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CHOOSING THE RIGHT
MEDICAL TREATMENT AND
RECENT ADVANCES
NEELIMA THAKUR, MD.
Epilepsy Burden
• The lifetime likelihood of
– Experiencing at least 1 seizure is ~ 9%.
– Receiving a diagnosis of epilepsy is ~3%.
• Approximately 200,000 new cases of seizures and epilepsy
occur each year.
• Epilepsy and seizures affect nearly 3 million Americans of all
ages, at an estimated annual cost of $17.6 billion in direct and
indirect costs.
Seizures are defined as abnormal discharge of electrical
activity from brain neurons resulting in transient loss of
motor, sensory or mental function.
Seizure types
• Provoked seizures
•
Acute symptomatic.
•
Often a reversible cause.
not epilepsy.
• Unprovoked seizures
•
By definition, these are
• 2 unprovoked seizures 24hrs apart is considered
epilepsy.
First unprovoked seizure – risk of
seizure recurrence.
• 24-74 % in first 5 years.
– Normal EEG and imaging studies – 24%
– Abnormal EEG and imaging studies- 74%
• After 2nd unprovoked seizure – 80%
First unprovoked seizure
• Risk factors for seizure recurrence
–
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Family history
Abnormal EEG
Abnormal neuroimaging.
Seizure in sleep.
First unprovoked seizure
• 50 % seizures recur in the first year
• 80% with in two years.
First unprovoked seizure
• Current Guidelines
– No antiepileptic drugs (AEDs) if
• There are no other risk factors
• Normal EEG.
Anti epileptic Drugs
Antiepileptic drugs
1st drug- 47 % seizure free
2nd drug- 13% seizure free
3rd / multi drugs - 4% seizure free
Refractory
1st drug
3rd drug
2nd drug
Epilepsy outcome at >7 years.
• Seizure free >7years - 59 %
• Seizure free >1 year and relapses- 16 %
Which AED to choose?
Anti epileptic Drugs
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1850 : Bromides
1910: Phenobarbital
1940: Phenytoin
1950: Ethosuximide
1958: ACTH
1954: Primidone
1968: Carbamazepine
1975: Clonazepam
1978: Depakote
1990s: Newer AEDs were developed.
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lamotrigine (Lamictal)
felbamate (Felbatol)
levetiracetam (Keppra)
topiramate (Topamax)
oxcarbazepine (Trileptal)
zonisamide (Zonegran)
pregabalin (Lyrica)
lacosamide (Vimpat)
rufinamide (Banzel)
vigabatrin (Sabril)
clobazam (Onfi)
ezogabine (Potiga)
perampanel (Fycompa)
eslicarbazepine (Aptiom)
•Good efficacy,
•Fewer toxic effects,
•Better tolerability
Following criteria may be helpful
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Type of epilepsy
Comorbidities
Side effect profile
Pharmacokinetics
Drug-drug interactions
Single dose-Compliance
Women
Elderly
Type of epilepsy
• Primarily generalized epilepsies.
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ethosuximide ( Absence seizures)
valproate
topiramate
zonisamide
lamotrigine
levetiracetam
rufinamaide
clobazam
vigabatrin.
Primarily generalized epilepsies
• Avoid carbamazepine, gabapentin,
Phenytoin.
Efficacy
Primarily generalized epilepsy
• Absence seizures
– ethosuximide, valproate are effective than
lamotrigine.
• Atonic seizures : clobazam.
• Primarily generalized epilepsies:
valproate>topamax and leviteracetam.
Type of epilepsy
• Partial Epilepsies
All AEDs except ethosuximide.
Efficacy-Partial seizures
• Not possible to compare efficacy as there
are no major head to head trials.
• The study population, inclusion and
exclusion criteria are different. ‘
Mechanism of action
Rational polypharmacy.
Comorbidities
• Bipolar disorder/depression/anxiety:
valproate, lamotrigine, carbamazepine, oxcarbazepine.
• Migraines:
valproate, topiramate, zonisamide.
• Obesity:
topiramate, zonisamide
• Neuropathy:
gabapentin, lyrica, carbamazepine, oxcarbazepine.
Comorbidities
AEDs to avoid
• Psychiatric/behavorial problems: levetiracetam.
• Osteoporosis: phenobarbital, phenytoin, valproate,
carbamazepine.
• Renal stones : topamax, zonegran.
• Obesity: valproate, pregabalin, gabapentin.
• Diabetes: valproate.
Liver dysfunction
Drugs of choice
• leviteracetam
• lacosamide
• pregabalin
• gabapentin
Renal dysfunction
Decrease drug doses that are cleared primarily by
kidneys
– levetiracetam
– lacosamide
– pregabalin
– gabapentin
Hemodialysis
Risk of drug removal is high for non protein bound drugs
Doses need to be adjusted accordingly.
• High risk
levetiracetam
lacosamide
phenobarbital
topiramate.
• Low risk
phenytoin
valproate
lamotrigine.
carbamazepine
Drug interactions
Liver enzyme(CYP 450 & UGT) inducers
phenytoin, phenobarbital, carbamazepine, oxcarbazepine,
topiramate, felbamate, rufinamide.
• Liver enzyme inhibitors
– valproate, felbamate.
