Evidence-Based

Evidence-Based Guidelines
Guidelines for
for the
the
Treatment
Treatment of
of Epileptic
Epileptic Seizures
Seizures with
with
AEDs
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• unpublished data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
ILAE GUIDELINES
GUIDELINES

Based
Based on
on the
the best
best evidence
evidence
available,
available, what
what is
is the
the optimal
optimal
initial
initial monotherapy
monotherapy for for patients
patients
with
with newly
newly diagnosed
diagnosed or or untreated
untreated
epilepsy?
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
InitialMonotherapy
Monotherapy
Idiopathic
IdiopathicLocalization
LocalizationRelated
Related
Epilepsy
EpilepsySyndromes:
Syndromes:
Benign
BenignEpilepsy
Epilepsywith
with
Centro-temporal
Centro-temporalSpikes
Spikes(BECTS)
(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
InitialMonotherapy
Monotherapy
Idiopathic
IdiopathicGeneralized
GeneralizedEpilepsy
EpilepsySyndromes:
Syndromes:
Juvenile
JuvenileMyoclonic
MyoclonicEpilepsy
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)
syndrome

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