disease modification in epilepsy therapy
TRANSCRIPT
?Disease Modification in Epilepsy
Therapy
Is epilepsy curable?
Gruenthal, M., Epilepsy Res., 29 (1998) 221-232.
Neuronal injury correlated with status duration
Seizure duration in min.
ip
sila
tera
l in
jury
(sc
ore
)
DeGiorgio et al. Neurology 1999;52:746–749
Elevation of NSE following status epilepticus
Convulsivestatus
Complex partial status
NSE and status epilepticus duration
NSE ng/ml
Status duration in hours
= Status duration= NSE in serum
Steinhoff B. et al. (1999) Epilepsy Res 36(1):75-82
Elevation of S-100 and NSE in temporal lobe epilepsy
Briellmann et al. (1998) Epilepsia 39(11):1174-1181
Hippocampal sclerosis / Hemicranial asymmetry
"To be able to assess whether and how the
course of epilepsy can be modified, it is essential to understand how an
epileptic fit occurs, how it is perpetuated and to
which underlying mechanisms neuronal
injury is due."
"To be able to assess whether and how the
course of epilepsy can be modified, it is essential to understand how an
epileptic fit occurs, how it is perpetuated and to
which underlying mechanisms neuronal
injury is due."
Acute and chronic neuronal injury
• Acute injury– Status epilepticus– Stroke (focal cerebral ischemia)– Craniocerebral trauma– Global hypoxia
• Chronic injury– Chronic epilepsy– Amyotrophic lateral sclerosis (ALS)– Alzheimer's disease– Parkinson's disease– Multiple sclerosis
Calcium ion influx
Early gene activation
Activation of kinases
Proteinexpression
Sprouting
Glialactivation
Neuronal cell death
Neuro-genesis
Susceptibility to seizures
1 sec. 1 day1 h1 min. 1 wk 1 month 1 year
modified after Cole A.J. (2000) Epilepsia 41(S2):13-22
Postictal cell changes
Time (logarithmic)
Cell changes & neuroplasticity:• altered receptors• altered ion channels• neuronal loss• sprouting• other unknown mechanisms
SeizureSeizures
Insult
Alteredstimulus conduction
Increasedexcitability
after Lynch MW et al. Curr Opin Neurol. 1996;9:97-102
• sprouting
Kindling hypothesis
Normal inter-neuronal inhibition
loop
Epileptogenicloop
Sprouting / Changes of the neuronal feedback mechanism
"Is the kindling hypothesis presented
here found only in animal studies, or can
you also see evidence of the applicability of this concept to humans?"
"Is the kindling hypothesis presented
here found only in animal studies, or can
you also see evidence of the applicability of this concept to humans?"
ChronicityEpileptogenesis
Cell injury(e.g. neuronal loss)
Altered stimulus conduction
Lowering of seizure threshold
Seizures
Seiz
ure
freq
uenc
y an
d se
verit
y
1st s
eizu
re
Time
Epileptogenesis and chronicity
Course of epilepsy / A progressive process
after Schmidt & Elger: Kwan & Brodie (2000) N Engl J Med 342:314-9
Seizure-free
Monotherapy
1st seizure
Combination therapy
Non-drug therapy
Early phase of epilepsy
Living with seizures Chronic epilepsy
Sei
zure
fre
quen
cy S
eiz
ure
sev
erity
R
isk
of n
euro
dege
nera
tion
Possible mechanisms of disease modification
• Delay / Prevention of epileptogenesis or
disease progress
• Sufficient prevention of seizures
• Prevention of neuronal injury
– seizure-associated
– primary
• Improvement of neuronal recovery and
regeneration
Possibilities for intervention
ChronicityEpileptogenesis
Cell injury(e.g. neuronal loss)
Altered stimulus conduction
Lowering of seizure threshold
Seizures
Seiz
ure
freq
uenc
y an
d se
verit
y
1st s
eizu
re
Time
Seizures
Possibilities for intervention
ChronicityEpileptogenesis
Cell injury(e.g. neuronal loss)
Altered stimulus conduction
Lowering of seizure threshold
Seizures
Seiz
ure
freq
uenc
y an
d se
verit
y
1st s
eizu
re
Time
Cell injury(e.g. neuronal loss)
Glu
Glu
Glu
Ca2+
Ca2+
NM
DA
VS
CC
Na+
Ca2+
Na+
AMPANa+C
Na+
G l u
Inflammatorymediators
Depolari- zation
Celldistension
Membranedegradation
Free radicals
Enzymeinduction
Mitochondrialinjury
DNA injury
Apoptosis
Neuronal injury cascadeDirnagl et al. Trends Neurosci 22:391-397
Glu
Glu
Glu
Ca2+
Ca2+
NM
DA
VS
CC
Na+
Ca2+
Na+
AMPA
Na+
G l u
Depolari-zation
Celldistension
Membranedegradation
Free radicals
Enzymeinduction
TopiramatePhenytoin
CarbamazepineValproic acidLamotrigine
Na+ channel blockers:
Na+C
Neuronal injury cascade / Action of AEDs
Glu
Glu
Glu
Ca2+
Ca2+
NM
DA
Na+
Ca2+
Na+
AMPA
Na+
G l u
Depolari-zation
Celldistension
Membranedegradation
Free radicals
Enzymeinduction
Na+C
TopiramateLamotrigineFelbamate
