Epilepsy and AEDs

1. Epilepsy and AEDs Steven C. Karceski, M.D. Assistant Professor of Neurology Director, Columbia Epilepsy Center

2. Treatment Goal • Complete control of seizures • No side effects

3. effective (in all seizure types) no adverse effects no long term risks no interactions with other drugs long lasting action safe in pregnancy inexpensive Ideal Treatment

4. AEDs • Seizure/epilepsy type • Pharmacokinetics • Absorption • Half-life • Elimination • Side effects • Drug-drug interactions

5. J.S. • 35-year-old man • Onset: age 16 • Seizure: aura, staring, oral automatisms • Frequency: up to 3/week • Duration: 60-120 seconds • Risk Factor: febrile seizure at 1 year

6. J.S • Tried Tegretol, Dilantin, Depakote, Neurontin • MRI: Left mesial temporal sclerosis • EEG: Focal left temporal epileptiform discharges • EMU: Left temporal onset seizures • Q: What should be considered next?

7. Seizure Type: Partial • Partial (onset) • Simple Partial (aura) • Complex Partial • Secondarily generalized • All AEDs are effective (exception: ethosuximide)

8. phenobarbital (Phenobarbital, Primidone) phenytoin (Dilantin) carbamazepine (Tegretol, Carbatrol) valproic acid (Depakote, Depakene) ethosuximide (Zarontin) methsuximide (Celontin) clonazepam (Klonopin) lorazepam (Ativan) gabapentin (Neurontin) felbamate (Felbatol) lamotrigine (Lamictal) topiramate (Topamax) tiagabine (Gabitril) levetiracetam (Keppra) oxcarbazepine (Trileptal) zonisimide (Zonegran) Available AEDs

9. J.S.: Temporal Lobe Epilepsy • Febrile seizure as a child, with return of partial seizures in adolescence • Seizures: simple and complex partial, secondarily generalized • Often refractory to medications

10. J.S. • Q: What are the chances that a new medication will accomplish the treatment goal? • A: 5-10% • Consider: temporal lobectomy

11. M.G. • 19-year-old woman • Onset: menarche (age 13) • Seizures: no aura • Generalized tonic-clonic seizures • Myoclonic seizures • Risk factor: twin sister has epilepsy

12. M.G. • Started on Depakote • Weight gain • Hair loss • Menstrual irregularity • Switched to Tegretol • Worsening of seizures

13. Seizure Type: Generalized • Generalized (onset): no aura • GTC • Tonic/Atonic • Absence • Myoclonic • AED options are more limited

14. phenobarbital (Phenobarbital, Primidone) phenytoin (Dilantin) carbamazepine (Tegretol, Carbatrol) valproic acid (Depakote, Depakene) ethosuximide (Zarontin) methsuximide (Celontin) clonazepam (Klonopin) lorazepam (Ativan) gabapentin (Neurontin) felbamate (Felbatol) lamotrigine (Lamictal) topiramate (Topamax) tiagabine (Gabitril) levetiracetam (Keppra) oxcarbazepine (Trileptal) zonisimide (Zonegran) The list of AEDs (again)

15. M.G.: Juvenile Myoclonic Epilepsy • Begins at puberty • Seizures: myoclonic, absence, GTCs • Normal intellect • Normal neurological examination • Normal MRI • Often responds to low doses of medications

16. Seizure Type: Generalized • Generalized (onset) • Fewer medication options • Some AEDs WORSEN generalized seizures

17. phenobarbital (Phenobarbital, Primidone) phenytoin (Dilantin) carbamazepine (Tegretol, Carbatrol) valproic acid (Depakote, Depakene) ethosuximide (Zarontin) methsuximide (Celontin) clonazepam (Klonopin) lorazepam (Ativan) gabapentin (Neurontin) felbamate (Felbatol) lamotrigine (Lamictal) topiramate (Topamax) tiagabine (Gabitril) levetiracetam (Keppra) oxcarbazepine (Trileptal) zonisimide (Zonegran) The list of AEDs (again)

18. AEDs • Broad spectrum (both generalized and partial seizures): felbamate, lamotrigine, levetiracetam, topiramate, valproate, zonisamide • Narrow spectrum (partial seizures only): All others

19. AED Side Effects • Sleepiness • Dizziness • Poor memory, concentration • Weight gain/loss • Long-term bone health issues • Women’s health

20. Newer AEDs • Tend to cause fewer side effects (bone health, changes in weight, etc.) • Most are qD or BID • Many are broad spectrum

21. AEDs and Rash • Virtually all have been reported to cause a rash/allergic reaction • Usually occurs within the first 3 months of therapy • Related to the speed of titration

22. AEDs and Rash • Erythematous • Maculopapular • Pruritic • All rashes should be evaluated carefully! • Not all rashes are due to medications! • Remember to ask about soaps, perfumes, etc.

