EPILEPSY ITS LONG AND MULTIDISCIPLINARY APPROACH
DR.WITJAHYAKARTA SPS
Definitions Seizure S i – the transient electroclinical h i l li i l
manifestation of an abnormal paroxysmal electrical discharge of neurons in the brain l i l di h f i h b i Epilepsy – any disorder characterized by
p p recurrent epileptic seizures.
KTBPG, October 2006
Epidemiology Incidence: 44/100,000 population/year I id / l ti / (Hauser et al) Excluding convulsions complicating febrile and other intercurrent illnesses or injuries j
à 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)
à Incidence increases again after age 60y
KTBPG, October 2006
Prevalence of Epilepsy p p y in Indonesia – The prevalence of epilepsy in Indonesia around 0.5% until 4%. That’ss mean if total population in Indonesia That ± 220 million so number of epilepsy patients is approximately 1.1 1 1 – 8.8 8 8 million based on data : Guideline in Treatment of Epilepsy, 3rd Ed. 2008 – POKDI PERDOSSI
Epilepsy p p y incidence byy age g
Incidencce per 100,000
1000
All epilepsy types
100
10 0
10
20
30
40 50 Age (years)
60
70
80
Hauser WA et al. Epilepsia 1991;32:429–45
Etiology Idiopathic à presumed to be genetic in origin p g g à epilepsy with no underlying structural lesion or other
neurologic signs and symptoms à age‐dependent: onset usually between 5‐20 years, but may start later in life t t l t i lif
Symptomatic à the cause of the seizures is identified with one or more
identifiable structural lesions in brain à most likely cause is related to age at onset
Probably symptomatic or cryptogenic à a symptomatic etiology is suspected but cannot be
identified
KTBPG, October 2006
Causes of Symptomatic Epilepsies perinatal anoxia or injury p 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
Antiepileptic drugs
TREATMENT OF EPILEPSY
Basic Principles of p Treatment
Try to use only one drug, gradually increasing the dose until seizures stop or side effects appear If 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 polypharmacy Consider the side effects of each AED you are y using, 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) ( )
63% seizure free among 470 previously untreated 6 % i f i l t t d
patients
à 47% seizure free on 1st AED Subsequent 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
à à 3% seizure free on 2 AEDs % i f
67% seizure free with single established AED vs. 7 g
69% 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 Complex Secondarily generalized
Generalized Tonicclonic
CBZ, OXC, PHT, GBP, TGB, PB, VPA, LTG, TPM, ZNS, LEV
Tonic Myoclonic Atonic Infantile spasms
VPA, ZNS, TPX, LEV
Absence
ACTH, ESX, VPA, VGB LTG, TPX, LEV, ZNS
VPA, LTG, TPM, ZNS, LEV, (FBM)
*Narrow spectrum drugs KTBPG, October 2006
Considerations in AED Selection Side effects & Safety
Special populations
à Cognitive
à Children
à Metabolic b l
à Pregnant Women
à Hematologic
à Renal or Hepatic
à Obstetric
Impairment à Elderly à Other comorbidities
à Bone à Weight à Teratogenic
KTBPG, October 2006
AEDs: Cognitive Profiles Best à Felbamate à Gabapentin à Lamotrigine L ti i à Levetiracetam à Valproate p Relatively Good à Carbamazepine C b i à Phenytoin à Oxcarbazepine KTBPG, October 2006
Intermediate Intermediate Tiagabine Zonisamide
Least Favorable Phenobarbital Phenobarbital Primidone Topiramate
Courtesy of Gregory Bergey, Johns Hopkins
AEDs in the Elderly DISADVANTAGES of Older AEDs: PB, CBZ, VPA, PHT Side effects à à à à
Cognitive and sedative Action tremors Osteoporosis w risk of fracture Hyponatremia
Potential for drug interactions à à
Enzyme inducers Protein binding
NEW AEDs with ADVANTAGES Less L side id effects ff t and d greater t continuation ti ti rates: t GBP GBP, LTG 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 Selection l i Need for rapid titration: GBP, LEV, PHT, VPA, PB Pharmacokinetics and drug interactions h k dd Compliance issues à Cost à Ease of dosing g
KTBPG, October 2006
AED Metabolism – Drug I t Interactions ti No Hepatic Induction à à à à à à
