1. Elinor Ben-Menachem, MD, PhD
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
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unpublished data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

3. 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

4. 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)

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

6. 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)

7. Guideline Methodology
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

8. Guideline Methodology
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

9. Guideline Methodology-Statistics
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 < 40% or > 60% (50% 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.

10. 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:
Primary outcome variable: efficacy or effectiveness
Treatment duration: ≥ 48 weeks (>24 wk seizure freedom data for efficacy or >48 wk retention data for effectiveness)
Study design: double blind
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
Study exit: not forced by a predetermined number of treatment emergent seizures
Appropriate statistical analysis

11. Criteria for Class II Study-ILAE
Class II: An RCT or meta-analysis meeting all the class I criteria except that:
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

12. 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

13. Guideline Methodology: Grading the evidence for each AED
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

14. 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

15. 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

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

17. 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)

18. Partial Seizures in Adults Listing of Class I-III Double-Blind RCTs
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, PHT Privitera (03) CBZ,TPM,VPA
Dam (89) CBZ,OXC Arroyo (05) TPM
Brodie (02) CBZ, REM Steiner (99) PHT, LTG
Ramsay (83) CBZ, PHT Gibberd (82) PHT, PNT
Mikkelsen (81) CBZ, CLP

19. Partial Seizures: Adults Recommendations
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

20. 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)

21. Partial Seizures: Children Class I-III RCTs
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)

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

23. 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)

24. Partial Seizures: Elderly Class I RCTs
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)

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

26. 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

27. Generalized Tonic Clonic Seizures: Adults Recommendations
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

28. 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

29. Generalized Tonic Clonic Seizures: Children Recommendations
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

30. 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

31. Childhood Absence Epilepsy: Recommendations
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

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

33. 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)

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

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

36. 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)

37. Juvenile Myoclonic Epilepsy : Recommendations
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

38. 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

39. Summary of Evidence and Recommendations Partial onset seizures
Seizure type or epilepsy syndrome
Class I
Class II
Class III
Level of efficacy and effectiveness evidence
(in alphabetical order)
POS: Adults 2 1 30
Level A: CBZ, PHT, (LEV)
Level B: VPA
Level C: GBP, LTG, OXC, PB, TPM, VGB
POS: Children 17
Level A: OXC
Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
POS: Elderly
Level A: GBP, LTG
Level C: CBZ

40. 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 23
Level A: None
Level B: None
Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA
GTC: Children 14
Level C: CBZ, PB, PHT, TPM, VPA
Absence seizures 6
Level C: ESM, LTG, VPA

41. Summary of Evidence and Recommendations Epilepsy syndromes
Seizure type or epilepsy syndrome
Class I
Class II
Class III
Level of efficacy and effectiveness evidence
(in alphabetical order)
BECTS 2
Level A: None
Level B: None
Level C: CBZ, VPA
JME
Level C: None

42. Variables that affect initial AED selection
AED-specific variables
Patient-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

43. Elinor Ben-Menachem, Chairman
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