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• Cochrane library• published literature/references• unpublished data• English/non-English studies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