Transcript 1) M Madhusudanan - Choice of AED

CHOICE OF
ANTIEPILEPTIC DRUG
Magnitude of the problem
 Epilepsy affects:
 approximately 1 in 50 children and 1 in
100 adults.

PHARMACOTHERAPY OF EPILEPSY:
The issues







Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED? Which dosage?
When should AED combinations be used?
Risks associated AED treatment?
How long should treatment be continued?
PHARMACOTHERAPY OF EPILEPSY:
The issues







Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED?
Which dosage?
When should AED combinations be used?
How long should treatment be continued?
Antiepileptic drug
development
AEDs
More
20
Levetiracetam
Oxcarbazepine
Tiagabine
15
Topiramate
Felbamate
Zonisamide
10
Fosphenytoin
Gabapentin
Lamotrigine
Vigabatrin
Sodium valproate
Carbamazepine
Ethosuximide
5
Phenobarbital
Phenytoin
Benzodiazepines
Primidone
Bromide
0
1840
1860
1880
1900
1920
Year
1940
1960
1980
2000
Major considerations in
choosing an AED
 Type of seizure
 Type of epileptic syndrome
 Adverse effect profile
 Age & gender
 Ease of use (fast and easy dose titration)
 Specific co-morbidities
 Cost
Best first AED
 Not a “ one size fits all” scenario
 Choice of drug:
 Depends on :
 Efficacy
 Tolerability
 affordability
Best first AED
 Efficacy:
Determined by the type of seizure / epileptic
syndrome
 Step.1:
 To diagnose epileptic syndrome
 Step 2.
 If not possible, try to exclude JME or absences
 Carbamzepine & phenytoin will aggravate JME
 CBZ, phenytoin, tiagabine & vigabatrin will aggravate Absences
 Step.3;
 Valproate, lamotrigine or topiramate, Levitiracetum
Epileptic syndrome
 The clinical event
 Ictal & interictal EEG characteristics
 Age of onset
 Characteristic evolution & progression.
 Presence or absence of family history
Why should we identify the
epileptic syndrome?
 Whether to investigate the patient further or
not
 Which drug to choose for the control of
seizure
 To predict prognosis
Drugs of choice in certain
epileptric syndromes
Epilepsy syndrome
Drugs of choice
Febrile seizure
Rectal diazepam
West’s syndrome
ACTH, Vigabatrin
Lennox-Gestaut
Valproate, lamotrigine, topiramate,
clobazam
BECTS
Carbamazepine, Valproate
Early onset Benign Occipital seizures
Intermittent rectal diazepam
Late onset childhood occipital seizure
carbamazepine
Absence epilepsy
Valproate, Ethosuximide, lamotrigine
Juvenile myoclonic epilepsy
Valproate, Lamotrigine
Best first AED
 Efficacy:
Step.2:
 If not possible, try to exclude JME or
absences
 Carbamazepine & phenytoin will
aggravate JME
 CBZ, phenytoin, tiagabine & vigabatrin
will aggravate Absences
 Step.3;
Best first AED
 Efficacy:
Step.3:
 If not possible, find out the type the
seizure
 Partial seizure / primary generalized
seizure
Choice of AED
 Partial / GTC Seizure
 Carbamazepine, phenytoin, valproic acid (sodium
valproate ), phenobarbital and primidone are all
effective
 CBZ –drug of choice
 All forms of generalised seizure:
 Valproate; drug of choice
 Absence seizures:
 Valproate, Ethosuximide
Best first AED
 Differentiation of partial Versus Generalised
epilepsy is not always possible in infants
 Eg: Dravet’s syndrome ( severe myoclonic epilespy
of chiildhood)
 usually presents with hemiconvulsion.
 Infantile spasm:
 Pattern can change from generalised to partial
seizures
Best first AED
 Efficacy:
 If the seizure can not be typed
 Valproate, lamotrigine or topiramate,
Levitiracetum
Best first AED
 Tolerability:
 Valproate & Carbamazepine are better tolerated
than Pheno or phenytoin
 Affordability;
 Newer AEDs are costly compared older ones
Newer AEDS
 What is real advantage of these newer drugs?
 Are they going to replace older drugs?
 Does high cost of these drugs justify its
usefulness?
 What are the situations where we can use
these drugs?
Newer drugs
 No major differences in efficacy between drugs
 Major differences in side effects profiles
 Drug interaction potential also differs
 Drug choice should be tailored to the patient
EFFICAY OF NEWER AED AS
MONOTHERAPY
 RCT have shown no major difference in seizure
control between:
 LTG vs CBZ
 LTG vs DPH
 OXC vs CBZ
 OXC vs VPA
 OXC vs DPH
 GBP vs CBZ
* LTG better tolerated
* LTG better tolerated
* CBZ increased allergy
* No difference
* withdrawal more in DPH
* Withdrawal more in GBP
 GBP vs LTG
 TPM vs CBZ & VPA
* No difference
UK NICE guidelines for the
use of new AED
 If established drugs have failed
 Typically carbamazepine or valproate
 If most appropriate older drug is contraindicated
 If older drugs could interact with other medications
 If older drugs are already known to be poorly
tolerated by the patient
 If patient is a woman of child bearing potential
Newer AEDs in Epilepsy Management
Among the newer AEDs, is there a
preference of any particular AED for a
specific type of seizure?
Broad spectrum AED




