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PA THOPHYSIOLOGY OF STATUS EPILEPTICUS
NEUROPHYSIOLOGICAL AND
NEUROCHEMICAL FACTORS
In this section, physiologic processes that lead to recurrent ictal activity, i.e., SE, will be discussed. As suggested by Prince et al. (1983), there is probably a continuum of gradually increasing neuronal excitability in
going from normal neuronal activity to interictal activity, to ictal episodes, and finally to repeated ictal
episodes or SE. However, the factors leading from normal to interictal discharges may be quite distinct from
factors that lead to repeated ictal episodes. The former
are beyond the scope of this review. The latter may
include an extension of factors important in the transition from interictal to ictal activity.
Extrasynaptic factors may favor the spread and
maintenance of S E
As reviewed by Dudek et al. (1986), localized ynchronization of neuronal activity may involve me hanisms such as electrotonic coupling via gap junctions
and electrical field effects (ephaptic interactions) in addition to recurrent excitatory chemical synapses. It is
also well known that changes in the concentration of
extracellular ions, especially increases in extracellular
K+ and decreases in extracellular Ca2+,can affect the
excitability of neurons (Prince and Schwartzkroin,
1978).
u,
Excitatory neurotransmitters are involved in SE
Synaptic mechanisms are probably more important
in the spread of epileptiform activity to nearby and
distant areas of the brain. This process is affected by
neurotransmitters and neuromodulators. As pointed
out by Fisher and Coyle ( 1991), all known neurotransmitters and neuromodulators are likely to be involved
in epilepsy, and they provide an interim list of 69 compounds; the list is constantly growing. The role played
by these compounds in a given situation is complex
and poorly understood in the context of SE. Nevertheless, a few useful, if overly simplistic, generalizations
regarding the role of neurotransmitters ‘can be made
in terms of excitatory and inhibitory processes.
Acetylcholine, glutamate, and aspartate seem to play
the major role as excitatory neurotransmitters. While
the role of subtypes of glutamate receptors in the
mechanisms of epileptogenicity and cell death are currently active areas of research, animal models exist in
which limbic SE is produced by cholinomimetic stimulation (Honchar et al,, 1983;Turski et al., 1983)(also,
see the section on “Animal models of SE”). However,
even in these models, there is evidence that once SE is
initiated, the release of endogenous excitatory amino
acids is responsible for the neuronal damage that is produced (see the section on “Excitotoxic mechanisms”).
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GABA plays a key role in seizure arrest
GABA appears to be the most important of the inhibitory neurotransmitters and many modes of therapy
of SE involve modulation of the activity of the
GABA,-benzodiazepine receptor complex with the
associated C1- ionophore (Olsen and Leeb-Lundberg,
1981). In addition to the role of GABAergic inhibition
in localized circuitry, where it may also play a role in
synchronization, GABAergic action in the substantia
nigra seems to interfere with the facilitation of seizure
propagation in both convulsive (Gale, 1985) and nonconvulsive generalized epilepsies (Depauliset al., 1989).
Although this system may be important in limiting SE,
it may also be affected by SE reciprocally. In the substantia nigra of kindled rats, 60 min of pilocarpineinduced SE caused a 50% reduction in the rate of synthesis of GABA (Wasterlain et al., in press). A parallel
decrease in glutamate levels is suggestive of decreased
availability of precursor for the synthesis of GABA in
this critical region during SE, which may be related to
compromised energy metabolism, as replenishment of
the precursor pool of glutamate would depend on the
sustained activity of the Krebs cycle.
Several factors predispose the immature brain to SE
The immature brain seems to have an increased tendency toward SE compared to the mature brain. It has
been stated that different mechanisms that control
neuronal excitation and synchronization develop separately in the immature brain, resulting in an increase
and then a decrease in seizure susceptibility. Peak epileptogenicity occurs when the various factors are maximally predisposed to both excitation and synchronization (Schwartzkroin, 1984). Glial proliferation is
incomplete in the immature cortex (Vernadakis and
Woodbury, 1965), which may result in reduced buffering of K+ in the extracellular space (Hablitz and Heinemann, 1987). Increased electrotonic coupling of
cortical neurons in the immature brain has also been
noted (Connors et al., 1983). The seizure-suppressive
function of the substantia nigra may not be sufficiently
developed in the immature brain (MoshC, 1989). It is
also possible that the immature cortex may be especially vulnerable to limitations in the availability of
precursors for the synthesis of GABA, as it may have
developmental restrictions on energy metabolism (see
the section on “Changes in brain metabolism during SE.”)
METABOLIC FACTORS IN S E
Cerebral blood flow
Changes in cerebral blood flow (CBF) are an adaptation to the seizure and its increased metabolic demands. The mechanism of these changes is still poorly
Epilepsia. Vol. 34, Suppl. 1, 1993