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GuidelinesTRANSCRIPT
Evidence-Based Guidelines for the Treatment of Epileptic Seizures with
AEDs Elinor Ben-Menachem, MD, PhDElinor Ben-Menachem, MD, PhD
Institution for Clinical NeuroscienceInstitution for Clinical NeuroscienceSahlgrenska Academy Sahlgrenska Academy
Sahlgrenska University Hospital Sahlgrenska University Hospital Göteborg, SwedenGöteborg, 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• Cochrane library• published literature/references• unpublished data• English/non-English studies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)
• Topic
Optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy
• Team 10 members
• Epileptologists• Clinical pharmacologists• Statistician• Methodologist
6 countries
GuidelineMethodology
ILAE Initial Monotherapy GuidelinesClinical 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)
• 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
GuidelineMethodology
• 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
GuidelineMethodology
• 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.
GuidelineMethodology-Statistics
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
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
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
• 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
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: AdultsAvailable 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)
Class IMattson (1985) CBZ, PB, PHT, PRM
Chadwick (99) CBZ, VGBClass II
Mattson (92) CBZ, VPAClass 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, PNTMikkelsen (81) CBZ, CLP
Partial Seizures in AdultsListing of Class I-III Double-Blind RCTs
Level A: CBZ, PHTLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGBLevel D: CZP, PRMLevel E: OthersLevel F: None
Partial Seizures: AdultsRecommendations
Partial Seizures: ChildrenAvailable 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)
Class IGuerreiro (97) OXC, PHT
Class II 0
Class IIITPM (n=2), CBZ/CZP (n=1), CBZ/ CLB (n=1), TPM/VPA/CBZ (n=1)
Partial Seizures: ChildrenClass I-III RCTs
Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPALevel D: LTG,VGBLevel E: OthersLevel F: None
Partial Seizures: ChildrenRecommendations
Partial Seizures: ElderlyAvailable 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)
Class IRowan (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: ElderlyClass I RCTs
Level A: GBP, LTG
Level B: None
Level C: CBZ
Level D: TPM, VPA
Level E: Others
Level F: None
Partial Seizures: ElderlyRecommendations
Generalized Tonic Clonic Seizures: AdultsAvailable 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
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: AdultsRecommendations
Generalized Tonic Clonic Seizures: ChildrenAvailable 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
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: ChildrenRecommendations
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
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
Initial MonotherapyIdiopathic 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)
Level A: None
Level B: None
Level C:CBZ, VPA
Level D: GBP,STM
Level E: Others
Level F: None
BECTS:Recommendations
Initial MonotherapyIdiopathic 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)
Level A: NoneLevel B: NoneLevel C: NoneLevel D: CZP, LTG*, LEV, TPM, VPA, ZNSLevel E: OthersLevel F: CBZ*, GBP, OXC*, PHT*, TGB, VGB
*may aggravate myoclonic seizure types, should be used with caution
Juvenile Myoclonic Epilepsy :Recommendations
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 RecommendationsPartial 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: VPALevel C: GBP, LTG, OXC, PB, TPM, VGB
POS: Children
1 0 17 Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA
POS: Elderly
1 1 2 Level A: GBP, LTGLevel B: NoneLevel C: CBZ
Summary of Evidence and RecommendationsGeneralized onset seizures
Seizure type or epilepsy syndrome
Class I
Class II
Class III
Level of efficacy and effectiveness evidence
(in alphabetical order)
GTC: Adults
0 0 23 Level A: NoneLevel B: None Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA
GTC: Children
0 0 14 Level A: NoneLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA
Absence seizures
0 0 6 Level A: NoneLevel B: NoneLevel C: ESM, LTG, VPA
Summary of Evidence and RecommendationsEpilepsy syndromes
Seizure type or epilepsy syndrome
Class I
Class II
Class III
Level of efficacy and effectiveness evidence
(in alphabetical order)
BECTS 0 0 2 Level A: NoneLevel B: NoneLevel C: CBZ, VPA
JME 0 0 0 Level A: NoneLevel B: NoneLevel C: None
Variables that affect initial AED selectionAED-specific variables Patient-specific
variablesNation-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
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