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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

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evidence based guidelines for the treatment of epileptic seizures with aeds

Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs

Elinor Ben-Menachem, MD, PhD

Institution for Clinical NeuroscienceSahlgrenska Academy Sahlgrenska University Hospital Göteborg, Sweden

guideline development
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      • unpublished data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 development3
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
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
GuidelineMethodology
  • 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
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)
guideline methodology7
GuidelineMethodology
  • 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 methodology8
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
guideline methodology statistics
GuidelineMethodology-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
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
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
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
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
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 only15
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

slide16

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

partial seizures adults available evidence
Partial Seizures: AdultsAvailable Evidence
  • A total of 33randomized 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
Partial Seizures in AdultsListing of Class I-III Double-Blind RCTs

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, 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
Partial Seizures: AdultsRecommendations

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
Partial Seizures: ChildrenAvailable Evidence
  • A total of 25RCTs 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
Partial Seizures: ChildrenClass I-III RCTs

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 recommendations
Partial Seizures: ChildrenRecommendations

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
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)
partial seizures elderly class i rcts
Partial Seizures: ElderlyClass I RCTs

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 recommendations
Partial Seizures: ElderlyRecommendations

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
Generalized Tonic Clonic Seizures: AdultsAvailable Evidence
  • A total of 23RCTs 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
Generalized Tonic Clonic Seizures: AdultsRecommendations

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
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
generalized tonic clonic seizures children recommendations
Generalized Tonic Clonic Seizures: ChildrenRecommendations

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
Childhood Absence Epilepsy:Available Evidence
  • A total of 6RCTs 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
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

slide32

Initial MonotherapyIdiopathic Localization RelatedEpilepsy Syndromes:Benign Epilepsy with Centro-temporal Spikes (BECTS)

bects available evidence
BECTS:Available Evidence
  • A total of 3RCTs 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
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

Initial MonotherapyIdiopathic Generalized Epilepsy Syndromes:Juvenile Myoclonic Epilepsy

juvenile myoclonic epilepsy available evidence
Juvenile Myoclonic Epilepsy:Available Evidence
  • A total of 0RCTs 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
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
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

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

Participants in the ILAE Subcommission on Antiepileptic Drug Guidelines