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Pathophysiology of

The genesis of a seizure remains poorly
Normal brain function, awake or asleep,
produces an organized, yet nonsynchronous,
EEG pattern.
A seizure results from a paroxysmal high
frequency or synchronous low frequency
electrical discharge that can arise from almost
any part of the cerebral cortex, except: the
cerebellum, brainstem, or spinal cord
A seizure begins as a spike discharge seen on the EEG &
results from thousands of localized pyramidal neurons
depolarizing synchronously.
Based on experimental models of epilepsy, the event is
thought to involve a reduction in cortical inhibition mediated
by GABA, combined w/ divergent excitation, probably
mediated by glutamate.
In a focal seizure, the synchronously depolarizing neurons
remain localized, while in a generalized seizure, the
synchronous depolarizations are present throughout both
Why a seizure terminates also is unknown but it likely is not
due to exhaustion of neuronal energyproducing substrates.
Mechanisms of Seizure Initiation &
Partial seizure activity can begin in a very
discrete region of cortex & then spread to
neighboring regions, i.e., there is a seizure
initiation phase & a seizure propagation
The initiation phase is characterized by two
concurrent events in an aggregate of neurons:
(1) high-frequency bursts of action potentials &
(2) hypersynchronization.
Mechanisms of Seizure Initiation &
The bursting activity is caused by a relatively long-
lasting depolarization of the neuronal membrane
due to influx of extracellular Ca2+, w/c leads to the
opening of voltage-dependent Na+ channels, influx
of Na+, & generation of repetitive action potentials.
This is followed by a hyperpolarizing after potential
mediated by GABA receptors or K +channels,
depending on the cell type.
The synchronized bursts from a sufficient number
of neurons result in a so-called spike discharge on
the EEG.
Mechanisms of Seizure Initiation &
Normally, the spread of bursting activity is
prevented by intact hyperpolarization and a
region of surrounding inhibition created by
inhibitory neurons.
With sufficient activation there is a
recruitment of surrounding neurons via a
number of mechanisms.
Mechanisms of Seizure Initiation &
Repetitive discharges lead to the following:
(1) an increase in extracellular K +, w/c blunts
hyperpolarization & depolarizes neighboring neurons;
(2) accumulation of Ca2+ in presynaptic terminals, leading to
enhanced neurotransmitter release;
(3) depolarization-induced activation of the N-methyl-D-
aspartate (NMDA) subtype of the excitatory amino acid
receptor, w/c causes Ca2+ influx & neuronal activation.
The recruitment of a sufficient number of neurons leads
to a loss of the surrounding inhibition and propagation of
seizure activity into contiguous areas via local cortical
connections, and to more distant areas via long
commissural pathways such as the corpus callosum.
Mechanisms of Epileptogenesis
It refers to the transformation of a normal neuronal
network into one that is chronically hyperexcitable.
There is often a delay of months to years between
an initial CNS injury such as trauma, stroke, or
infection and the first seizure.
The injury appears to initiate a process that
gradually lowers the seizure threshold in the
affected region until a spontaneous seizure occurs.
In many genetic and idiopathic forms of epilepsy,
epileptogenesis is presumably determined by
developmentally regulated events.
Mechanisms of Epileptogenesis
Pathologic studies of the hippocampus from
patients with temporal lobe epilepsy have led
to the suggestion that some forms of
epileptogenesis are related to structural
changes in neuronal networks
Mechanisms of Epileptogenesis
Many patients w/ MTLE have a highly
selective loss of neurons that may contribute
to inhibition of the main excitatory neurons
w/in the dentate gyrus.
There is also evidence that, in response to the
loss of neurons, there is reorganization or
"sprouting" of surviving neurons in a way that
affects the excitability of the network.
Mechanisms of Epileptogenesis
An initial injury such as head injury may lead
to a very focal, confined region of structural
change that causes local hyperexcitability.
The local hyperexcitability leads to further
structural changes that evolve over time until
the focal lesion produces clinically evident
Similar models have also provided strong
evidence for long-term alterations in intrinsic,
biochemical properties of cells within the
network, such as chronic changes in
glutamate or GABA receptor function.