Transcript Levetiracetam in the Treatment of Epilepsy

Epilepsy
Yung-Yang Lin (林永煬), MD, PhD
National Yang-Ming University
Taipei Veterans General Hospital
Outline
 Epidemiology
 Diagnosis
 Etiologies and Mechanisms
 Treatment
Epidemiology
 The incidence is around 50/100 000/year.
 Prevalence of active epilepsy is in the range of 5-10/1000.
 Age-specific incidence rates: a decrease in younger age groups and an
increase in persons above 60 years
 Overall prognosis for seizure control is good and over 70% will enter
remission.
 Increased risk of premature death particularly in patients with chronic
epilepsy (Sudden unexpected death )
Diagnosis
 History of event
 Medical history
 Blood tests
 Electroencephalography (EEG)
 Simultaneous EEG and video recordings
 Brain scanning (CT scan, MRI) - to discover if the
patient has symptomatic epilepsy; a structural cause for
their seizures
 PET, SPECT, MRS
 Magnetoencephalography (MEG)
Etiologies and Mechanisms
Degenerative brain
disorder 3.5%
Infection 2.5%
Neoplasm 4.1%
Idiopathic
and
cryptogenic
epilepsy
65.5%
Vascular
injury 10.9%
Trauma 5.5%
Congenital causes 8.0%
100
90
80
70
60
50
40
30
20
10
0
Others
Degenerative
Cerebrovascular
Brain tumour
Trauma
Infection
Development
0–4
5–14
15–24
25–44
45–64
65+
In rare cases patients may have one specific trigger that brings
on a seizure, for example:
Flashing visual
stimuli
Looking at a particular
kind of pattern
Hearing a particular
piece of music
Reading
 In the majority of cases an epileptic seizure ends of its
own accord
 Status epilepticus is a condition characterized by an
epileptic seizure that is so frequently repeated or
prolonged as to create a fixed and lasting condition
 It is a medical emergency that requires prompt and
appropriate treatment
An abnormal synchronous and sustained activity
(overexcitation) in a group of nerve cells
This group of nerve cells = epileptogenic focus
Abnormal interictal activity
When this focus recruits surrounding, normal nerve cells
into a synchronous pattern of larger abnormal activity
(burst firing), there is transition from interictal to ictal activity
= SEIZURE
Excess excitation
Lack of inhibition
epileptic seizures
epileptic seizures
Hippocampal sclerosis
(1) Extensive neuronal loss and gliosis in the areas of
CA1 and the hilus but also in other hippocampal
regions to varying degrees.
(2) Synaptic reorganization, although not necessarily
limited to the mossy fibers of the dentate gyrus.
(3) Dispersion of the dentate granule cells.
(4) Extrahippocampal pathology (i.e.neuronal loss in
the neighboring entorhinal cortex and amygdala).
Neural circuits in hippocampal formation
output
input
Hilar neuronal loss and mossy fiber sprouting
Sprouting is classically seen as a response to the loss of
neuronal targets:
the loss of mossy cells and somatostatin-positive interneurons in the
hilus lead to mossy fiber sprouting in the inner and outer molecular
layers.
Mossy fibers in humans with MTLE and in animal MTLE
models:
form excitatory recurrent circuits through collaterals synapsing onto
granule cell and interneuron dendrites in the supragranular layer and
onto new subgranular dendrites in the hilus.
Molecular mechanisms underlying epileptogenesis
NMDA receptor activation
Group I mGluR activation in CA3 pyramidal neurons
TrkB signaling
Cross-talk between neurons and astrocytes
(synchronous epileptiform activity in CA1 pyramidal neurons)
Activation of NMDA receptors (at postsynaptic sites on dendritic spines)
Ca2+ influx
CaMKII and calcineurin activation
CaMKII
calcineurin
GluR1 of AMPA receptors
internalization of GABAA receptor
[Ca2+]i
GABA-mediated synaptic inhibition
Ca2+-dependent gene expression
Mossy fiber sprouting
Epileptogenesis
KCC2
TrkB signaling promotes epileptogenesis in kindling
Astrogliosis – abnormal shape and increased numbers of astrocytes – is a
prominent feature of Ammon’s horn sclerosis.
Glu released from neurons can activate mGluR on astrocytes.
Glu released from an astrocyte is sufficient to trigger a PDS (paroxysmal
depolarizing shift) in neighboring neuron.
A novel mechanism for the synchronization of neuronal firing
Positive feedback model
Dynamic cross-talk
PDS (paroxysmal depolarizing shift) : a brief(250ms) massive membrane depolarization with
an accompanying burst of AP. (best cellular marker of an epileptic event)
Treatment
 Treatment of underlying causes
 Trigger avoidance
 Drug therapy
 Surgery
 Ketogenic diet
 Vagus nerve stimulation
 Deep brain stimulation
 Complementary therapies
Medications and action mechanisms
 Selection of antiepileptic drugs (AEDs) based on:
 ‘Standard’ vs ‘new’ drug
 Spectrum of efficacy
 Tolerability
 Pharmacokinetics
 Mode of action
Standard
Phenytoin (PHT), Pfizer
(Dilantin)
Carbamazepine (CBZ), Novartis
(Tegretol)
Sodium valproate (VPA), Sanofi
Synthelabo (Depakine)
Ethosuximide (ESM), Pfizer
Barbiturates
Phenobarbital (PB)
Primidone (PRM)
New
Felbamate (FBM), Carter-Wallace
Vigabatrin (VGB), Aventis(Sabril)
Lamotrigine (LTG), GSK(Lamictal)
Gabapentin (GBP), Pfizer(Neurontin)
Topiramate (TPM), Janssen-Cilag(Topamax)
Tiagabine (TGB), Sanofi Synthelabo(Gabatril)
Oxcarbazepine (OCBZ), Novartis(Trileptal)
Benzodiazepines
Clonazepam (CZP)
Clobazam (CLB)
Zonisamide (ZNS), Athena
 Decreased excitation – via blockade of sodium
channels, interaction with voltage-sensitive calcium
channels or blockade of glutamate receptors.
 Increased inhibition – via an increase in the
concentration of GABA in the synaptic cleft.
First drug
Success rate 50%
Failure rate 50%
Alternative monotherapy
Success rate 20%
Failure rate 30%
Dual therapy
Success rate 5%
Failure rate 25%
1. Sub-dural grid used to localise the
site of seizure onset
2. Frontal lobectomy of non-dominant
hemisphere (red area indicates the
extent of resection)
Vagus nerve stimulation
Vagus nerve stimulation
 Alteration of norepinephrine release by projections of
solitary tract to the locus coeruleus

 Elevated levels of inhibitory GABA related to vagal
stimulation
 Inhibition of aberrant cortical activity by reticular
system activation
Deep brain stimulation
Deep brain stimulation
 Probably mimics that of high frequency DBS for
movement disorders

 Neurons adjacent to stimulating electrodes appear to
undergo long term inactivation following stimulation,
leading to interruption of pathologic network activity