Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs Elinor Ben-Menachem, MD, PhDInstitution for Clinical Neuroscience Sahlgrenska Academy Sahlgrenska University Hospital Gteborg, Sweden

Guideline Development Overview of activitiesPick topicBuild ateamForm a clinical questionEvidencea. Findb. Abstractc. Analyze d. Grade/RateDevelopRecommendationsAnd AlgorithmValidateDisseminate

Guideline Development Find the evidenceDefine inclusion/exclusion criteriaSearch clinical question + inclusion/exclusion criteriaPotential sources to searchelectronic databases (MEDLINE, Current Contents)Cochrane librarypublished literature/referencesunpublished dataEnglish/non-English studiesPerform multiple searches

Guideline Development 2Abstract, Analyze and Grade/Rate the evidenceSpecific relevant variables as measure of qualityMajor variablesRandomizationControl group Masked outcome assessmentAdequate comparator (assay sensitivity)Adequate enrollment to detect difference Minimal detectable difference

Guideline Development 3Abstract, Analyze and Grade/Rate the evidenceMinor variablesPrimary outcome clearly definedInclusion/Exclusion criteria clearly definedEquivalent treatment groups at baseline Adequate duration of assessmentDrop out rate and how it is handled statistically Summarize abstraction/analysis into tabular formEvidence tables

Guideline Development 3Abstract, Analyze and Grade/Rate the evidenceGrading/rating scale based on relevant variables

Usually four categoriesTop group RCTs with best evidence, meet all criteriaNext group RCTs missing some minor criteriaThird group Trial missing some major criteriaLast group Low quality trials missing most or all major criteria OR only expert opinion

Significant variability in grading/rating scales across guidelines

Guideline Development Translate evidence and develop recommendations Usually 4 or 5 levels of recommendationsLevels defined using output of grading/rating scaleAt least one recommendation per questionDevelop algorithm (if possible)Validate guidelineInternal/External Peer review Implement and disseminate guideline

Guidelines for newly diagnosed epilepsyInternationalILAE 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

NationalAAN (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)

GuidelineMethodologyTopicOptimal initial monotherapy for patients with newly diagnosed or untreated epilepsy

Team10 members EpileptologistsClinical pharmacologistsStatisticianMethodologist6 countries

ILAE Initial Monotherapy GuidelinesClinical Questions (n=8) :Q1-Q3: Patients (adults/elderly/children) with partial-onset seizuresQ4-Q5: Patients (adults/children) with generalized-onset tonic-clonic seizuresQ6: Children with idiopathic localization-related epilepsies and syndromes (BECTS)Q7-Q8: Children with idiopathic-generalized epilepsies (CAE, JME)

GuidelineMethodologyEvidence - Key rating variablesRandomizedMasked outcome assessment (Minimal potential for bias)Clearly defined efficacy/effectiveness outcome variableAppropriate statistical analysisUse of adequate comparatorAppropriate minimal duration of treatmentAcceptable minimally detectable difference

GuidelineMethodologyAdequate comparatorAssay sensitivityCriteria: AED superior to another drug, another dose of the same drug, another treatment modality or placebo

Appropriate minimal duration of treatmentSet at 48 weeks

GuidelineMethodology-StatisticsAcceptable minimally detectable differenceSet at 20% by 1998 ILAE guidelineSet as relative difference for this projectAssume 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 effectiveMinimal detectable difference calculated for all RCTs based on 80% power, p set at < 0.05 and a non-inferiority analysis.

EpilepsyGuidelinesRating 4 ClassesClass I: A masked RCT, meeting all key variable criteria

Class II: A masked prospective matched-group cohort study in a representative population that meets all key variable criteria OR an RCT in a representative population that lacks one of the key variable criteria

Class III: All other controlled trials in a representative population, where outcome assessment is independent of patient treatment

Class IV: Evidence from uncontrolled studies, case series, case reports or expert opinionFrench JA, Epilepsia 2004, 45(5):401-409 and 410-423

Criteria for Class I Study-ILAEA 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 effectivenessTreatment duration: 48 weeks (>24 wk seizure freedom data for efficacy or >48 wk retention data for effectiveness)Study design: double blindSuperiority 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 Study exit: not forced by a predetermined number of treatment emergent seizuresAppropriate statistical analysis

Criteria for Class II Study-ILAEClass II: An RCT or meta-analysis meeting all the class I criteria except that:No superiority was demonstrated and the studys actual sample was sufficient only to show noninferiority at a 21-30% relative difference in effectiveness/efficayOR2. Treatment duration: 24 wks but 48 wks

Criteria for Class III-IV Studies-ILAEClass 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 AEDRecommendations 6 LevelsLevel 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

Relationship between level of evidence and conclusions Evidence LevelA

B

C

ConclusionsAED established as efficacious or effective as initial monotherapy AED probably efficacious or effective as initial monotherapyAED possibly efficacious or effective as initial monotherapy

Relationship between clinical trial ratings, level of evidence and conclusions Evidence LevelD

E

FConclusionsAED potentially efficacious or effective as initial monotherapy

No data available to assess if AED is effective as initial monotherapy

AED established as ineffective 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 candidateEvidence 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 EvidenceA total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizures Division of trialsClass I (n=2)Class II (n=1)Class III (n=30)

