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Strategies for Pharmacotherapy in Generalized Epilepsy Joon Soo Lee, M.D., Ph.D. Pediatric Epilepsy Clinic, Department of Pediatrics Severance Children’s Hospital Yonsei University College of Medicine Drug Treatment in Epilepsy Goal ¾ ¾ Mode of therapy ¾ ¾ No seizures & no side effect Improving QOL Monotherapy Combination therapy AEDs ¾ ¾ Conventional drugs: CBZ, PHT, VPA, ESM, PRM, BZD New drugs: LMT, OXC, TPM, ZNS, GBP, VGB, LTM, TGB Choice of AEDs: Factors for Consideration Drugs ¾ Conventional/new AEDs: about 18 drugs ¾ Efficacy/adverse events ¾ PK/PD properties ¾ Mechanism of action, potential sz. aggravation ¾ Costs, titration, dosing, formulations, etc. Epilepsy ¾ Seizure types/epileptic syndromes ¾ Etiologies, frequency/severity of sz. Patients ¾ Age, sex, pregnancy, jobs, etc. ¾ Concomitant drugs and illness ¾ Psychosocial functions, QOL, etc Complexities of Clinical Decision Making 1. 2. 3. 4. Evidence Patient data Basic, clinical, and epidemiologic research Randomized trials Systematic reviews Knowledge CLINICAL DECISION Guidelines 1. 2. 3. 4. 1. 2. 3. 4. Patient/physician factors Cultural benefits Personal values Experiences Education Ethics Constraints Formal policies, laws Community standards Time Reimbursement Mulrow, CD, et. al. Ann Intern Med 1997:126;389-91 Generalized Epilepsy: Idiopathic/Symptomatic or Probablic symptomatic Idiopathic Benign neonatal familial convulsions Benign neonatal convulsions Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal (GTCS) seizures on awakening Other generalized idiopathic epilepsies not defined above Epilepsies with seizures precipitated by specific modes of activation Symptomatic/Probably symptomatic Early myoclonic encephalopathy Early infantile epileptic encephalopathy Infantile spasm Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic absences Epilepsy with continuous spikewaves during slow wave sleep Acquired epileptic aphasia (LandauKleffner syndrome) Other symptomatic generalized epilepsies not defined above Current Treatment Options Partial Simple Complex Secondarily generalized PHT, CBZ, OXC, GBP, TGB, VGB, ZNA, LTM Generalized Tonicclonic Tonic Myoclonic Atonic ZNA VPA, LTG, TPM (FBM) (ZNA & LTM?) Infantile Absence spasms ACTH, VGB ESX Evidence Based Medicine New paradigm in medical education and practice Definition The conscientious, explicit and judicious use of current best evidence in making clinical decisions for the care of individual patients Providing more succinct, accurate, and usable information about diagnostic and treatment options Best evidence requires scientifically rigorous approach ¾ RCT, meta-analysis, systematic review, guidelines, etc Definitions for classification of evidence Rating of recommendation A – Established as effective, ineffective, or harmful for the given condition in the specified population Translation of evidence To recommendations Level A rating requires at least one convincing class Ⅰ study or at least two consistent, convincing class Ⅱ studies Rating of therapeutic article Class Ⅰ: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population The following are required: a) primary outcome(s) is/are clearly defined b) exclusion/inclusion criteria are clearly defined c) adequate accounting for dropdrop-outs and crosscross-overs with numbers sufficiently low to have minimal potential for bias bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences B – Probably effective, ineffective, Level B rating requires or harmful for the given at least one convincing condition in the specified class Ⅱ study or at population least three consistent class Ⅲ studies Class Ⅱ: Prospective matched group cohort study in a representative population with masked outcome assessment that meets aa-d above or a RCT in a representative population that lacks one criterion aa-d C – Possibly effective, ineffective, or harmful for the given condition in the specified population Class Ⅲ : All other controlled trials (including wellwell-defined natural history controls or patients serving as own controls) controls) in a representative population where outcome assessment is independent of patient treatment U – Data inadequate or conflicting given current knowledge, treatment is unproven Level C rating requires at least two convincing and consistent class Ⅲ studies Class Ⅳ : Evidence from uncontrolled studies, case series, case reports, or expert opinion Rating of Therapeutic Article Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) is/are clearly defined b) exclusion/inclusion criteria are clearly defined c) adequate accounting for drop-outs and crossovers with numbers sufficiently low to have minimal potential for bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a–d above or a RCT in a representative population that lacks one criterion a–d Class III: All other controlled trials (including well defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion Rating of Recommendation Level A: Established as effective, ineffective, or harmful for the given condition in the specified population: at least one convincing class I study or at least two consistent, convincing class II studies Level B: Probably effective, ineffective, or harmful for the given condition in the specified population: at least one convincing class II study or at least three consistent class III studies Level C: Possibly effective, ineffective, or harmful for the given condition in the specified population: at least two convincing and consistent class III studies Level U: Data inadequate or conflicting; given current knowledge, treatment is unproven Neurology 2004;62:1252-1260 AAN (NICE) Evidence-based Guidelines of Using New AEDs in Newly Diagnosed Epilepsy Drug Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Newly diagnosed monotherapy partial/mixed Newly diagnosed absence Yes* Yes* Yes* No Yes No No No Yes* No No No No No * Not Food and Drug Administration–approved for this indication. Neurology 