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Levetiracetam in the Treatment of Epilepsy

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Epilepsy Yung-Yang Lin ( ), MD, PhD National Yang-Ming University Taipei Veterans General Hospital * * * * * * * * * * * * * * * First drug Success rate 50% ... – PowerPoint PPT presentation

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Title: Levetiracetam in the Treatment of Epilepsy


1
Epilepsy
Yung-Yang Lin (???), MD, PhD National Yang-Ming
University Taipei Veterans General Hospital
2
Outline
  • Epidemiology
  • Diagnosis
  • Etiologies and Mechanisms
  • Treatment

3
  • Epidemiology

4
  • 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 )

5
  • Diagnosis

6
  • 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)

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10
  • Etiologies and Mechanisms

11
Aetiologies of epilepsy
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
12
Symptomatic seizures in different age groups
13
Seizure triggers
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
14
Status epilepticus
  • 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

15
Electrophysiological basis for epileptic seizures
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
16
Imbalance between excitation and inhibition
Lack of inhibition
Excess excitation
epileptic seizures
epileptic seizures
17
Hippocampal sclerosis
  • 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).

18
Neural circuits in hippocampal formation
input
output
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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.

21
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)

22
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
Ca2i
GABA-mediated synaptic
inhibition Ca2-dependent gene expression
KCC2 Mossy
fiber sprouting

Epileptogenesis
23
TrkB signaling promotes epileptogenesis in
kindling
24
Astrocytes and epileptiform activity
  • Astrogliosis abnormal shape and increased
    numbers of astrocytes is a prominent feature of
    Ammons 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

25
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)
26
  • Treatment

27
  • Treatment of underlying causes
  • Trigger avoidance
  • Drug therapy
  • Surgery
  • Ketogenic diet
  • Vagus nerve stimulation
  • Deep brain stimulation
  • Complementary therapies

28
  • Medications and action mechanisms

29
Medication therapy
  • Selection of antiepileptic drugs (AEDs) based on
  • Standard vs new drug
  • Spectrum of efficacy
  • Tolerability
  • Pharmacokinetics
  • Mode of action

30
Generations of AEDs
31
Modes of action
  • 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.

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Likely outcomes in patients with newly diagnosed
epilepsy
First drug
35
Focal resection the seizure focus is localised
and excised (in this case, by a frontal lobectomy)
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)
36
  • Vagus nerve stimulation

37
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

38
  • Deep brain stimulation

39
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
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