Single daily dose
Improves Patient compliance.
XR formulations may have lesser side effects.
• Q day AEDs
Phenytoin, Phenobarbital and zonegran.
• XR formulation
Depakote ER, Lamictal XR, Keppra XR, Oxtellar XR and Trokendi XR.
Epilepsy in Elderly
• The prevalence and incidence of epilepsy are highest in
later life!!
• Approximately 7% of seniors have epilepsy.
• 25% of new cases occur in elderly
AEDs : Elderly
• Older people with a first unprovoked seizure are more
likely to develop recurring seizures than are younger
adults.
• Starting AEDs after a single unprovoked seizure may be
appropriate in some cases.
AEDs: Elderly
AEDs - Elderly
TREAT CAUTIOUSLY!
– Elderly are more susceptible to the adverse effects of
drugs than their younger patients.
– Pharmacokinetics and pharmacodynamics of AEDs
differ in old age .
– Drug-drug interactions
AEDs- Elderly
Treatment Challenges
• Comorbidities complicate the treatment options.
• Polypharmacy make them susceptible to drug
interactions.
• Adherence may not be as good in elderly patients with
epilepsy.
AEDs - Elderly
• Pharmacokinetic
–
Albumin results in free fraction phenytoin,
carbamazepine and valproate.
– Drug metabolism is affected by decreased liver
enzymes.
– Drug excretion is affected by decreased renal
clearance.
AEDs - Elderly
• In general the preferred drugs are
– levetiracetam
– lamotrigine
– gabapentin
AEDs-Pregnancy
Concerns
–
Effect of AEDs on Fetus and infant during
• Pregnancy
• Breast feeding.
– AED pharmacokinetics affecting levels during
• Pregnancy
• Postpartum
AEDs - Pregnancy
Teratogenic risks mono vs polytherapy.
• Single AED
• Two AEDs
• Three AEDs
3.1 %
5.8 %
8.3%
AEDs - Pregnancy
• Major malformations with monotherapy
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valproate
phenobarbital
topiramate
carbamazepine
phenytoin
levetiracetam
lamotrigine
9.3%
5.5 %
4.2 %
3%
2.9%
2.4%
2.0%
AEDs - Pregnancy
• Pharmacokinetics
lamotrigine & levetiracetam
clearance during pregnancy
level up to 50% of baseline.
• Postpartumclearance returns to baseline and drug levels.
• Check monthly levels and adjust dose.
AEDs - Pregnancy
In general, levetiracetam, lamotrigine,
oxcarbazepine and carbamazepine are
considered relatively safe.
Newer AEDs
• Ezogabine (Potiga)
• Perampanel (Fycompa)
• Eslicarbazepine (Aptiom)
Ezogabine (Potiga)
2011
• Mechanism of action: Potassium Channel
• Approved for add on treatment for Partial
epilepsy.
• It is the first neuronal potassium channel
opener developed for the treatment of
epilepsy .
Ezogabine (Potiga)
• Mechanism of action: Potassium Channel
• Approved as add on treatment for Partial epilepsy
.
• First neuronal potassium channel opener
developed for the treatment of epilepsy .
Ezogabine (Potiga)
Absorption and Metabolism:
– Well absorbed. Food has no influence.
– Not known whether excreted in human milk.
– Metabolized in liver.
– Dosage adjustment is required in patients with moderate and
greater renal or hepatic impairment .
– *urine bilirubin can show falsely elevated readings
Ezogabine (Potiga)
• Drug interactions
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Carbamazepine, phenytoin may Potiga levels.
Potiga has no effect on other AED levels.
POTIGA may digoxin serum concentrations.
Alcohol systemic exposure to POTIGA
Ezogabine (Potiga)
Adverse reactions
FDA warning blue skin discoloration and eye abnormalities characterized by
pigment changes in the retina
Initial and periodic eye exams are recommended.
– Urinary retention
– Neuropsychiatric symptoms- confusion, psychosis
– QT interval prolongation
Perampanel (Fycompa)
2012
• Mechanism of action: AMPA glutamate
receptor noncompetitive antagonist.
• Approved as add on treatment for Partial
epilepsy.
Perampanel (Fycompa)
• Absorption and Metabolism:
– Well absorbed. Food has no influence.
– Not known whether excreted in human milk.
– Metabolized in liver. Dosage adjustment is required in patients
with moderate and greater renal or hepatic impairment .
Perampanel(Fycompa)
Drug interactions
– Does not effect other AEDs.
– Enzyme inducers perampanel levels.
Perampanel (Fycompa)
• Adverse reactions
– Neuro-psychiatric symptoms ( black box
warning for aggression and hostility).
– Dizziness , Somnolence fatigue, blurred vision.
– Pregnancy category C
Eslicarbazepine (Aptiom)
2013
• Mechanism of action: Na channel blocker.
the prodrug metabolizes to eslicarbazepine..
• Approved as add on treatment for Partial
epilepsy.
Eslicarbazepine (Aptiom)
• Absorption and Metabolism:
– Well absorbed. Food has no influence.
– Metabolized in liver and kidneys.
• Drug interactions and Side effects
Similar but more tolerable than oxcarbazepine
Thank you