IntermediateFelbamateGabapentinL t i i

IntermediateTiagabineZonisamide

LamotrigineLevetiracetamValproate

Least FavorablePhenobarbitalp

Relatively GoodC b i

PhenobarbitalPrimidoneTopiramate

CarbamazepinePhenytoinOxcarbazepineOxcarbazepine

KTBPG, October 2006

Courtesy of Gregory Bergey, Johns Hopkins

AEDs in the ElderlyAEDs in the ElderlyDISADVANTAGES of Older AEDs: PB, CBZ, VPA, PHT

Side effectsCognitive and sedativeAction tremorsOsteoporosis w risk of fractureHyponatremia

Potential for drug interactions Enzyme inducersProtein binding

NEW AEDs with ADVANTAGESL id ff t d t ti ti t GBP LTG LEVLess side effects and greater continuation rates: GBP, LTG, LEV Much less potential for drug interactions: GBP, LTG, LEV, TGB, ZNS

KTBPG, October 2006

Ensrud et al. Neurology 2004; Ramsay&Rowan, 2003; Cramer et al, AES 2003; Werz et al, AES 2003; Koopmans et al, AES 2003

Considerations in AED l iSelection

Need for rapid titration: GBP, LEV, PHT, VPA, PB

h k d dPharmacokinetics and drug interactions

Compliance issuesCompliance issuesCostEase of dosingg

KTBPG, October 2006

AED Metabolism – Drug I t tiInteractions

No Hepatic InductionGabapentin

Populations where inducing drugs may be undesirable

LamotrigineLevetiracetamTiagabine

gPatients using oral contraceptives, oral anticoagulants, h h    

gValproateZonisamide

chemotherapy, protease inhibitorsPatients predisposed to osteoporosis

Hepatic InductionCarbamazepineOxcarbazepine (small)

osteoporosis

Oxcarbazepine (small)PhenobarbitalPhenytoinTopiramate (small) Topiramate (small) 

KTBPG, October 2006Courtesy of Gregory Bergey, Johns Hopkins

Drug Interactions with New AEDs

No effect on other AEDs

Not affected by other AEDs: GBP, LVT

Reduced by inducing AEDs: LTG, TGB, ZNS

Affect other AED levels; reduced by inducing AEDs

Felbamate – increases PB, PHT, VPA, CBZ epoxide

Oxcarbazepine – increases phenytoin

Topiramate – increases phenytoin (~25%)

KTBPG, October 2006 Courtesy of Gregory Bergey, Johns Hopkins

Mechanisms of Action of AEDsMechanisms of Action of AEDs

h dd d h d hWhen adding new drugs, choose a drug with a different mechanism of action and different side effectsside effects

KTBPG, October 2006

Inhibitory Current = HyperpolarizationInhibitory Current = HyperpolarizationInward movement of an anion,

such as chloride

Cl-

N

Excitatory current = DepolarizationInward cationic movement

C ++

Cl-

AEDs augmentNa+Ca++ AEDs augmentsuch action

Resting membrane

AEDs antagonize

++++++++++++++++++++++++++ ++++++++++++++++++++++++++++++++++++++

Resting membrane potential ~ -70mV

KTBPG, October 2006

- - - - - - - - - - - - -- - - - - - - - - -Courtesy of Raman Sankar, UCLA

Modulation of Excitation by Modulation of Excitation by AEDs

C ++FBM

PHTCBZOCBVPA

N +

Na+ Na+

Ca++

TPM

VPAFBMLTGTPMNa+

GlutamateGly

TPMZNS

V

AMPAKA NMDA

Mg++Ligand gated Ligand gated

KTBPG, October 2006 Sankar, 2000

Voltage gated Na channel

Ligand gated Na channel

g gCa channel

Models and Mechanisms: Models and Mechanisms: Antagonism of Excitatory Currents

Reduction of Calcium currents

T‐type Ca Currents (thalamic pacemaker currents)T type Ca Currents (thalamic pacemaker currents)ETHSX, VPA, ZNS

High voltage activated Ca CurrentsHigh voltage activated Ca CurrentsN‐type > P/Q type: LVT, LTG GBP, Pregabalin

