Epileptogenesis:

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Epileptogenesis From normal to epilepsy
Dan Lowenstein, UCSF
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Case Study A 49 y.o. man who developed epilepsy
following a serious motor vehicle accident in
1980.
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Video-EEG Telemetry
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Relative Risks for Developing Epilepsy
Brain tumor Family history Simple febrile
seizures Alzheimer disease SAH Hemorrhagic
stroke Ischemic stroke Bacterial
meningitis Encephalitis Mild TBI Moderate
TBI Severe TBI
2.5
2
7.5
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9.7
4.2
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1.5
4
29
0
10
20
30
40
RR 1
Herman, Neurology 59S21, 2002
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Time of 1st Late Seizure in 481 Patients With
Post-Traumatic Epilepsy
30
25
20
of patients
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10
5
0
0.4
1
2
3
4
5
6
7
8
9
10
gt10
Years
Jennett, 1975
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Key research questions related to epilepsy that
arises from acquired brain lesions
1. What are the changes (structural--gtmolecular)
that transform a normal neural network into one
with abnormal excitability?
2. What explains the time delay often seen
between an initial injury and the epilepsy
phenotype?
3. Are current animal models relevant to the
human condition?
4. What strategies can be developed for
preventing or reversing epileptogenesis?
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Temporal lobe epilepsy and the hippocampus as
model systems for the study of epileptogenesis
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Examples of changes (structural--gtmolecular)
observed in the hippocampus and associated with
epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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Examples of changes (structural--gtmolecular)
observed in the hippocampus and associated with
epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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Neuronal loss in the hippocampus of a patient
with temporal lobe epilepsy
Control
TLE
Robert Sloviter, U. of Arizona
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Long-term decrease in threshold to seizure-like
activity in response to high-frequency
stimulation in combined hippocampal-entorhinal
cortex slices
Santhakumar et al, Ann Neurol. 50708, 2001
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Examples of changes observed in the
hippocampus associated with epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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CA3
Hilus
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Helen Scharfman, Columbia
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Robert Sloviter, U. Arizona
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Examples of changes observed in the
hippocampus associated with epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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Houser et al, 1990
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Examples of changes observed in the
hippocampus associated with epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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Functional alterations in GABAA receptor response
properties of dentate granule neurons isolated
from epileptic rats
Brooks-Kayal et al, Nature Med 41166, 1998
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Subunit composition of the GABA receptor
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aRNA expression profiling of GABA receptor
subunits in a single dentate granule cell from a
rat with temporal lobe epilepsy after
chemoconvulsant injury
Brooks-Kayal et al, Nature Med 41166, 1998
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Relative Expression (fraction of total GABAR)
a1 a2 a3 a4 a5 a6 a1
- Control
- Chronic epilepsy
Relative Expression (fraction of total GABAR)
b1 b2 b3 g1 g2 g3 d e
Brooks-Kayal et al, Nature Med 41166, 1998
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Examples of changes observed in the
hippocampus associated with epileptogenesis
1. Selective neuronal loss
2. Axonal and dendritic reorganization, including
mossy fiber sprouting
3. Dispersion of the dentate granule cell layer
and appearance of ectopic granule cells
4. Altered expression of neurotransmitters and
their receptors
5. Changes in glial architecture
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Astrogliosis in the hippocampus following
seizure-induced injury
Borges et al, J Exp Neurol 18221, 2003
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Calcium waves between cultured murine hippocampal
astrocytes
Fluo-3
NADH
16 µm/s
Evoked by focal contact of a pipette with an
astrocyte in the center of the field
Barbara Innocenti and Phil Haydon, Dept. of
Neuroscience, U. Penn
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Conclusions
1. Epilepsy can result from a wide variety of
acquired lesions such as head trauma, stroke
and infections.
2. These lesions appear to transform a normal
neural network into one the has a predilection
for abnormal excitability
3. Numerous structural and molecular changes have
been observed in the setting of epileptogenesis,
but very little is known about the true
mechanistic role these changes may have in the
pathogenesis of epilepsy.
4. The field is in need of reliable and valid
animal models.
5. There is an incredible need for preventive
strategies that will protect patients at risk
from ever developing epilepsy.
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