Lamotrigine
Topiramate
Levitiracetum
Clobazam
Newer AED for generalised
seizure




Lamotrigine,
Topiramate,
Zonisamide, and
Levetiracetam
 Oxcarbazepine, tiagabine and gabapentine are
ineffective
AED for JME
 Valproate is superior
 Second choice
 Levitiracetum
 Clobazam
 Topiramate
 Lamotrigine
JME
 When on lamotrigine:
 If tonic-clonic seizures have been controlled,
but myoclonic seziures persist
 Add clonezepam , before changing to valproate,
topiramate or levetiracetam
Newer AED for Partial
seizure
 Lamotrigine, Oxcarbazepine, Clobazam
Gabapentin and Topiramate
 is same as that of carbamazepine or phenytoin.
NEWER AED FOR PARTIAL
SEIZURE
 AAN guideline recommendations for new
onset partial seizure
 Gabapentin
 Topiramate
 Oxcarbamazepine
 Lamotrigine
 However, levitiracetum, zonisamide & tiagabine are
also effective
Drugs effective for both
generalized & partial;
 Valproate, LTG, Topiramate, Levetiracetum
and Zonisamide.
Efficacy Spectrum of
Available AEDs
Absences & certain
myoclonic seizures
Broad spectrum
Partial &
generalised
Partial seizures
Absence only
Valproic acid
Ethosuximide
Sodium valproate
Lamotrigine* *
Carbamazepine
Phenytoin*
Ethosuximide
Topiramate
Oxcarbazepine*
Levitiracetam
Vigabatrin*
Zonisamide
Gabapentin*
Tiagabine*
* May exacerbate myoclonic and absence seizures
Vigabatrin is also effective in infantile spasms
* * Lamotrigine may aggravate severe myoclonic epilepsy
TOLERABILTY OF NEW AEDS
 Gabapentin
 Levetiracetum
 Lamotrigine
Well tolerated
 Oxcarbamazepine
 Tiagabine
 Topiramate
 Vigabatrin
Higher treatment withdrawal
EFFECT ON COGNITION
 Levetiracetum
 Lamotrigine
 Tiagabine
No significant effect on
Cognition,
How long the AED will take to produce
its effect?
Time to achieve steady state
Time to achieve steady state
of AEDs
DRUG
HALF LIFE
TIME TO ACHIEVE
STEADY STATE
Phenytoin
15-30 hrs
5-15 days
Carbamazepine
11-17 hrs
3-5 days
Valproate
6-18 hrs
2-4 days
Oxcarbamazepine
8-10 hrs
3-4 days
Lamotrigine
10-15 hrs
5-15 days
Topiramate
20-24 hrs
5 days
Levetiracetum
7-8 hrs
2-3 days
Gabapentin
5-7 days
1-2 days
Inappropriate AED choice
and
seizure worsening
Wrong
selection of drugs can worsen seizure
AEDs which may aggravate some epileptic syndromes
Drug
Syndrome
Carbamazepine
Absence epilepsy
Juvenile myoclonic epilepsy
Progressive Myoclonus E.
Rolandic Epilepsy
Phenytoin
Absence epilepsy
Progressive Myoclonus E
Phenobarbitone
Absence epilepsy
Benzodiazepines
Lennox-Gastaut syndrome
AEDs which may aggravate some epileptic syndromes
Drug
Syndrome
Vigabatrin
Absence epilepsy
Epilepsies with myoclonus
Gabapentin
Absence epilepsy
Epilepsies with myoclonus
Lamotrigine
Severe myoclonic epilepsy
Juvenile myoclonic epilepsy
Paradoxical effects of AEDs
 CBZ in partial epilepsies;
 FLE, BECTS, LKS, BEOP, Angelman’s syndrome
 Negative myoclonus & atypical absences
 Correlates with bilaterally synchronous discharges in
EEG
 I/V BZD precipitates tonic status in LGS, even
when child is already on oral BZDs
Paradoxical effects of AEDs
 VPA increases absences in CAE
 LTG:
