Management of Epilepsy

Robert L. Macdonald M.D., Ph.D.

Department of Neurology

Vanderbilt University Medical Center

Nashville, TN

Management of Epilepsy – Learning Objectives

Identify the differences between seizures and epilepsy.

Describe the management of a patient after a first seizure.

Describe the management of a patient with epilepsy.

Discuss the management of epilepsy in women of child bearing age.

Epidemiology of Seizures and Epilepsy

Seizures Incidence: approximately 80/100,000 per yearLifetime prevalence: 9% (1/3 benign febrile convulsions)

Epilepsy Chronic recurring, unprovoked seizuresIncidence: approximately 45/100,000 per yearPoint prevalence: 0.5-1%

Seizure Classification

Partial seizures (focal or local origin)Simple partial seizures with:

motor signssomatosensory or special sensory symptomsautonomic symptoms or signspsychic symptoms (disturbance of higher cerebral function)

Complex partial seizures with:Impaired consciousnessPresence and nature of aura (simple partial origin)Automatisms and other motor activity

Secondary generalized seizures

Seizure Classification

Primary generalized seizures (bilateral origin)AbsenceMyoclonicAtonicTonicTonic-clonic

Epilepsy Syndromes

Partial epilepsiesIdiopathicSymptomaticCryptogenic

Generalized epilepsiesIdiopathicSymptomaticCryptogenic

Undetermined epilepsies

Special syndromes

Questions Raised by a First Seizure

Seizure or not?

Partial (focal) or generalized onset?

Evidence of CNS dysfunction?

Seizure type? Syndrome type?

Metabolic or other precipitant?

Studies?

Treatment - start an antiepileptic drug (AED)?

Evaluation of a First Seizure

History, physical exam

Blood tests: CBC, electrolytes, glucose, Ca, Mg, hepatic and renal function

Lumbar puncture only if meningitis or encephalitis suspected and potential for brain herniation is ruled out

Blood or urine screen for drugs

Partial seizures are presumed to be due to a structural lesion unless proven otherwise.

Electroencephalogram if indicated

CT or MR brain scan if indicated

Evaluation of a First Seizure-Precipitants

Metabolic and Electrolyte ImbalanceLow (occ high) blood glucose, Na, Ca, Mg

Stimulant/other proconvulsant intoxicationIV drug use, cocaine, ephedrine, herbal remediesSedative/medication reduction

Sleep deprivation, stress

Hormonal variations

Infection

Medical Management of First Seizure

Whether or not to treat a first seizure is controversial.

The risk of recurrence within 5 years is 16-62% and with a single unprovoked seizure (normal EEG and MRI) is about 40%.

Abnormal imaging, abnormal EEG or + family history of epilepsy increase recurrence risk.

Quality of life issues are important for AED Rx.

Was the seizure “precipitated”? If so, Rx with an AED is not necessary – remove the precipitant.

Treat a first seizure if there is a high likelihood of developing epilepsy (recurrence rate is reduced by AED treatment).

Medical Management of Epilepsy

First diagnose seizure type(s), epilepsy syndrome, and etiology.

Try pharmacotherapy first (unless etiology necessitates surgery).

Use monotherapy with an AED that is the most appropriate for seizure type/epilepsy syndrome (but other considerations also play a role), and safest.

Start at a low dose, increase slowly.

Medical Management of Epilepsy

Try to reach the lowest effective dose.Target: seizure control with no side effectsWe may use drug levels if needed (but we should not be bound by the drug levels)

If drug A fails, try drug B monotherapy.

Try polytherapy if monotherapy fails.anticipate drug interactions

Choosing an AED

Seizure type

Epilepsy syndrome

Pharmacokinetic profile

Interactions/other medical conditions

Efficacy

Expected adverse effects

Useful as monotherapy - simplifies treatment and reduces adverse effects

Cost

Antiepileptic Drugs old new

Phenytoin (Dilantin)

Carbamazepine (Tegretol, Carbatrol)

Valproate (Depakote)

Phenobarbital

Primidone (Mysoline)

Clonazepam (Klonopin)

Ethosuximide (Zarontin)

Methsuximide (Celontin)

Felbamate (Felbatol) *

Gabapentin (Neurontin) ¶

Lamotrigine (Lamictal) *

Topiramate (Topamax) *

Tiagabine (Gabitril)

Levetiracetam (Keppra) ¶

Oxcarbazepine (Trileptal) *

Zonisamide (Zonegran)

Pregabalin (Lyrica)

* new drugs approved to be used in monotherapy¶ no monotherapy indication, but comparative monotherapy trial

