1. CHOOSING THE RIGHT MEDICAL TREATMENT AND RECENT ADVANCES NEELIMA THAKUR, MD.

2. 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.

3. Seizures are defined as abnormal discharge of electrical activity from brain neurons resulting in transient loss of motor, sensory or mental function.

4. 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

5. 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 2 nd unprovoked seizure – 80%

6. First unprovoked seizure Risk factors for seizure recurrence –Family history -Abnormal EEG -Abnormal neuroimaging. -Seizure in sleep.

7. First unprovoked seizure 50 % seizures recur in the first year 80% with in two years.

8. First unprovoked seizure Current Guidelines –No antiepileptic drugs (AEDs) if There are no other risk factors Normal EEG.

9. Anti epileptic Drugs

10. Antiepileptic drugs 1 st drug- 47 % seizure free 2 nd drug- 13% seizure free 3 rd / multi drugs - 4% seizure free

11. Epilepsy outcome at >7 years. Seizure free >7years - 59 % Seizure free >1 year and relapses- 16 %

12. Which AED to choose?

13. Anti epileptic Drugs 1850 : Bromides 1910: Phenobarbital 1940: Phenytoin 1950: Ethosuximide 1958: ACTH 1954: Primidone 1968: Carbamazepine 1975: Clonazepam 1978: Depakote

14. 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

15. Following criteria may be helpful –Type of epilepsy –Comorbidities –Side effect profile –Pharmacokinetics –Drug-drug interactions –Single dose-Compliance –Women –Elderly

16. Type of epilepsy Primarily generalized epilepsies. –ethosuximide ( Absence seizures) –valproate –topiramate –zonisamide –lamotrigine –levetiracetam –rufinamaide –clobazam –vigabatrin.

17. Primarily generalized epilepsies Avoid carbamazepine, gabapentin, Phenytoin.

18. Efficacy Primarily generalized epilepsy Absence seizures –ethosuximide, valproate are effective than lamotrigine. Atonic seizures : clobazam. Primarily generalized epilepsies: valproate>topamax and leviteracetam.

19. Type of epilepsy Partial Epilepsies All AEDs except ethosuximide.

20. 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. ‘

21. Mechanism of action Rational polypharmacy.

22. Comorbidities Bipolar disorder/depression/anxiety: valproate, lamotrigine, carbamazepine, oxcarbazepine. Migraines: valproate, topiramate, zonisamide. Obesity: topiramate, zonisamide Neuropathy: gabapentin, lyrica, carbamazepine, oxcarbazepine.

23. Comorbidities AEDs to avoid Psychiatric/behavorial problems: levetiracetam. Osteoporosis: phenobarbital, phenytoin, valproate, carbamazepine. Renal stones : topamax, zonegran. Obesity: valproate, pregabalin, gabapentin. Diabetes: valproate.

24. Liver dysfunction Drugs of choice leviteracetam lacosamide pregabalin gabapentin

25. Renal dysfunction Decrease drug doses that are cleared primarily by kidneys –levetiracetam –lacosamide –pregabalin –gabapentin

26. 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

27. Drug interactions Liver enzyme(CYP 450 & UGT) inducers phenytoin, phenobarbital, carbamazepine, oxcarbazepine, topiramate, felbamate, rufinamide. Liver enzyme inhibitors –valproate, felbamate.

28. 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.

29. 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

30. 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.

31. AEDs: Elderly

32. 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

33. 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.

34. 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.

35. AEDs - Elderly In general the preferred drugs are –levetiracetam –lamotrigine –gabapentin

36. AEDs-Pregnancy Concerns – Effect of AEDs on Fetus and infant during Pregnancy Breast feeding. –AED pharmacokinetics affecting levels during Pregnancy Postpartum

37. AEDs - Pregnancy Teratogenic risks mono vs polytherapy. Single AED 3.1 % Two AEDs 5.8 % Three AEDs 8.3%

38. 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%

39. AEDs - Pregnancy Pharmacokinetics lamotrigine & levetiracetam clearance during pregnancy level up to 50% of baseline. Postpartum- clearance returns to baseline and drug levels. Check monthly levels and adjust dose.

40. AEDs - Pregnancy In general, levetiracetam, lamotrigine, oxcarbazepine and carbamazepine are considered relatively safe.

41. Newer AEDs Ezogabine (Potiga) Perampanel (Fycompa) Eslicarbazepine (Aptiom)

42. 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.

43. 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.

44. 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

45. 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

46. Ezogabine (Potiga) Adverse reactions FDA 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

47. Perampanel (Fycompa) 2012 Mechanism of action: AMPA glutamate receptor noncompetitive antagonist. Approved as add on treatment for Partial epilepsy.

48. 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.

49. Perampanel(Fycompa) Drug interactions –Does not effect other AEDs. –Enzyme inducers perampanel levels.

50. Perampanel (Fycompa) Adverse reactions –Neuro-psychiatric symptoms ( black box warning for aggression and hostility). –Dizziness, Somnolence fatigue, blurred vision. –Pregnancy category C

51. Eslicarbazepine (Aptiom) 2013 Mechanism of action: Na channel blocker. the prodrug metabolizes to eslicarbazepine.. Approved as add on treatment for Partial epilepsy.

52. Eslicarbazepine (Aptiom) Absorption and Metabolism: –Well absorbed. Food has no influence. –Metabolized in liver and kidneys. Drug interactions and Side effects Similar but more tolerable than oxcarbazepine

53. Thank you