 Precipiates absence seziures in BECTS
 Myoclonic status in LGS
 Levitiracetum
 Seizure exacerbation in refractory epilepsy with
LEV at doses more than 30 mg/kg/d
Are two drugs better than
one?
 Monotherapy can control seziures in 60%
 When to start polytherapy?
 When two monotherapy trials fail!
Which initial drug?
Initial treatment of idiopathic
generalized epilepsy (expert committee)
CLINICAL SITUATION
GTCS
ABSENCE S
MYOCLONIC
EPILEPSY
Initial monotherapy
Valproate
Lamotrigine
Topiramate
Valproate
Ethosuximide
Lamotrigine
Valproate
Second monotherapy
( Valproate failure)
Lamotrigine
Topiramate
Levitirecetum
Ethosuximide
Lamotrigine
Zonisamide
Levitiracetum
Topiramate
Second monotherapy
( lamotrigine failure)
Valproate
Topiramate
Levitiracetum
Zonisamide
Valproate
Ethosuximide
Valproate
zonisamide
Second monotherapy
( Topiramte failure)
Valproate
Lamotrigine
Valproate
Ethosuximde
Lamotrigine
Valproate
If valproate fails
 If valproate fails as the first AED
 Lamotrigine monotherapy is unlikely to be successful
)
 Prefer Topiramate or levetiracetam.
(Nicolson et al. 2004
 With generalized tonic-clonic seizures alone
 the choice is wider
 includes carbamazepine or oxcarbazepine in addition
Drugs recommended for focal
epilepsy ( expert committee)
SIMPLE PARTIAL SEIZURE
COMPLEX PARTIAL
SEIZURE
SECONDARILY
GENERALISED SEIZURE
Carbamazepine
Carbamazepine
Carbamazepine
Oxcarbamazepine
Lamotrigine
Oxcarbamazepine
Lamotrigine
Oxcarbamazepine
Lamotrigine
Levitiracetum
levitiracetum
Levitiracetum
ILAE /AES Guidelines
 According ILAE treatment guidelines,
 First-generation AEDs carbamazepine, phenytoin,
and probably valproic acid have demonstrated
effectiveness as monotherapy for partial-onset
seizures.
 According to AAN/AES subcommittees,
 Of the second generation AEDS, lamotrigine,
oxcarbazepine, and topiramate may be effective
for monotherapy,
 although the ILAE has added that gabapentin, and
vigabatrin may also be efficacious or effective as
monotherapy.
Alternative choice in
partial seizures
 If carbamazepine is effective against seizures
but poorly tolerated
 Try oxcarbazepine or lamotrigine next.
 If carbamazepine fails to control seizures
 Levetiracetam or topiramate are likely to be more
powerful than gabapentin or lamotrigine
 valproate remains an option.
SANAD STUDY
Standard and New antiepileptic Drugs
 SANAD was an unblinded randomised
controlled trial in hospital-based outpatient
clinics in the UK
 Aim is to study of effectiveness of
carbamazepine, gabapentin, lamotrigine,
oxcarbazepine, or topiramate for
treatment of partial epilepsy:
SANAD STUDY
 Lamotrigine is clinically better than
carbamazepine for time to treatment
failure outcomes
SANAD STUDY
 Study of effectiveness of valproate,
lamotrigine, or topiramate for generalised
and unclassifiable epilepsy:
SANAD STUDY
 Valproate is better tolerated than
topiramate and more efficacious than
lamotrigine, and should remain the drug of
first choice for many patients with
generalised and unclassified epilepsies.
PHARMACOTHERAPY OF EPILEPSY:
The issues








Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED?
Risks associated AED treatment?
Which dosage?
When should AED combinations be used?
How long should treatment be continued?
Pharmacoresistent epilepsy
 If Patient fails on 2 or 3 monotherapy trials:
Polytherapy
 Which drugs for add-on?
RECOMMENDED AED COMBINATION
in Generalised seizure
DRUG IN USE
RECOMMEDED COMBINATION
Valproate
Lamotrigine
Topiramate
Levetiracetum
zonisamide
Drugs found to be useful as
Add-on in Primary generalised
seizures ( by RCTS)
 Lamotrigine, Topiramate

 Felbamate and topiramate in LGS
RECOMMENDED AED COMBINATION
IN FOCAL SEIZURE
DRUG IN USE
RECOMMEDED COMBINATION
Carbamazepine Levetiracetum
Lamotrigine
Topiramate
Zonisamide
SUCCESS RATES OF NEWER AED for
Partial seizure (As add–on)
 27-29%: WITH
 OXC, Levitiracetam, topiramate
 12-20% WITH
 LTG, Gabapentin , Zonisamide
COMPLAINTS RATES OF NEWER
AED(as add on)
 -28 TO -82
 Gabapentin, Levitiracetam and zonisamide
 -113 to -205
 OXC, topiramate and LTG
 Hence the ideal drug is Levitiracetam.
OXC and Topiramate are equally effective but less
tolerable.
EPILEPSY - MANAGEMENT
CHOICE OF DRUGS
 ARE SPECIFIC COMBINATIONS USEFUL?
* Combination of VPA & Ethosuximide
-- in absences
* Combination of VPA & clonezepam
-- In myoclonic seizure
* Combination of CBZ & vigabatrin
-- In partial seizure
* Combination of LTG & Valproate
-- In partial, generalized, JME
How to combine drugs?
 Use AEDs with different mechanisms of action:
 , e.g. a sodium channel blocker (carbamazepine) with a
GABA-ergic agent (valproate);
 Use AEDs with favourable pharmacokinetic interactions:
 e.g. valproate and lamotrigine.
(enabling lower doses of lamotrigine to be used);
 Avoid combinations with similar mechanisms of action
and/or unhelpful phamacokinetic interactions:
 e.g. Carbamazepine and phenytoin
Carbamazepine and Lamotrigine
If combination therapy
fails!
 Consider surgery!
 If this is not an option;
 Go back to the combination that gave optimum,
control
INFANTILE SPASMS
 ACTH, Vigabatrin
 Zonisamide ( open label studies)
 Levitiracetum
PHARMACOTHERAPY OF EPILEPSY:
The issues








Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED?
Risks associated AED treatment?
Which dosage?
When should AED combinations be used?
How long should treatment be continued?
Getting the dosage right
 As important as choosing the right drug!
 Some AEDs require slow titration e.g. CBZ,
LTG, TPM and TGB
 Dosage should be tailored to meet individual
needs
 Monitoring drug levels may help with dose
tailoring
EPILEPSY - MANAGEMENT
DRUG DOSE & INTERVAL
 May not always require the std dose.
 Gen. seizure requires less dose than partial
 Dose interval is determined by half -life
Eg: Pheno, DPH,LTG
= OD
CBZ, VPA, Topiramate
= BD
 Multiple AEDs = shorten half life
 Larger doses in children than adults
DRUG INTERACTION
Enzyme induction
Enzyme inhibition
DPH
VPA
CBZ
PB
PMD
ETX
DRUG INTERACTION
Effect of older AEDs on newer AEDs
GPB LTG TPM TGN LEV
DPH
CBZ
Pheno
PRM
VPA
ZON OXC
Gabap Lamot Topira Tiaga
entine rigine mate bine
Levetir Zoniza Oxcarba
acetam mide
zepine
None
None
None
None None None None Slight
DRUG INTERACTION
Effect of Newer AEDs on old AEDs
 New AEDs have no significant effect on the
blood level of old AEDs.
 Phenytoin, carbamazepine, pheno or primidone
 Valproate level is decreased by 25%
DRUG –DRUG INTERCATION
POTENTIAL OF THE AEDs
HIGH
INTERMEDIATE
MINIMAL OR NONE
phenytoin
Topiramate
Gabapentin
Carbamazepine
lamotrigine
Levitiracetum
valproate
Tiagabine
Vigabatrin
Phenobarbitone
Oxcarbazepine
primidone
zonisamide
Pharmacotherapy in children
 Both old & newer drugs can be used
 Requires dose adjustments;
 Slow GI absorption.
 Higher volume of distribution
 Shorter clearance periods
 Eg: dose of CBZ infants : 30-50mg/KG
 Vs 15-35 mg/kg in older children
Pharmacokinetics in children
 Pharmacokinetic Parametres in infants
 VPA & Pb have favourable kinetics
 CBZ & DPH have unfavourable kinetics
 CBZ dose is in higher & should be given tid dosage
 DPH –difficult to determine adequate dose
 In view of non-linear pharmacokinetics
 Slight change in dose may produce toxicity/
subtherapeutic level
 Increased clearance of LTG and Topiramate

PHARMACOTHERAPY OF EPILEPSY:
The issues








Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED?
Risks associated AED treatment?
Which dosage?
When should AED combinations be used?
How long should treatment be continued?
Side effect profile of AEDS
 Quality of life
 Not only related to the magnitude of seizure
reduction
 but also to the impact of the AED on






cognition,
mood (eg, depression, anxiety, and irritability),
psychomotor dysfunction,
sexual dysfunction,
cosmetic effects,
bone health, weight gain etc.
Risks associated with AED
treatment
 Failure to achieve complete seizure control
 Dose-dependent CNS side effects
 Idiosyncratic reactions
 Chronic adverse effects
 Adverse drug interactions
The devil that we do not know:
Latency to discovery of some adverse
effects
Drug
Adverse Effect
Incidence
Latent Period
PHT
Osteomalacia
Up to 5%
1938
1967
FBM
Aplastic anaemia
1:4000
1993
1994
VGB
Visual field defects
33%
1989
1997
TPM
 intraocular
pressure
?
1995
2001
Side effects mandating
stopping treatment:
 Clobazam:
 Behavioral changes, irritabilty
 Topiramate:

