Levetiracetam in the Treatment of Epilepsy

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Epilepsy
Yung-Yang Lin (???), MD, PhD National Yang-Ming
University Taipei Veterans General Hospital
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Outline

• Epidemiology
• Diagnosis
• Etiologies and Mechanisms
• Treatment

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• Epidemiology

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• 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 )

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• Diagnosis

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• 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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• Etiologies and Mechanisms

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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
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Symptomatic seizures in different age groups
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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 particularpiece of music
Reading
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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

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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
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Imbalance between excitation and inhibition
Lack of inhibition
Excess excitation
epileptic seizures
epileptic seizures
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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).

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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.

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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)

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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
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TrkB signaling promotes epileptogenesis in
kindling
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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

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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)
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• Treatment

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

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• Medications and action mechanisms

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Medication therapy

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

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Generations of AEDs
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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
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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)
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• Vagus nerve stimulation

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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

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• Deep brain stimulation

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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