Pathophysiology of Seizures

Pathophysiology
The genesis of a seizure remains poorly understood.
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
Pathophysiology
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 hemispheres.
Why a seizure terminates also is unknown but it likely is not due
to exhaustion of neuronal energy–producing substrates.
Mechanisms of Seizure Initiation & Propagation
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 phase.
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 & Propagation
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 & Propagation
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 & Propagation
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 seizures.
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.