Gabapentin Lamotrigine Levetiracetam Tiagabine g Valproate Zonisamide
Hepatic Induction à à à à à
Populations where inducing
g drugs may be undesirable à Patients using oral contraceptives, oral anticoagulants, chemotherapy, protease h h inhibitors à Patients predisposed to osteoporosis
Carbamazepine Oxcarbazepine (small) Phenobarbital Phenytoin Topiramate (small) Courtesy of Gregory Bergey, Johns Hopkins
KTBPG, October 2006
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 AEDs When adding new drugs, choose a drug with a h dd d h d h
different mechanism of action and different side effects
KTBPG, October 2006
Inhibitory Current = Hyperpolarization Inward movement of an anion, such as chloride
Cl-
Excitatory current = Depolarization Inward cationic movement
Ca++ C
AEDs augment such action
Na+ N
AEDs antagonize
++++++++++ ++++ +++
----------
Courtesy of Raman Sankar, KTBPG, October 2006 UCLA
Resting membrane potential ~ -70mV +++++++++++++++
-------------
Modulation of Excitation by AEDs
Na+ N
PHT CBZ OCB VPA FBM LTG TPM ZNS
V Voltage gated Na channel KTBPG, October 2006
FBM Na+
Na+
TPM
Glutamate AMPA KA Ligand gated Na channel
Ca++ C
Gly NMDA Ligand g gated g Ca channel
Mg++
Sankar, 2000
Models and Mechanisms: Antagonism of Excitatory Currents Reduction of Calcium currents T T‐type Ca Currents type Ca Currents (thalamic pacemaker currents) ETHSX, VPA, ZNS à High voltage activated Ca Currents N‐type > P/Q type: LVT, LTG GBP, Pregabalin
Sankar, 2000 KTBPG, October 2006
Models and Mechanisms: Augmentation of Inhibitory GABA Currents l
Enhancement of GABA‐ mediated Cl Channel di d Cl Ch l Opening
l
Barbiturates, FBM, BZD, TPX
Blockade of GABA Bl k d f 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, 2000 Rogawski & Loscher, 2004
Models and Mechanisms: ode s a d ec a s s Modulation of Neurotransmitter Release
LVT binds to synaptic vesicle protein SV2A
which plays an important role in exocytosis and neurotransmitter release
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Advantages of New AED Over Older AED in Selected Populations More desirable pharmakokinetics Fewer drug interactions F d i t ti Less need for serum monitoring Better safety profile f fl Better tolerability Better cognitive profile Nonepilepsy uses
KTBPG, October 2006
New AEDs: Allergic Reactions AED Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Tiagabine T i Topiramate t Zonisamide *Increased
KTBPG, October 2006
Incidence 10% 1% 10%* 1% 4% 5% 4% % 3%*
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 Partial, mixed
Refractory epilepsy
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§
Yesפפ
Yes§
Yesפפ
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
Yesפפ
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
Yesפפפפ
NA
No
NA
No
NA
No
NA
KTBPG, October 2006
Beghi, Lancet neurol, Oct 2004.
Safety of New AEDS: Adverse Events (Adapted from 2004 AAN guideline summary) AED
Serious AE
Non-serious AE
G b Gabapentin ti
N None
Weight W i ht gain, i edema, d Behavioral changes
Lamotrigine
Rash, including TEN, SJS
Tics, insomnia
Levetiracetam
None
Irritability/behavior changes
Oxcarbazepine
Hyponatremia
None
Tiagabine
Spike wave stupor
Weakness
T i Topiramate t
Renall calculi, R l li glaucoma, l hypohidrosis
Weight W i ht lloss, metabolic t b li acidosis, language problem
Z i Zonisamide id
Rash, R h renall calculi, l li hypohidrosis
IIrritability, i bili weight i h lloss, photosensitivity
KTBPG, October 2006
French et al., AAN & AES guidelines, Neurology 2004
DIAGNOSIS BANDING Serangan epileptik harus dibedakan dengan non epileptik yang mempunyai gejala hampir sama seperti di bawah ini: Neonatus dan bayi: Jitterines, Apnea, Serangan angkat bahu, Refluks gastro-esofagus Anak: Breath-holding spells, Reflex syncope, Parasomnia, Benign g p paroxysmal y vertigo, g , Tics Remaja dan dewasa: Migrain, Transient global amnesia, Transient ischemic attack,, Narcolepsy, p y, Gangguan gg gerakan,, g Serangan psikogenik (hiperventilasi, panik), Cardiac syncope (disritmia, kelainan katup, kardio-miopati)
