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

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sources to search electronic databases (MEDLINE, Current Contents) Cochrane library published literature/references unpublished data English/non-English studies Perform multiple searches

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

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)

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

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)

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

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

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% + 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.

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

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

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

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

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

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

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

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)

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

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

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)

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)

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

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)

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)

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

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

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

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

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

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

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

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

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)

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

Initial Monotherapy Idiopathic Generalized Epilepsy Syndromes: Juvenile Myoclonic Epilepsy

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)

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

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

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

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

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

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

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