23. AEDs and Rash • Signs of a more serious rash • Fever • Adenopathy • Oral ulcerations • Malaise, flu-like symptoms • Stop the medicine immediately

24. Bone Health • Women • Age • Exercise • Diet (vitamin D, calcium) • Need 1000 to 1500 mg per day • AEDs have been associated with bone loss

25. AEDs and Bone Health • Studies are ongoing • May cause osteopenia, osteoporosis: phenytoin, phenobarbital, valproate, carbamazepine • Appear to be bone “neutral”: lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide

26. Evaluation of Bone Health • DEXA scan (bone density) • Obtain a baseline study • Follow-up yearly (or every other year) • Counseling about Calcium, vitamins, exercise

27. Poor Bone Health • Osteoporosis/osteopenia • Start calcium, vitamins (if not already done) • Consider Fosamax, Miacalcin, or other agent • Follow-up treatment with DEXA every 6-12 months

28. Sleep affects Seizures • REM sleep may prevent focal seizures • 133 patients; 613 seizures • Seizures were rare during REM sleep • Research may identify the critical difference in REM, leading to the development of newer treatments Herman S. Epilepsia. 2001.

29. Seizures affect Sleep • Seizures disrupt the sleep-wake cycle • Seizures cause post-ictal fatigue • Seizures decrease total sleep time • Seizures suppress REM sleep • Seizures prolong REM latency • Interictal sleep is also disordered – even brief seizures can affect sleep Vaugn BV. Sem Neurol. 2004.

30. AEDs affect Sleep • Some medications cause sleepiness • Some medications cause insomnia • Others affect sleep architecture • The effect may be unpredictable • The mechanisms are unclear: is it due to neuronal inhibition? excitation?

31. AEDs and Sleep • Newer AEDs: fewer effects on sleep • Gabapentin may increase sleep efficiency • Increases slow-wave and REM sleep • Levetiracetam improves subjective sleep • Fewer recognized awakenings • But still overall sleepier

32. AEDs and Sleep • Sleep “promoting”: gabapentin • Sleep “disruptive”: phenytoin, felbamate

33. Newer AEDs and weight • Weight gain: gabapentin, valproate • Weight loss: felbamate, topiramate, zonisamide • Weight “neutral”: lamotrigine, oxcarbazepine, levetiracetam

34. Newer AEDs and Dosing • qD dosing – zonisamide • BID dosing – XR forms of carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate • TID dosing – gabapentin, tiagabine

35. AEDs and Women’s Health • AEDs can affect oral contraceptives • Enzyme inducers: carbamazepine, phenobarbital, phenytoin, oxcarbazepine • AEDs can affect fertility • PCOS: valproate • AEDs can affect the fetus

36. Pregnancy “D” Dilantin Tegretol Depakote Phenobarbital Zarontin The “older” AEDs Pregnancy “C” All “newer” AEDs! AEDs and Teratogenicity

37. AEDs & Birth Defects • 2-3 % of normal women • Single AED: 4-6 % • Multiple AEDs: 6-9% or higher • Risk also increases with higher doses of AEDs

38. Seizures & Pregnancy • GTCs cause early delivery, fetal distress • One case: CPS may also cause fetal distress • Maintain seizure control! • Use a single medication at the lowest needed dose • Folate, folate, folate!

39. AEDs and Aging • Drug-drug interactions: the average senior takes 5-12 medications • Medications are absorbed differently • Seniors have slower metabolism (liver) • Seniors have slower elimination (kidneys) • A higher percentage is “unbound”

40. AEDs and Aging • Dosing must be lowered accordingly! • A lower dose may produce the same level as in a younger adult

41. Summary Age Seizure Type “Refractoriness” Gender Pharmacokinetics Treatment