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.

• Provoked seizures• Acute symptomatic.

• Often a reversible cause.

•By definition, these are not epilepsy.

• Unprovoked seizures• 2 unprovoked seizures 24hrs apart is considered

epilepsy.

Seizure types

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 – 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

2nd drug

3rd drug

Refractory

1st drug- 47 % seizure free2nd drug- 13% seizure free3rd / multi drugs - 4% seizure free

Epilepsy outcome at >7 years.

• Seizure free >7years - 59 %• Seizure free >1 year and relapses- 16 %

Which AED to choose?

Anti epileptic Drugs

• 1850 : Bromides• 1910: Phenobarbital• 1940: Phenytoin• 1950: Ethosuximide• 1958: ACTH• 1954: Primidone• 1968: Carbamazepine• 1975: Clonazepam• 1978: Depakote

1990s: Newer AEDs were developed.

• 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

– Type of epilepsy– Comorbidities– Side effect profile– Pharmacokinetics– Drug-drug interactions– Single dose-Compliance– Women– Elderly

Type of epilepsy• Primarily generalized epilepsies.

– 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 EpilepsiesAll 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.

ComorbiditiesAEDs 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) inducersphenytoin, 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 3.1 %• Two AEDs 5.8 %• Three AEDs 8.3%

AEDs - Pregnancy

• Major malformations with monotherapy– valproate 9.3%– phenobarbital 5.5 %– topiramate 4.2 %– carbamazepine 3%– phenytoin 2.9%– levetiracetam 2.4%– lamotrigine 2.0%

AEDs - Pregnancy

• Pharmacokineticslamotrigine & levetiracetam

clearance during pregnancy

level up to 50% of baseline.• Postpartum-

clearance 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– 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 reactionsFDA 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 effectsSimilar but more tolerable than oxcarbazepine

Thank you