Febrile Convulsion and Benign Afebrile Seizures in Infancy

Transcription

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
Epilepsy: Absence Seizure
Epilepsy: Myoclonic Seizure
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
Absence seizure
Juvenile Myoclonic Epilepsy
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!!