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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)