CHOICE OF ANTIEPILEPTIC DRUG

1. CHOICE OF ANTIEPILEPTIC DRUG

2. Magnitude of the problem • Epilepsy affects: • approximately 1 in 50 children and 1 in 100 adults.

3. PHARMACOTHERAPY OF EPILEPSY: The issues • Is treatment justified? • When to start treatment? • How to start drug treatment? • Which AED? Which dosage? • When should AED combinations be used? • Risks associated AED treatment? • How long should treatment be continued?

4. PHARMACOTHERAPY OF EPILEPSY: The issues Is treatment justified? When to start treatment? How to start drug treatment? Which AED? Which dosage? When should AED combinations be used? How long should treatment be continued?

5. Antiepileptic drug development AEDs More 20 Levetiracetam Oxcarbazepine Tiagabine 15 Fosphenytoin Topiramate Gabapentin Felbamate Lamotrigine Zonisamide 10 Vigabatrin Sodium valproate Carbamazepine Benzodiazepines Ethosuximide 5 Phenytoin Primidone Phenobarbital Bromide 0 1840 1860 1880 1900 1920 1940 1960 1980 2000 Year

6. Major considerations in choosing an AED • Type of seizure • Type of epileptic syndrome • Adverse effect profile • Age & gender • Ease of use (fast and easy dose titration) • Specific co-morbidities • Cost

7. Best first AED • Not a “ one size fits all” scenario • Choice of drug: • Depends on : • Efficacy • Tolerability • affordability

8. Best first AED • Efficacy: Determined by the type of seizure / epileptic syndrome • Step.1: • To diagnose epileptic syndrome • Step 2. • If not possible, try to exclude JME or absences • Carbamzepine & phenytoin will aggravate JME • CBZ, phenytoin, tiagabine & vigabatrin will aggravate Absences • Step.3; • Valproate, lamotrigine or topiramate, Levitiracetum

9. Epileptic syndrome • The clinical event • Ictal & interictal EEG characteristics • Age of onset • Characteristic evolution & progression. • Presence or absence of family history

10. Why should we identify the epileptic syndrome? • Whether to investigate the patient further or not • Which drug to choose for the control of seizure • To predict prognosis

11. Drugs of choice in certain epileptric syndromes

12. Best first AED • Efficacy: Step.2: • If not possible, try to exclude JME or absences • Carbamazepine & phenytoin will aggravate JME • CBZ, phenytoin, tiagabine & vigabatrin will aggravate Absences • Step.3; • If the seziure can not be typed • Valproate, lamotrigine or topiramate, Levitiracetum

13. Best first AED • Efficacy: Step.3: • If not possible, find out the type the seizure • Partial seizure / primary generalized seizure

14. Choice of AED • Partial / GTC Seizure • Carbamazepine, phenytoin, valproic acid (sodium valproate ), phenobarbital and primidone are all effective • CBZ –drug of choice • All forms of generalised seizure: • Valproate; drug of choice • Absence seizures: • Valproate, Ethosuximide

15. Best first AED • Differentiation of partial Versus Generalised epilepsy is not always possible in infants • Eg: Dravet’s syndrome ( severe myoclonic epilespy of chiildhood) • usually presents with hemiconvulsion. • Infantile spasm: • Pattern can change from generalised to partial seizures

16. Best first AED • Efficacy: • If the seizure can not be typed • Valproate, lamotrigine or topiramate, Levitiracetum

17. Best first AED • Tolerability: • Valproate & Carbamazepine are better tolerated than Pheno or phenytoin • Affordability; • Newer AEDs are costly compared older ones

18. Newer AEDS • What is real advantage of these newer drugs? • Are they going to replace older drugs? • Does high cost of these drugs justify its usefulness? • What are the situations where we can use these drugs?

19. Newer drugs • No major differences in efficacy between drugs • Major differences in side effects profiles • Drug interaction potential also differs • Drug choice should be tailored to the patient

20. EFFICAY OF NEWER AED AS MONOTHERAPY RCT have shown no major difference in seizure control between: LTG vs CBZ * LTG better tolerated LTG vs DPH * LTG better tolerated OXC vs CBZ * CBZ increased allergy OXC vs VPA * No difference OXC vs DPH * withdrawal more in DPH GBP vs CBZ * Withdrawal more in GBP GBP vs LTG TPM vs CBZ & VPA * No difference

21. UK NICE guidelines for the use of new AED • If established drugs have failed • Typically carbamazepine or valproate • If most appropriate older drug is contraindicated • If older drugs could interact with other medications • If older drugs are already known to be poorly tolerated by the patient • If patient is a woman of child bearing potential

22. Newer AEDs in Epilepsy Management Among the newer AEDs, is there a preference of any particular AED for a specific type of seizure?  

