1. Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs Elinor Ben-Menachem, MD, PhD Institution for Clinical Neuroscience Sahlgrenska Academy Sahlgrenska University Hospital Göteborg, Sweden

2. Guideline Development Overview of activities Pick topic Build a team Form a clinical question Evidence a. Find b. Abstract c. Analyze d. Grade/Rate Develop Recommendations And Algorithm Validate Disseminate

3. Guideline Development Find the evidence  Define inclusion/exclusion criteria  Search clinical question + inclusion/exclusion criteria  Potential sources to search electronic databases (MEDLINE, Current Contents) Cochrane library published literature/references unpublished data English/non-English studies  Perform multiple searches

4. Guideline Development – 2 Abstract, Analyze and Grade/Rate the evidence  Specific relevant variables as measure of quality  “Major” variables Randomization Control group Masked outcome assessment Adequate comparator (assay sensitivity) Adequate enrollment to detect difference  Minimal detectable difference

5. Guideline Development – 3 Abstract, Analyze and Grade/Rate the evidence  “Minor” variables Primary outcome clearly defined Inclusion/Exclusion criteria clearly defined Equivalent treatment groups at baseline Adequate duration of assessment Drop out rate and how it is handled statistically  Summarize abstraction/analysis into tabular form Evidence tables

6. Guideline Development – 3 Abstract, Analyze and Grade/Rate the evidence  Grading/rating scale based on relevant variables  Usually four categories Top group – RCTs with best evidence, meet all criteria Next group – RCTs missing some “minor” criteria Third group – Trial missing some “major” criteria Last group – Low quality trials missing most or all “major” criteria OR only expert opinion  Significant variability in grading/rating scales across guidelines

7. Guideline Development Translate evidence and develop recommendations  Usually 4 or 5 levels of recommendations  Levels defined using output of grading/rating scale  At least one recommendation per question Develop algorithm (if possible) Validate guideline  Internal/External Peer review Implement and disseminate guideline

8. Guidelines for newly diagnosed epilepsy International  ILAE Treatment Guidelines : Evidence-based Analysis of Anitepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes by Glauser, Ben-Menachem, Bourgeois, Cnaan, Chadwick, Guerreiro, Kälviäinen, Mattson,Perucca and Tomson. Epilepsia 47(7):1-27,2006 National  AAN (Efficacy and tolerability of the new AEDs I and II)  NICE ( Diagnosis and management of the epilepsies in adults and children in primary and secondary care)  SIGN (Diagnosis and management of epilepsy in adults)

9. Topic  Optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy Team  10 members Epileptologists Clinical pharmacologists Statistician Methodologist  6 countries Guideline Methodology

10. ILAE Initial Monotherapy Guidelines Clinical Questions (n=8) : Q1-Q3: Patients (adults/elderly/children) with partial- onset seizures Q4-Q5: Patients (adults/children) with generalized- onset tonic-clonic seizures Q6: Children with idiopathic localization-related epilepsies and syndromes (BECTS) Q7-Q8: Children with idiopathic-generalized epilepsies (CAE, JME)

11. Evidence - Key rating variables Randomized Masked outcome assessment (Minimal potential for bias) Clearly defined efficacy/effectiveness outcome variable Appropriate statistical analysis Use of adequate comparator Appropriate minimal duration of treatment Acceptable minimally detectable difference Guideline Methodology

12. Adequate comparator  Assay sensitivity  Criteria: AED superior to another drug, another dose of the same drug, another treatment modality or placebo Appropriate minimal duration of treatment  Set at 48 weeks Guideline Methodology

13. Acceptable minimally detectable difference  Set at 20% by 1998 ILAE guideline  Set as relative difference for this project Assume comparator’s seizure freedom rate 50% AED with seizure freedom rate 60% (50% + 0.2 x 50%) would be clinically significant.  Protects against ineffective AEDs labeled as effective  Minimal detectable difference calculated for all RCTs based on 80% power, p set at < 0.05 and a non-inferiority analysis. Guideline Methodology-Statistics

14. Epilepsy Guidelines Rating – 4 Classes  Class I: A masked RCT, meeting all key variable criteria  Class II: A masked prospective matched-group cohort study in a representative population that meets all key variable criteria OR an RCT in a representative population that lacks one of the key variable criteria  Class III: All other controlled trials in a representative population, where outcome assessment is independent of patient treatment  Class IV: Evidence from uncontrolled studies, case series, case reports or expert opinion French JA, Epilepsia 2004, 45(5):401-409 and 410-423

