Evidence-Based Guidelines for the Treatment of Epileptic Seizures by stephan2

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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
     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        • unpublished data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:
    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
                  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
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

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


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
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
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
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     Class   Class   Class       Level of efficacy and effectiveness
type or       I       II      III                     evidence
epilepsy                                      (in alphabetical order)
syndrom
e
POS:         2       1       30     Level A: CBZ, PHT, (LEV)
Adults                              Level B: VPA
                                    Level C: GBP, LTG, OXC, PB, TPM, VGB
POS:         1       0       17     Level A: OXC
Children                            Level B: None
                                    Level C: CBZ, PB, PHT, TPM, VPA
POS:         1       1       2      Level A: GBP, LTG
Elderly                             Level B: None
                                    Level C: CBZ
           Summary of Evidence and Recommendations
                  Generalized onset seizures


Seizure      Class   Class   Class       Level of efficacy and effectiveness
type or        I       II      III                     evidence
epilepsy                                       (in alphabetical order)
syndrome
GTC:          0       0       23     Level A: None
Adults                               Level B: None
                                     Level C: CBZ, LTG, OXC, PB, PHT, TPM,
                                     VPA
GTC:          0       0       14     Level A: None
Children                             Level B: None
                                     Level C: CBZ, PB, PHT, TPM, VPA
Absence       0       0       6      Level A: None
seizures                             Level B: None
                                     Level C: ESM, LTG, VPA
        Summary of Evidence and Recommendations
                   Epilepsy syndromes


Seizure    Class   Clas    Clas      Level of efficacy and effectiveness
type or      I      s II   s III                   evidence
epilepsy                                   (in alphabetical order)
syndrom
e
BECTS       0       0       2      Level A: None
                                   Level B: None
                                   Level C: CBZ, VPA
JME         0       0       0      Level A: None
                                   Level B: None
                                   Level C: None
Variables that affect initial AED selection
  AED-specific variables     Patient-specific      Nation-specific variables
                             variables
  •Seizure type or           •Genetic background   •AED availability
  epilepsy syndrome
  specific efficacy or
  effectiveness              •Age                  •AED cost
  •Dose-dependent            •Gender               •Insurance coverage
  adverse effects            •Comedications
  •Idiosyncratic reactions   •Comorbidities
  •Chronic toxicities        •Insurance coverage
  •Teratogenicity            •Ability to swallow
  •Carcinogenicity           pills/tablets
  •Pharmacokinetics
  •Interaction potential
  •Formulations
Participants in the ILAE Subcommission on
       Antiepileptic Drug Guidelines


             •   Elinor Ben-Menachem, Chairman
•   Tracy Glauser, USA          •   Reetta Kalviainen, Finland
•   Blaise Bourgeois, USA       •   Richard Mattson, USA
•   David Chadwick, UK          •   Emilio Perruca, Italy
•   Avital Cnaan, USA           •   Torbjörn Tomson, Sweden
•   Carlos Guerreiro, Brazil

								
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