Valproic acidNimodipine
Ca2+ channel blockers:
VS
CC
Neuronal injury cascade / Action of AEDs
Glu
Glu
Glu
Ca2+
Ca2+
NM
DA
Na+
Ca2+
Na+
AMPA
Na+
G l u
Depolari- zation
Celldistension
Membranedegradation
Free radicals
Enzymeinduction
Na+C
VS
CC
FelbamateMK801
Ketamine
NMDA antagonists
Neuronal injury cascade / Action of AEDs
Glu
Glu
Glu
Ca2+
Ca2+
NM
DA
Na+
Ca2+
Na+
AMPA
Na+
G l u
Depolari-zation
Celldistension
Membranedegradation
Free radicals
Enzymeinduction
Na+C
VS
CC
TopiramatePhenobarbital
AMPA antagonists
Neuronal injury cascade / Action of AEDs
Mechanisms of action of AEDs
AED Na+ channel
Glutamatereceptor
Ca2+
channelGABAreceptor
Carbonic anhydrase-inhibition
Topiramate ++
(AMPA/Kainate)+ (L type) + +
Phenobarbital -+
(AMPA/Kainate)- + -
Felbamate + NMDA + (L type) + -
Lamotrigine + - + (L type) - -
Gabapentin + - + (L type) + -
Levetiracetam - - - - -
Phenytoin + - - - -
Carbamazepine + - - - -
Valproic acid + - + (L type) + (?) -
Ethosuximide - - + (L type) - -
Dirnagl U, Wiegand F (2000) Thieme Perspektiven Neurologie: Disease Modification p16
Effect of different receptors on known neuronal injury models
White S. (2000) Symposium: Expanding the Therapeutic Options
Disease model
Mechanism ofaction
IschemiaHypoxia
Cerebrocranialtrauma
Cerebral palsy ALSStatus epilepticus
induced cellinjury
Na+ channelblocker
++ ++ ++ ++ -
Ca2+ channelblocker
+ + - - -
NMDA receptorantagonist
++ ++ - - -
Non- NMDAreceptorantagonist
+++ ++ +++ +++ +++
GABA receptormodulator
+ + ? ? -
+++ good; ++ moderate; + minimal; - no effect
Effect of different receptors on known neuronal injury models
White S. (2000) Symposium: Expanding the Therapeutic Options
Disease model
Mechanism ofaction
IschemiaHypoxia
Cerebrocranialtrauma
Cerebral palsy ALSStatus epilepticus
induced cellinjury
Na+ channelblocker
++ ++ ++ ++ -
Ca2+ channelblocker
+ + - - -
NMDA receptorantagonist
++ ++ - - -
Non- NMDAreceptorantagonist
+++ ++ +++ +++ +++
GABA receptormodulator
+ + ? ? -
+++ good; ++ moderate; + minimal; - no effect = Study data with topiramate
Chronicity
Seiz
ure
freq
uenc
y an
d se
verit
y
1st s
eizu
re
Time
Clinical studies / Outcome parameters
Epileptogenesis
Combination therapystudies
Combination therapystudiesMonotherapy studiesMonotherapy studies
EfficacySafety inchronic epilepsy
EfficacySafety inchronic epilepsy
Tolerability and(broad) efficacyin early use
Tolerability and(broad) efficacyin early use
Potential for disease modificationPotential for disease modification
Number Needed to Treat(95% confidence interval)
0 3 6 9 12 15 18 21
Zonisamide II
Tiagabin I I
Vigabatrin I I
Gabapentin I I
Topiramate I I
Lamotrigine I I
Elferink AJA, Van Zwieten-Boot BJ. Brit Med J 314: 603, 1997
Comparison of efficacy of new antiepileptics
Meta-analysis of controlled studies
focal seizures
primarily generalized tonic-clonic seizures
Lennox-Gastaut syndrome
Adjuvant therapy in adults and children of 2 years and over
* Date of information: 03/2000
TOPAMAX® registration status in Germany*
Seizure classification in newly diagnosed epilepsy
0
20
40
60
Pat
ien
ts,
%
*75% 15 yrs; Manford M et al. Arch Neurol 49:801, 1992**Berg AT et al. Epilepsia 41:1269, 2000
50%
13%
37%
0
20
40
60
59%
29%
12%
Adults (N=508)* Children (N=613)**
focal seizures prim. gen. seiz. undetermined
Decision phase<7 days
TPM 200 mg
CBZ 600 mg
TPM 100 mg
TPM 200 mg
VPA 1250 mg
TPM 100 mg
Titration35 days
Maintenance therapy
Randomization
Randomization
Investigator’s decision:CBZ or VPA
Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
TOPAMAX® comparative study
Diagnosis of epilepsy 3 months before beginning of studyInclusion independent of type of seizure
Design
Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
TOPAMAX® comparative study
Age 6 years
Weight > 30 kg
Diagnosis of epilepsy 3 months before beginning of study
Patient characteristics
Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
1 unprovoked seizure within the last 3 months
Maximum AED treatment < 6 weeks
TOPAMAX® comparative study
Diagnosis of epilepsy or 2 seizures
TPM CBZ VPA
N 409 126 78
Sex (f/m, %) 45/55 48/52 56/44
Age (median) 29 years 34 years 25 years
Time since 1st seizure 4.0 mths 5.5 mths 5.5 mths(median)
Time since diagnosis 4.0 mths 1.0 mth 1.0 mth(median)
No AED at beginning 58% 62% 59%of study
Poster presentation AES 2000, Los Angeles
Comparative study / Patient characteristics