Language disturbances, glaucoma
 Levitiracetum:
 Mood and behavioral changes
 Lamotrigine:
 Drug rash & SJ syndrome
 Zonisamide:
 Mental slowing, hypohidrosis
 Vigabatrin:
 Visual field defects
Tolerability in infants & children
 Valproate
 Valproate hepatotoxicity
 Increased below the age of 2 yrs
 Polytherapy
 Presence of associated psychomotor delay
 Look for undiagnosed inherited metabolic diseases
 Carnitine deficiency/ Alper’s disease
(Valproate interferes with mitochondrial function)
Pharmacotherapy in children
 Valproate;
 Preferably avoid in infants with
 Abnormal LFT,
 multiorgan failure,
 polytherapy
 or in those where exact aetiology is unclear
Tolerability in infants & children
 Pheno induced behavioural side effects
 1/3 develop hyperexcitability / insomnia
 Benzodiazepines induced paradoxical
hyperexcitation
 Bronchorrhoea / dysphagia with clonezepam
 Vigabatrin
 Hypotonia & somnolence
 Retinal toxicity is less inchildren
 Topiramate
 Metabolic acidosis is more in infants.
 PHT worsens PME ( both myoclonus & ataxia)
Emerging new AEDS
 Brivaracetam.
 Derivative of levetiracetam.
 Mech of action;
 It is a high-affinity synaptic vesicle protein 2A
(SV2A) ligand
 inhibitory activity at neuronal voltage-dependent
sodium channels
 High responder rate ( 55% versus 16%)
 Excellent tolerability
Emerging new AEDS
 Carisbamate.
 Adjunctive treatment for partial-onset seizures
 It inhibits voltage-gated sodium channels
 has a broad-spectrum of activity in a number of
animal models of seizure and drug refractory
epilepsy
 Responder rate( 28% versus 6%)
 Mode of action: unknown
 Efficacy & tolerability data are limited
Emerging new AEDS
 Eslicarbazepine acetate.
 A voltage-gated sodium channel action blocker,
 a prodrug that is structurally similar to
carbamazepine and oxcarbazepine.
 It has improved tolerability,
 Responder rate 41% versus 28%
 Once daily dosing is enough
Emerging new AEDS
 Lacosamide.
 Approved by FDA
 Adjunctive therapy for partial-onset seizures
 Oral and intravenous forms of this drug are available.
 Responder rate (41% versus 20%)
 Unique action:
 It selectively enhances slow inactivation of voltage-gated
sodium channels without affecting fast inactivation
 Lack of sedation, high intolerance rate
Emerging new AEDS
 Retigabine.
 Adjunctive therapy for partial-onset seizures in
refractory epilepsy,
 Acts on voltage-gated potassium channels.
 It is a neuronal potassium channel opener
 Responder rate (45% versus 15%)
 High discontinuation rate due to side effects
Emerging new AEDS
 Rufinamide.
 Approved by FDA
 Adjunctive treatment of seizures
 In Lennox-Gastaut syndrome
 Acts on sodium channel.
Emerging new AEDS
 Stiripentol.
 This AED appears to enhance GABA release and
has a positive effect on GABAA receptors.
 It has been used in the treatment of Dravet
syndrome (severe myoclonic epilepsy)i
Emerging new AEDS undergoing trials
 Flurofelbamate
 Ganaxolone
 Huperzine A
 Losigamone
 Safinamide
 Talampanal
 Tonabersat
 Valrocemide
 ADD SANAD STUDY
Thank You
Effect of non-AEDS on newer
AEDs
 Rifampicin decrease the blood level of
lamotrigine; INH increases it.
 Anti HIV agents increases the level of
Lamotrigine, Levitiracetum & gabapentin
AED & oral contraceptives
 Topiramate,oxcarbazepine, and felbamate
are weak inducers & can reduce the oral
contraceptive effect.
 AEDs that are safe to use in the presence of
oral contraceptives include
 valproate, gabapentin, lamotrigine,
levetiracetam, and zonisamide.
NEWER DRUGS IN STATUS:
 i/v Valproate:
 i/v Levetiracetum;
 Oral Clobazam
 Oral Topiramate
NEWER DRUGS IN STATUS:
I/V valproate
 CSF penetration is similar to I/V diazepam
 Good alternative to phenytoin.
 Seizure control in 80% of patients
 More effective than Phenytoin (66% vs 42%)
 No significant side effect:
 No sedation, No hypotension.
:
I/V valproate
NEWER DRUGS IN STATUS
 Dose:
 I/V bolus: adult dose: 15-30 mg/kg
Children; 20-40 mg/kg
 At the rate of 50mg /mt
 Adverse effects:
 Hyperammonemic encephalopathy
 Pancreatitis
 Thrombocytopenia
 Contraindication
 Children with acute liver failure
 Patients with inherited metabolic diseases
:
I/V Levetiracetum
NEWER DRUGS IN STATUS
 Advantages:
 Rapid titration.
 No drug interaction
 Good safety profile
 Excellent choice in hepatic failure
 I/V dose;
 1000 mg i/v
 Efficacy: 100% efficacy in BZD resistant SE
:
Topiramate
NEWER DRUGS IN STATUS
 Oral loading Topiramate:
 10mg/kg followed by 5mg/kg/day
USE & SIDE EFFECT PROFILE
OF NEWER AEDS
CLOBAZAM
 Highly effective as an add-on
 Antiepileptic effect:
 Broad spectrum;
 Partial, secondarily generalised,
 Absences, myoclonus
 LGS, ESES
 Alcohol withdrawal seizures
 Benign childhood partial epilepsies
 Intermittent therapy in catamenial epilepsy
CLOBAZAM
 Side effects;
 Behavioral disturbances, irritability
 Sedation
 Tolerance
Topiramate
 Broad spectrum\:
 Partial, secondarily generalised
 Primary generalised
 LGS
 Childhood epilepsy syndromes
 Infantile spasms
 SMEI
 Atypical absence & tonic seizures
Topiramate induced cognitive
& langauge problems
 Risk factors:
 Dependent on the rate of dose escalation

