Management of Epilepsy

1. Management of Epilepsy Robert L. Macdonald M.D., Ph.D. Department of Neurology Vanderbilt University Medical Center Nashville, TN

2. 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.

3. Epidemiology of Seizures and Epilepsy • Seizures • Incidence: approximately 80/100,000 per year • Lifetime prevalence: 9% (1/3 benign febrile convulsions) • Epilepsy • Chronic recurring, unprovoked seizures • Incidence: approximately 45/100,000 per year • Point prevalence: 0.5-1%

4. Seizure Classification • Partial seizures (focal or local origin) • Simple partial seizures with: • motor signs • somatosensory or special sensory symptoms • autonomic symptoms or signs • psychic symptoms (disturbance of higher cerebral function) • Complex partial seizures with: • Impaired consciousness • Presence and nature of aura (simple partial origin) • Automatisms and other motor activity • Secondary generalized seizures

5. Seizure Classification • Primary generalized seizures (bilateral origin) • Absence • Myoclonic • Atonic • Tonic • Tonic-clonic

6. Epilepsy Syndromes • Partial epilepsies • Idiopathic • Symptomatic • Cryptogenic • Generalized epilepsies • Idiopathic • Symptomatic • Cryptogenic • Undetermined epilepsies • Special syndromes

7. 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)?

8. 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

9. Evaluation of a First Seizure-Precipitants • Metabolic and Electrolyte Imbalance • Low (occ high) blood glucose, Na, Ca, Mg • Stimulant/other proconvulsant intoxication • IV drug use, cocaine, ephedrine, herbal remedies • Sedative/medication reduction • Sleep deprivation, stress • Hormonal variations • Infection

10. 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).

11. 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.

12. Medical Management of Epilepsy • Try to reach the lowest effective dose. • Target: seizure control with no side effects • We 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

13. 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

14. 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) Antiepileptic Drugs oldnew *new drugs approved to be used in monotherapy ¶no monotherapy indication, but comparative monotherapy trial

15. Spectrum of Efficacy of Old AEDs AED Partial AbsenceMyoclonic Phenytoin ++ - - Carbamazepine ++ - - Valproate ++++++ Primidone + - - Phenobarbital + - - Clonazepam + + + Methsuximide + + + Ethosuximide - ++ -

16. 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) + - -

17. 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)

18. Generalized Seizures- The First AED • Generalized onset seizures Absence: valproate* = ethosuximide Myoclonic: valproate, clonazepam Tonic-clonic: valproate = phenytoin, carbamazepine * the risk of valproate-induced hepatic failure must be carefully weighed in young children

19. 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 tests • CBC, platelets, LFTs • Initiate therapy with an appropriate dose. • Monitor AED levels when appropriate.

20. 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

21. 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.

22. Evaluation After Seizure Recurrence • Progressive pathology? • Avoidable precipitant? • If on an AED • Problem with compliance or pharmacokinetic factor? • Increase dose? • Change medication? • If on multiple AEDs • Convert to monotherapy from polytherapy? • Eliminate sedative drugs first • Withdraw antiepileptic drugs slowly over several months • If not on AED • Start therapy?

23. 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.

24. 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.

25. 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.

26. Non-Drug Treatment/Lifestyle Modifications • Adequate sleep • Avoidance of alcohol, stimulants, etc. • Avoidance of non-precipitants • Stress reduction — specific techniques • Adequate diet • Exercise

27. Discontinuing AEDs • Seizure free 2 years implies overall >60% chance of successful withdrawal in some epilepsy syndromes • Favorable factors • Control achieved easily on one drug at low dose • No previous unsuccessful attempts at withdrawal • Normal neurologic status and EEG? • Primarily generalized seizures except JME • “Benign” syndrome • Consider relative risks/benefits (driving, pregnancy)

28. Questions?