KTBPG, October 2006

Sankar, 2000

Models and Mechanisms: Augmentation of Inhibitory GABA Currents

l Enhancement of GABA‐di d Cl Ch l mediated Cl Channel 

Opening Barbiturates, FBM, BZD, TPX

l Bl k d   f GABA l Blockade of GABA reuptake and metabolism

VGB, TGB

• Inhibition of ability of zinc and β‐carbolines to interrupt chloride influx at GABAA‐R

LVT, CLZP, VPA

KTBPG, October 2006

Sankar, 2000Rogawski & Loscher, 2004

Models and Mechanisms: ode s a d ec a s sModulation of Neurotransmitter Release

LVT binds to synaptic vesicle protein SV2A which plays an important role in exocytosis and neurotransmitter release

KTBPG, October 2006

Advantages of New AED Over Older AED in Selected PopulationsPopulations

More desirable pharmakokineticsF  d  i t tiFewer drug interactionsLess need for serum monitoring

f f lBetter safety profileBetter tolerabilityBetter cognitive profileNonepilepsy uses

KTBPG, October 2006

New AEDs: Allergic Reactions

AEDFelbamateGabapentin

Incidence10%1%Gabapentin

LamotrigineLevetiracetam

1%10%*1%

OxcarbazepineTiagabineT i t

4% 5%%Topiramate

Zonisamide4%3%*

KTBPG, October 2006

*Increased risk of Stevens-Johnson Syndrome

Courtesy of Gregory Bergey, Johns Hopkins

Table 2. Summary of the US and UK guideline recommendations for use of new antiepileptic drugs

Drug Newly diagnosed epilepsy Refractory epilepsy

Partial, mixed Absence Partial Partial monotherapy

Idiopathic generalised

Symptomatic generalised

US UK US UK US UK US UK US UK US UK

Felbamate* No NA No NA Yes† NA Yes NA No NA Yes‡ NA

Gabapentin Yes§ No No No Yes Yes¶ No No No No No No

Lamotrigine Yes§ Yes Yes§ Yes Yes Yes** Yes Yes No Yes** Yes Yes**

Levetiracetam No No No No Yes Yes†† No No No No No No

Oxcarbazepine Yes Yes¶ No No Yes Yes¶ Yes Yes¶ No No No No

Tiagabine No No No No Yes Yes No No No No No No

Topiramate Yes§ Yes¶ No No Yes Yes** Yes§ Yes¶ Yes‡‡ Yes ‡‡

**Yes Yes**

Vigabatrin§§ NA No NA No NA Yes NA No NA No NA Yes¶¶

Zonisamide No NA No NA Yes NA No NA No NA No NA

KTBPG, October 2006

Zonisamide No NA No NA Yes NA No NA No NA No NA

Beghi, Lancet neurol, Oct 2004.

Safety of New AEDS:  Adverse Events (Adapted from 2004 AAN guideline summary)Events

AED Serious AE Non-serious AE

G b ti N W i ht i d

(Adapted from 2004 AAN guideline summary)

Gabapentin None Weight gain, edema,Behavioral changes

Lamotrigine Rash, including TEN, SJS Tics, insomnia

Levetiracetam None Irritability/behaviorchanges

Oxcarbazepine Hyponatremia NoneOxcarbazepine Hyponatremia None

Tiagabine Spike wave stupor Weakness

T i t R l l li l W i ht l t b liTopiramate Renal calculi, glaucoma, hypohidrosis

Weight loss, metabolic acidosis, language problem

Z i id R h l l li I i bili i h lZonisamide Rash, renal calculi,hypohidrosis

Irritability, weight loss, photosensitivity

KTBPG, October 2006 French et al., AAN & AES guidelines, Neurology 2004

DIAGNOSIS BANDINGDIAGNOSIS BANDING

Serangan epileptik harus dibedakan dengan non Serangan epileptik harus dibedakan dengan non epileptik yang mempunyai gejala hampir sama seperti dibawah ini:

Neonatus dan bayi: Jitterines, Apnea, Serangan angkat bahu, Refluks gastro-esofagus

Anak: Breath-holding spells, Reflex syncope, Parasomnia, Benign paroxysmal vertigo, Ticsg p y g ,

Remaja dan dewasa: Migrain, Transient global amnesia, Transient ischemic attack, Narcolepsy, Gangguan gerakan, , p y, gg g ,Serangan psikogenik (hiperventilasi, panik), Cardiac syncope (disritmia, kelainan katup, kardio-miopati)