the risk of cognitive dysfunction with predominant word finding
difficulties can be reduced if the dose is built up by no more than
25 mg per week or fortnight,
 a family history of psychiatric disorder
 Family history of epilepsy
 history of febrile convulsions and generalised tonic-clonic
seizures
Topiramate : other side
effects
 Acute ocular problems;
 Reduced visual acuity, myopia, and increased
intraocular pressure
 Combination of topiramate with valproate
can be hepatotoxic.
 Renal stones
 Hypohidrosis
Levitiracetum
 Broad spectrum;
 Partial seizures, secondarily generalised
 Photosensitive epilepsy
 Idiopathic generalised epilepsy
 Absences
 Myoclonus-JME
Levitiracetum
 Advantages:
 Highly effective
 Generally well tolerated
 No significant drug interaction
 Main disadvantge:
 Mood & behavioral changes
Zonisamide
 Broad spectrum:
 Particularly useful in:
 LGS, infantile spasms,
 PROGRESSIVE MYOCLONIC EPILEPSY
Zonisamide;
 Side effects;
 Ataxia, dizziness
 Mental slowing, Impaired concentration.
 Hypohidrosis-heat stroke
 Renal calculi
 Weight loss
Lamotrigine
 Broad spectrum:
 Partial, generalised. LGS, Infantile spasm
 Advantage:
 Moderate effectiveness, well tolerated.
 Main side effect:
 High instance of rash (appears within 4 weeks)
 Slow titration
 Extensive drug interactions
PHARMACOTHERAPY OF EPILEPSY: The
issues








Is treatment justified?
When to start treatment?
How to start drug treatment?
Which AED?
Risks associated AED treatment?
Which dosage?
When should AED combinations be used?
How long should treatment be continued?
DRUG TREATMENT -When
to stop?
 # Factors to be considered:
1. Probability of relapse
2. Presence of adverse effect
3. Psychological attitude
4. Legal implications
When to stop AED
 Recurrence risk in all types of epilepsy after 2
years of seizure free period : 29%
 Most Recurrences occur in the first year
 If a patient is seizure free for more than 2
years after stopping treatment, subsequent
recurrent risk is very low.
When to stop AED
RISK FACTORS FOR HIGH RECURRENCE :
 Patients with abnormal EEG
 Known structural lesion and /or neurol.deficit
 Occurrence of many seizures before control
 Long duration between therapy & seizure control
 More than one type of seizure
 Adult onset complex partial seizure
 The seizure type
When to stop AED
 Early versus late withdrawal
( < 2 yrs)
Early discontinuation was associated
with greater relapse rate in patients with
partial epilepsy and in those with
abnormal EEG
PROGNOSIS OF EPILEPSY
 RELAPSE RATE:
# MOST IMPORTANT PREDICATORS:
* Seizure type
myoclonic/atonic/tonic
* Symptomatic partial
* Syndromic forms
eg: JME
PROGNOSIS OF EPILEPSY
 RELAPSE RATE:
# JME
- 85 -95%
# GTC on awakening
- 30-90%
# Symptomatic partial - 25 -75%
# Childhood absence
- 5 -25%
# Benign rolandic epilepsy - 0%
PROGNOSIS OF EPILEPSY
 GOOD PROGNOSIS IN:
1. Febrile seizure
2. Benign rolandic epilepsy
3. Absence seizures
4. Idiopathic gen. tonic clonic seizure
( with onset between 1 - 10 yrs)
PROGNOSIS OF EPILEPSY
 POOR PROGNOSIS IN:
1. Complex partial seizure
2. Symptomatic partial epilepsy
3. All forms of minor motor seizures
4. Generalised tonic clonic seizures
( With onset in infancy or puberty)
Thank You