15. Criteria for Class I Study-ILAE A prospective, randomised, controlled clinical trial (RCT) or meta-analysis of RCTs, in a representative population that meets all six criteria: 1.Primary outcome variable: efficacy or effectiveness 2.Treatment duration: ≥ 48 weeks (>24 wk seizure freedom data for efficacy or >48 wk retention data for effectiveness) 3.Study design: double blind 4.Superiority demonstrated or, if no superiority demonstrated, the study’s actual sample size was sufficient to show non-inferiority of no worse than a 20% relative difference in effectiveness/efficacy 5.Study exit: not forced by a predetermined number of treatment emergent seizures 6.Appropriate statistical analysis

16. Criteria for Class II Study-ILAE Class II: An RCT or meta-analysis meeting all the class I criteria except that: 1.No superiority was demonstrated and the study’s actual sample was sufficient only to show noninferiority at a 21-30% relative difference in effectiveness/efficay OR 2. Treatment duration: ≥24 wks but ≤ 48 wks

17. Criteria for Class III-IV Studies-ILAE Class III: An RCT or meta-analysis not meeting the criteria for any class I or class II category Class IV: Evidence from nonrandomized, prospective, controlled or uncontrolled studies, case series or expert reports

18. Recommendations – 6 Levels  Level A:  1 Class I RCTs OR  2 Class II RCTs  Level B: 1 Class II RCTs OR  3 Class III RCTs  Level C: 2 Class III RCTs  Level D: Class III, or IV RCTs OR expert opinions  Level E: Absence of clinical evidence  Level F: Positive evidence of lack of efficacy OR Significant risk of seizure aggravation Guideline Methodology: Grading the evidence for each AED

19. Relationship between level of evidence and conclusions Evidence Level A B C Conclusions AED established as efficacious or effective as initial monotherapy AED probably efficacious or effective as initial monotherapy AED possibly efficacious or effective as initial monotherapy

20. Relationship between clinical trial ratings, level of evidence and conclusions Evidence Level D E F Conclusions AED potentially efficacious or effective as initial monotherapy No data available to assess if AED is effective as initial monotherapy AED established as ineffective or significant risk of seizure aggravation

21. Recommendation (Based on efficacy and effectiveness data only) Evidence Level A-B AED should be considered for initial monotherapy – First line monotherapy candidate Evidence Level C AED may be considered for initial monotherapy – Alternative first line monotherapy candidates

22. Recommendation (Based on efficacy and effectiveness data only) Evidence Level D Weak efficacy or effectiveness data available to support the use of the AED for initial monotherapy Evidence Level E Either no data or inadequate efficacy or effectiveness data available to decide if AED could be considered for initial monotherapy. Evidence Level F AED should not be used for initial monotherapy

23. ILAE GUIDELINES Based on the best evidence available, what is the optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy?

24. Partial Seizures: Adults Available Evidence A total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizures Division of trials  Class I (n=2)  Class II (n=1)  Class III (n=30)

25. Class I Mattson (1985) CBZ, PB, PHT, PRM Chadwick (99) CBZ, VGB Class II Mattson (92) CBZ, VPA Class III ( Because of low power (DNIB) or forced exit) Brodie (95) CBZ, LTG Chadwick (98) GBP Brodie (02) GBP, LTG Sachdeo (00) TPM Christe (97) OXC, VPA Gilliam (03) TPM Bill (97) OXC, PHTPrivitera (03) CBZ,TPM,VPA Dam (89) CBZ,OXC Arroyo (05) TPM Brodie (02) CBZ, REMSteiner (99) PHT, LTG Ramsay (83) CBZ, PHTGibberd (82) PHT, PNT Mikkelsen (81) CBZ, CLP Partial Seizures in Adults Listing of Class I-III Double-Blind RCTs

26. Level A: CBZ, PHT Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Level D: CZP, PRM Level E: Others Level F: None Partial Seizures: Adults Recommendations

27. Partial Seizures: Children Available Evidence A total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures Division of trials  Class I (n=1)  Class II (n=0)  Class III (n=17)

28. Class I Guerreiro (97) OXC, PHT Class II 0 Class III TPM (n=2), CBZ/CZP (n=1), CBZ/ CLB (n=1), TPM/VPA/CBZ (n=1) Partial Seizures: Children Class I-III RCTs

29. Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA Level D: LTG,VGB Level E: Others Level F: None Partial Seizures: Children Recommendations

30. Partial Seizures: Elderly Available Evidence A total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizures Division of trials  Class I (n=1)  Class II (n=1)  Class III (n=2)

31. Class I Rowan (05)CBZ, GBP, LTG Class II Brodie ( 99) CBZ,LTG Class III Privitera (03) CBZ, TPM, VPA Nieto-Barrera (01) CBZ, LTG (Open Label) Partial Seizures: Elderly Class I RCTs

32. Level A: GBP, LTG Level B: None Level C: CBZ Level D: TPM, VPA Level E: Others Level F: None Partial Seizures: Elderly Recommendations

33. Generalized Tonic Clonic Seizures: Adults Available Evidence A total of 23 RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures Division of trials  Class I (n=0)  Class II (n=0)  Class III (n=10):CBZ, GBP, LTG, OXC, PB, PHT, TPM, VPA

