Disease modification in epilepsy therapy

?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