2004;62:1261-1273 AAN (NICE) Evidence-based Guidelines of Using New AEDs in Refractory Epilepsy Drug Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Vigabatrin Primary generalized Symptomatic generalized No No (Yes in UK) Yes (GTC in US) No No No No NA (No in UK) No Yes Yes No No No No NA (Yes in UK) Limitations of evidence-based AED guidelines ► Guidelines provide only a list of AEDs having evidence of effectiveness for use in general clinical situations ► Not applicable for choosing the best AED for the individual patients AEDs having no evidence don’t mean no or less efficacy in a given clinical situation Each guidelines may be different for given clinical environment (countries, continents, economical status, etc) Guidelines are often out of dated Treatment of epilepsy in adults - expert opinion, 2005 ► S Karceski, MJ Morrell, and D Carpenter Epilepsy & Behavior : 2001: 2 : A1-A50 Epilepsy & Behavior : 2005: 7 : S1-S64 Methods ► Experts - leaders in the field of epilepsy - a group of experts (n=50) polled from geographic cross sections in US - 43 respondents to the current survey, 29 (67%) also respondents to the 2001 survey Mail-in survey Statistical(quantitative) analysis of results from expert opinion to from the consensus Epilepsy survey rating evaluation scale Rating 9 7-8 4-6 2-3 1 Description Extremely appropriate; this is the treatment of choice (may have more than one per question) Usually appropriate; an agent you would often use in this situation Equivocal; an agent you would sometime use, e.g, if the first choice(s) failed, or was contraindicated Usually inappropriate; an agent you would rarely use, or use in special circumstances only Extremely inappropriate; a treatment that should not be used in this situation Overall Strategy for Idiopathic Generalized Epilepsy S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 Initial Strategy for Idiopathic Generalized Epilepsy: GTC Seizure S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 Initial Strategy for Idiopathic Generalized Epilepsy: Absence Seizure S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 Initial Strategy for Idiopathic Generalized Epilepsy: Myoclonic Seizure S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 S. Karceski et al. / Epilepsy & Behavior 7 (2005) S1–S64 Treatment of pediatric epilepsy - expert opinion, 2005 ► J W Wheless, DF Clarke, D Carpenter J Child Neurol : 2005:20: S1-S56 Methods ► Experts - leaders in the field of epilepsy - a group of experts (n=41) polled from geographic cross sections in US - 39 respondents to the current survey - 33 question, 645 treatment option - symptomatic myoclonic and GTC, CPS, neonatal sz, IS, LGS, FS, BRE, absence, JME, newly diagnosed epilepsy in EMC, SE. Mail-in survey Statistical(quantitative) analysis of results from expert opinion to from the consensus Epilepsy survey rating evaluation scale Rating 9 7-8 4-6 2-3 1 Description Extremely appropriate; this is the treatment of choice (may have more than one per question) Usually appropriate; an agent you would often use in this situation Equivocal; an agent you would sometime use, e.g, if the first choice(s) failed, or was contraindicated Usually inappropriate; an agent you would rarely use, or use in special circumstances only Extremely inappropriate; a treatment that should not be used in this situation J W Wheless, et al J Child Neurol : 2005:20: S1-S56 J W Wheless, et al J Child Neurol : 2005:20: S1-S56 Infantile spasms Lennox-Gastaut Syndrome Absence seizure Juvenile Myoclonic Epilepsy 2007, European pediatric expert 2007, European pediatric expert 2007, European pediatric expert Absence seizure 2007, European pediatric expert Juvenile Myoclonic Epilepsy 2007, European pediatric expert Expert opinions : limitations ► Limitations The experts may be wrong. - a group of experts agrees does not mean they are correct. Expert opinion can also change. In other parts of the world, where other medicines and therapies may be available, expert opinion may differ ( individuals, clinical environments, regions, etc). Practices in a private setting may differ. Seizure aggravation in idiopathic generalized epilepsies by AEDS ► ► ► ► The pathophysiology of seizure aggravation is poorly understood non-specific effects such as those associated with sedation, drug-induced encephalopathy, paradoxical or inverse pharmacodynamic effects. Drugs that modulate Na+-channels and GABAergic drugs CBZ, OXC, VGB, GBP, PHT - CAE, JAE LTG, VGB, GBP, PHT - JME, Severe myoclonic epilepsy Ketogenic Diet Most potent anti-epileptic treatment among nonsurgical modalities Most difficult treatment for prolonged maintenance Benefits to prevent major cognitive side effects of multiple medications commonly used in intractable epilepsy Many early and late complications Seizure Free Rate of Ketogenic Diet Compared with New AED’s for Intractable Epilepsy Drugs Felbamate Gabapentin Topiramate Levetiracetam Vigabatrin Ketogenic diet Seizure type Follow-up Seizure-free rate LGS PS PS LGS GS PS PS Total LGS PS 8 wks 12 wks 12 wks 8 wks 12 wks 12 wks 12 wks 12 wks 12 wks 12 wks 8% 1% 12% 2% 4% 8.2% 6% 35% 26% 42% Anti-epileptic Efficacy of Ketogenic Diet in Intractable Epilepsy J. Freeman et al. / Epilepsy Research 68 (2006) 145–180 Anti-epileptic Efficacy of Ketogenic Diet in Intractable Infantile Spasm S.H. Eun et al. / Brain & Development 28 (2006) 566–571 Summary z Valproate is the drug of choice in IGE such as GTC, CAE, JAE, JME, and symptomatic myoclonic and GTC Szs, LGS, - Pediatric / Adult z Lamotrigine is the another drug of choice in CAE, JME, z ESM is the another drug of choice in CAE. z Vigabatrin is the drug of choice in IS with TS, IS with symptomatic etiology z z ACTH or prednisolone is the another drug of choice in IS Ketogenic diet may be a powerful tools for Intractable epilepsy Goal of Treatment in Epilepsy Recovery from Pathologic Neuro-psycho-social Condition and Maintenance of Normal Life Thank you for your attention!!