Partial Seizures in AdultsListing of Class I-III Double-Blind RCTsClass IMattson (1985) CBZ, PB, PHT, PRM Chadwick (99) CBZ, VGBClass IIMattson (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, PHTPrivitera (03) CBZ,TPM,VPA Dam (89) CBZ,OXC Arroyo (05) TPM Brodie (02) CBZ, REMSteiner (99) PHT, LTG Ramsay (83) CBZ, PHTGibberd (82) PHT, PNTMikkelsen (81) CBZ, CLP

Partial Seizures: AdultsRecommendationsLevel A: CBZ, PHTLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGBLevel D: CZP, PRMLevel E: OthersLevel F: None

Partial Seizures: ChildrenAvailable EvidenceA total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures Division of trialsClass I (n=1) Class II (n=0)Class III (n=17)

Partial Seizures: ChildrenClass I-III RCTs

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: ChildrenRecommendationsLevel A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPALevel D: LTG,VGBLevel E: OthersLevel F: None

Partial Seizures: ElderlyAvailable EvidenceA total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizures Division of trialsClass I (n=1)Class II (n=1)Class III (n=2)

Partial Seizures: ElderlyClass I RCTsClass IRowan (05)CBZ, GBP, LTG

Class II Brodie ( 99) CBZ,LTGClass III Privitera (03) CBZ, TPM, VPA Nieto-Barrera (01) CBZ, LTG (Open Label)

Partial Seizures: ElderlyRecommendationsLevel A: GBP, LTGLevel B: NoneLevel C: CBZLevel D: TPM, VPALevel E: OthersLevel F: None

Generalized Tonic Clonic Seizures: AdultsAvailable EvidenceA total of 23 RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures Division of trialsClass I (n=0)Class II (n=0)Class III (n=10):CBZ, GBP, LTG, OXC, PB, PHT, TPM, VPA

Generalized Tonic Clonic Seizures: AdultsRecommendationsLevel A: NoneLevel B: NoneLevel C: CBZ*,LTG,OXC*,PB, PHT*,TPM,VPALevel D: GBP,VGBLevel E: OthersLevel F: None*=may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution

Generalized Tonic Clonic Seizures: ChildrenAvailable Evidence

A total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures Division of trialsClass I (n=0)Class II (n=0)Class III (n=14): CBZ, CLB, OXC, PB, PHT, TPM, VPA

Generalized Tonic Clonic Seizures: ChildrenRecommendationsLevel A: NoneLevel B: NoneLevel C: CBZ*,PB, PHT*,TPM,VPALevel D: OXC*Level E: OthersLevel F: None

*may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution

Childhood Absence Epilepsy:Available EvidenceA total of 6 RCTs examined initial monotherapy of children with Childhood Absence EpilepsyDivision of trialsClass I (n=0)Class II (n=0)Class III (n=6) -3 Double BlindedETX, LTG, VPA

Childhood Absence Epilepsy:RecommendationsLevel A: NoneLevel B: NoneLevel C: ESM, LTG, VPALevel D: NoneLevel E: OthersLevel F: CBZ, GBP, OXC, PB, PHT,TGB,VGB

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

BECTS:Available EvidenceA total of 3 RCTs examined initial monotherapy of children with BECTS, 2 were DB

Division of trialsClass I (n=0)Class II (n=0)Class III (n=2)

BECTS:RecommendationsLevel A: NoneLevel B: NoneLevel C:CBZ, VPALevel D: GBP,STMLevel E: OthersLevel F: None

Initial MonotherapyIdiopathic Generalized Epilepsy Syndromes:Juvenile Myoclonic Epilepsy

Juvenile Myoclonic Epilepsy:Available EvidenceA total of 0 RCTs examined initial monotherapy of children with Juvenile Myoclonic EpilepsyDivision of trialsClass I (n=0)Class II (n=0)Class IIII (n=0)

Juvenile Myoclonic Epilepsy :RecommendationsLevel 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 epilepsyDrugs to be avoidedClinical 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 syndromeClass IClass IIClass IIILevel of efficacy and effectiveness evidence(in alphabetical order)POS: Adults 2130Level A: CBZ, PHT, (LEV)Level B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGBPOS: Children1017Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPAPOS: Elderly112Level A: GBP, LTGLevel B: NoneLevel C: CBZ

Summary of Evidence and RecommendationsGeneralized onset seizures

Seizure type or epilepsy syndromeClass IClass IIClass IIILevel of efficacy and effectiveness evidence(in alphabetical order)GTC: Adults0023Level A: NoneLevel B: None Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPAGTC: Children0014Level A: NoneLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPAAbsence seizures006Level A: NoneLevel B: NoneLevel C: ESM, LTG, VPA

Summary of Evidence and RecommendationsEpilepsy syndromes

Seizure type or epilepsy syndromeClass IClass IIClass IIILevel of efficacy and effectiveness evidence(in alphabetical order)BECTS002Level A: NoneLevel B: NoneLevel C: CBZ, VPAJME000Level A: NoneLevel B: NoneLevel C: None

Variables that affect initial AED selection

Participants in the ILAE Subcommission on Antiepileptic Drug Guidelines

Elinor Ben-Menachem, ChairmanTracy Glauser, USABlaise Bourgeois, USA David Chadwick, UKAvital Cnaan, USACarlos Guerreiro, Brazil

Reetta Kalviainen, FinlandRichard Mattson, USAEmilio Perruca, ItalyTorbjrn Tomson, Sweden