23. Broad spectrum AED • Lamotrigine • Topiramate • Levitiracetum • Clobazam

24. Newer AED for generalised seizure • Lamotrigine, • Topiramate, • Zonisamide, and • Levetiracetam • Oxcarbazepine, tiagabine and gabapentine are ineffective

25. AED for JME • Valproate is superior • Second choice • Levitiracetum • Clobazam • Topiramate • Lamotrigine

26. JME • When on lamotrigine: • If tonic-clonic seizures have been controlled, but myoclonic seziures persist • Add clonezepam , before changing to valproate, topiramate or levetiracetam

27. Newer AED for Partial seizure • Lamotrigine, Oxcarbazepine, Clobazam Gabapentin and Topiramate • is same as that of carbamazepine or phenytoin.

28. NEWER AED FOR PARTIAL SEIZURE • AAN guideline recommendations for new onset partial seizure • Gabapentin • Topiramate • Oxcarbamazepine • Lamotrigine • However, levitiracetum, zonisamide & tiagabine are also effective

29. Drugs effective for both generalized & partial; • Valproate, LTG, Topiramate, Levetiracetum and Zonisamide.

30. Efficacy Spectrum of Available AEDs *May exacerbate myoclonic and absence seizures Vigabatrin is also effective in infantile spasms * *Lamotrigine may aggravate severe myoclonic epilepsy

31. TOLERABILTY OF NEW AEDS • Gabapentin • Levetiracetum • Lamotrigine • Oxcarbamazepine • Tiagabine • Topiramate • Vigabatrin Well tolerated Higher treatment withdrawal

32. EFFECT ON COGNITION • Levetiracetum • Lamotrigine • Tiagabine No significant effect on Cognition,

33. How long the AED will take to produce its effect? Time to achieve steady state

34. Time to achieve steady stateof AEDs

35. Inappropriate AED choice • and • seizure worsening • Wrong selection of drugs can worsen seizure

36. AEDs which may aggravate some epileptic syndromes DrugSyndrome Carbamazepine Absence epilepsy Juvenile myoclonic epilepsy Progressive Myoclonus E. Rolandic Epilepsy Phenytoin Absence epilepsy Progressive Myoclonus E Phenobarbitone Absence epilepsy Benzodiazepines Lennox-Gastaut syndrome

37. AEDs which may aggravate some epileptic syndromes DrugSyndrome VigabatrinAbsence epilepsy Epilepsies with myoclonus Gabapentin Absence epilepsy Epilepsies with myoclonus Lamotrigine Severe myoclonic epilepsy Juvenile myoclonic epilepsy

38. Paradoxical effects of AEDs • CBZ in partial epilepsies; • FLE, BECTS, LKS, BEOP, Angelman’s syndrome • Negative myoclonus & atypical absences • Correlates with bilaterally synchronous discharges in EEG • I/V BZD precipitates tonic status in LGS, even when child is already on oral BZDs

39. Paradoxical effects of AEDs • VPA increases absences in CAE • LTG: • Precipiates absence seziures in BECTS • Myoclonic status in LGS • Levitiracetum • Seizure exacerbation in refractory epilepsy with LEV at doses more than 30 mg/kg/d

42. Are two drugs better than one? • Monotherapy can control seziures in 60% • When to start polytherapy? • When two monotherapy trials fail!

43. Which initial drug?

44. Initial treatment of idiopathic generalized epilepsy (expert committee)

45. If valproate fails • If valproate fails as the first AED • Lamotrigine monotherapy is unlikely to be successful (Nicolson et al. 2004) • Prefer Topiramate or levetiracetam. • With generalized tonic-clonic seizures alone • the choice is wider • includes carbamazepine or oxcarbazepine in addition

46. Drugs recommended for focal epilepsy ( expert committee)

47. ILAE /AES Guidelines • According ILAE treatment guidelines, • First-generation AEDs carbamazepine, phenytoin, and probably valproic acid have demonstrated effectiveness as monotherapy for partial-onset seizures. • According to AAN/AES subcommittees, • Of the second generation AEDS, lamotrigine, oxcarbazepine, and topiramate may be effective for monotherapy, • although the ILAE has added that gabapentin, and vigabatrin may also be efficacious or effective as monotherapy.

48. Alternative choice in partial seizures • If carbamazepine is effective against seizures but poorly tolerated • Try oxcarbazepine or lamotrigine next. • If carbamazepine fails to control seizures • Levetiracetam or topiramate are likely to be more powerful than gabapentin or lamotrigine • valproate remains an option.

49. SANAD STUDYStandard and New antiepileptic Drugs • SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK • Aim is to study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy:

50. SANAD STUDY • Lamotrigine is clinically better than carbamazepine for time to treatment failure outcomes