Spectrum of Efficacy of Old AEDs

AED Partial Absence Myoclonic

Phenytoin ++ - -

Carbamazepine ++ -

-

Valproate ++ ++ ++

Primidone + - -

Phenobarbital + - -

Clonazepam + + +

Methsuximide + + +

Ethosuximide - ++ -

Spectrum of Efficacy of New AEDs

AED Partial Absence Myoclonic

Felbamate (Felbatol) + + +

Gabapentin (Neurontin) + - -

Lamotrigine (Lamictal) + +

+/-

Topiramate (Topamax) + +/- +

Tiagabine (Gabitril) + - -

Levetiracetam (Keppra) + + +

Oxcarbazepine (Trileptal) + - -

Zonisamide (Zonegran) + +

+

Pregabalin (Lyrica) + - -

Partial Seizures- The First AED

First AED - in general:Carbamazepine (Tegretol, Carbatrol)Phenytoin (Dilantin)Oxcarbazepine (Trileptal)Topiramate (Topamax)Valproate (Depakote)

First AED - special situations when other AEDs may be considered

Gabapentin (Neurontin)Lamotrigine (Lamictal)Levetiracetam (Keppra)?Zonisamide (Zonegran), ?Pregabalin (Lyrica)

Generalized Seizures- The First AED

Generalized onset seizuresAbsence: valproate* = ethosuximide

Myoclonic: valproate, clonazepam

Tonic-clonic: valproate = phenytoin, carbamazepine* the risk of valproate-induced hepatic failure must be carefully weighed in

young children

AED Initiation and Monitoring

Discuss likely and unlikely but important adverse effects.

Discuss likelihood of success.

Discuss recording/reporting seizures (seizure calendar), adverse effects, potential precipitants.

Obtain appropriate “baseline” laboratory testsCBC, platelets, LFTs

Initiate therapy with an appropriate dose.

Monitor AED levels when appropriate.

AED Interactions

AEDs that induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital

AEDs that inhibit metabolism of other drugs: valproate, felbamate

AEDs that are highly protein bound: valproate, phenytoin, tiagabine

Other drugs may alter metabolism or protein binding of antiepileptic drugs

AED Serum Concentrations

In general AED serum concentrations can be used as a guide for evaluating the efficacy of medication therapy for epilepsy.

Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions.

They should be used to monitor pharmacodynamic and pharmacokinetic interactions.

Evaluation After Seizure Recurrence

Progressive pathology?

Avoidable precipitant?

If on an AEDProblem with compliance or pharmacokinetic factor?

Increase dose?

Change medication?

If on multiple AEDsConvert to monotherapy from polytherapy?

Eliminate sedative drugs firstWithdraw antiepileptic drugs slowly over several months

If not on AEDStart therapy?

Preconception Counseling and Teratogenicity

Preconception information should be offered to all females with childbearing potential since most major malformations occur at an early stage in pregnancy, often before the woman knows she is pregnant.

If changes in AED medication are to be made, they should be completed before conception.

If AED treatment is needed, a single agent is preferred.

Preconception Counseling and Teratogenicity

The use of phenytoin, valproate, carbamazepine, lamotrigine, and phenobarbital has been associated with an increased risk of major malformations and minor morphological anomalies. (3% with carbamazepine or lamotrigine, 7% with valproate, and 15% with two or more AEDs).

It is not known if vigabatrin, gabapentin, levetiracetam, topiramate, oxcarbazepine, pregabalin, and tiagabine are associated with a risk of fetal abnormalities in humans.

Women with epilepsy who are planning a pregnancy should take folic acid 1 mg/day in the preconception period and throughout the pregnancy; vitamin K should be used in the last month of pregnancy in women on enzyme-inducing AEDs.

Contraception and AEDs

For women on nonenzyme-inducing AEDs (valproate, benzodiazepines, vigabatrin, gabapentin, tiagabine, levetiracetam, pregabalin), all current contraceptive methods are suitable.

Hormonal forms of contraception are affected by enzyme-inducing AEDs (phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate [>200 mg/day], and lamotrigine); women taking these forms of contraception should be counseled on their risks and benefits.

Non-Drug Treatment/Lifestyle Modifications

Adequate sleep

Avoidance of alcohol, stimulants, etc.

Avoidance of non-precipitants

Stress reduction — specific techniques

Adequate diet

Exercise

Discontinuing AEDs

Seizure free 2 years implies overall >60% chance of successful withdrawal in some epilepsy syndromes

Favorable factorsControl achieved easily on one drug at low doseNo previous unsuccessful attempts at withdrawalNormal neurologic status and EEG?Primarily generalized seizures except JME“Benign” syndrome

Consider relative risks/benefits (driving, pregnancy)

Questions?