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
Gteborg, 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unpublished data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, Klviinen, 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
Guideline
Methodology
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)

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
Acceptable minimally detectable difference
Set at 20% by 1998 ILAE guideline
Set as relative difference for this project
Assume comparators 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.

Guideline
Methodology-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 studys 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
studys 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: 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)
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 in Adults
Listing of Class I-III Double-Blind RCTs
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: Adults
Recommendations
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)

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
Class I-III RCTs
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: Children
Recommendations
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)
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
Class I RCTs
Level A: GBP, LTG
Level B: None
Level C: CBZ
Level D: TPM, VPA
Level E: Others
Level F: None

Partial Seizures: Elderly
Recommendations
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

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: Adults
Recommendations
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


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: Children
Recommendations
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 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)

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

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 :
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 Recommendations
Partial onset seizures
Seizure
type or
epilepsy
syndrom
e
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
1 0 17 Level A: OXC
Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
POS:
Elderly
1 1 2 Level A: GBP, LTG
Level B: None
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
0 0 23 Level A: None
Level B: None
Level C: CBZ, LTG, OXC, PB, PHT, TPM,
VPA
GTC:
Children
0 0 14 Level A: None
Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
Absence
seizures
0 0 6 Level A: None
Level B: None
Level C: ESM, LTG, VPA
Summary of Evidence and Recommendations
Epilepsy syndromes
Seizure
type or
epilepsy
syndrom
e
Class
I
Clas
s II
Clas
s III
Level of efficacy and effectiveness
evidence
(in alphabetical order)
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
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
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
Torbjrn Tomson, Sweden