34. Level A: None Level B: None Level C: CBZ*,LTG,OXC*, PB, PHT*,TPM,VPA Level D: GBP,VGB Level E: Others Level F: None *=may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution Generalized Tonic Clonic Seizures: Adults Recommendations

35. Generalized Tonic Clonic Seizures: Children Available Evidence A total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures Division of trials  Class I (n=0)  Class II (n=0)  Class III (n=14): CBZ, CLB, OXC, PB, PHT, TPM, VPA

36. Level A: None Level B: None Level C: CBZ*,PB, PHT*,TPM,VPA Level D: OXC* Level E: Others Level F: None *may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution Generalized Tonic Clonic Seizures: Children Recommendations

37. Childhood Absence Epilepsy: Available Evidence A total of 6 RCTs examined initial monotherapy of children with Childhood Absence Epilepsy Division of trials  Class I (n=0)  Class II (n=0)  Class III (n=6) -3 Double Blinded ETX, LTG, VPA

38. Level A: None Level B: None Level C: ESM, LTG, VPA Level D: None Level E: Others Level F: CBZ, GBP, OXC, PB, PHT,TGB,VGB Childhood Absence Epilepsy: Recommendations

39. Initial Monotherapy Idiopathic Localization Related Epilepsy Syndromes: Benign Epilepsy with Centro-temporal Spikes (BECTS)

40. BECTS: Available Evidence A total of 3 RCTs examined initial monotherapy of children with BECTS, 2 were DB Division of trials  Class I (n=0)  Class II (n=0)  Class III (n=2)

41. Level A: None Level B: None Level C:CBZ, VPA Level D: GBP,STM Level E: Others Level F: None BECTS: Recommendations

42. Initial Monotherapy Idiopathic Generalized Epilepsy Syndromes: Juvenile Myoclonic Epilepsy

43. Juvenile Myoclonic Epilepsy: Available Evidence A total of 0 RCTs examined initial monotherapy of children with Juvenile Myoclonic Epilepsy Division of trials  Class I (n=0)  Class II (n=0)  Class IIII (n=0)

44. Level A: None Level B: None Level C: None Level D: CZP, LTG*, LEV, TPM, VPA, ZNS Level E: Others Level F: CBZ*, GBP, OXC*, PHT*, TGB, VGB *may aggravate myoclonic seizure types, should be used with caution Juvenile Myoclonic Epilepsy : Recommendations

45. Juvenile myoclonic epilepsy Drugs to be avoided Clinical evidence has been provided that PHT, CBZ, OXC, VGB, TGB, GBP (PRE?) may aggravate absence and myoclonic seizures LTG has been shown to aggravate severe myoclonic epilepsies in infancy and in JME Level of Evidence III-IV, Recommendation C

46. Summary of Evidence and Recommendations Partial onset seizures Seizure type or epilepsy syndrom e Class I Class II Class III Level of efficacy and effectiveness evidence (in alphabetical order) POS: Adults 2130Level A: CBZ, PHT, (LEV) Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB POS: Children 1017Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA POS: Elderly 112Level A: GBP, LTG Level B: None Level C: CBZ

47. Summary of Evidence and Recommendations Generalized onset seizures Seizure type or epilepsy syndrome Class I Class II Class III Level of efficacy and effectiveness evidence (in alphabetical order) GTC: Adults 0023Level A: None Level B: None Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA GTC: Children 0014Level A: None Level B: None Level C: CBZ, PB, PHT, TPM, VPA Absence seizures 006Level A: None Level B: None Level C: ESM, LTG, VPA

48. Summary of Evidence and Recommendations Epilepsy syndromes Seizure type or epilepsy syndrom e Class I Clas s II Clas s III Level of efficacy and effectiveness evidence (in alphabetical order) BECTS002Level A: None Level B: None Level C: CBZ, VPA JME000Level A: None Level B: None Level C: None

49. Variables that affect initial AED selection AED-specific variablesPatient-specific variables Nation-specific variables Seizure type or epilepsy syndrome specific efficacy or effectiveness Dose-dependent adverse effects Idiosyncratic reactions Chronic toxicities Teratogenicity Carcinogenicity Pharmacokinetics Interaction potential Formulations Genetic background Age Gender Comedications Comorbidities Insurance coverage Ability to swallow pills/tablets AED availability AED cost Insurance coverage

50. Participants in the ILAE Subcommission on Antiepileptic Drug Guidelines Elinor Ben-Menachem, Chairman Tracy Glauser, USA Blaise Bourgeois, USA David Chadwick, UK Avital Cnaan, USA Carlos Guerreiro, Brazil Reetta Kalviainen, Finland Richard Mattson, USA Emilio Perruca, Italy Torbjörn Tomson, Sweden