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. 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

15. Spectrum of Efficacy of Old AEDs AED Partial Absence Myoclonic 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?