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Egilepsitr. 34(Suppl. I):S37-S53, 1993
Raven Press, Ltd., New York
0 International League Against Epilepsy
Pathophysiological Mechanisms of Brain Damage
from Status Epilepticus
*$[[ClaudeG. Wasterlain, tS 11 Denson G. Fujikawa, *$LaRoy Penix, and *$$Raman Sankar
*Epilepsy Research and ?Experimental Neurology Laboratories, Veterans Affairs Medical Center, Sepulveda; and
Departments qf!fSNeitrologyand §Pediatrics, and 11 Brain Research Institute,
UCLA School of Medicine, Los Angeles, Caljfornia, U.S.A.
Summary: Human status epilepticus (SE) is consistently
associated with cognitive problems, and with widespread
neuronal necrosis in hippocampus and other brain regions.
In animal models, convulsive SE causes extensive neuronal
necrosis. Nonconvulsive SE in adult animals also leads to
widespread neuronal necrosis in vulnerable regions, although
lesions develop more slowly than they would in the presence
of convulsions or anoxia. In very young rats, nonconvulsive
normoxic SE spares hippocampal pyramidal cells, but other
types of neurons may not show the same resistance, and inhibition of brain growth, DNA and protein synthesis, and of
myelin formation and of synaptogenesis may lead to altered
brain development. Lesions induced by SE may be epileptogenic by leading to misdirected regeneration. In SE, glutamate, aspartate, and acetylcholine play major roles as excitatory neurotransmitters, and GABA is the dominant
inhibitory neurotransmitter. GABA metabolism in substantia
nigra (SN) plays a key role in seizure arrest. When seizures
stop, a major increase in GABA synthesis is seen in SN postictally. GABA synthesis in SN may fail in SE. Extrasynaptic
factors may also play an important role in seizure spread and
in maintaining SE. Glial immaturity, increased electrotonic
coupling, and SN immaturity facilitate SE development in
the immature brain. Major increases in cerebral blood flow
(CBF) protect the brain in early SE, but CBF falls in late SE
as blood pressure falters. At the same time, large increases
in cerebral metabolic rate for glucose and oxygen continue
throughout SE. Adenosine triphosphate (ATP) depletion and
lactate accumulation are associated with hypermetabolic
neuronal necrosis. Excitotoxic mechanisms mediated by both
N-methyl-D-aspartate (NMDA) and non-NMDA glutamate
receptors open ionic channels permeable to calcium and play
a major role in neuronal injury from SE. Hypoxia, systemic
lactic acidosis, C 0 2 narcosis, hyperkalemia, hypoglycemia,
shock, cardiac arrhythmias, pulmonary edema, acute renal
tubular necrosis, high output failure, aspiration pneumonia,
hyperpyrexia, blood leukocytosis and CSF pleocytosis are
‘common and potentially serious complications of SE. Our
improved understanding of the pathophysiology of brain
damage in SE should lead to further improvement in treatment and outcome. Key Words: Status epilepticus-Seizures- Epilepsy-Necrosis-Neurons.
Status epilepticus&) is a neurologic emergency that
may rapidly lead to brain damage or death. Drawing
general conclusions from studies of SE has been difficult
because of differing definitions of duration, clinical
presentation, and the association of SE with other epileptic syndromes.
to produce an unvarying and enduring epileptic condition” (Gastaut, 1973). The minimum duration necessary for a diagnosis of SE is not specified in this definition and thus duration as a criterion for inclusion
into clinical studies has been an arbitrary distinction.
There is a gray area between a prolonged generalized
tonic-clonic seizure and major motor SE. Many studies
use as a definition a period of continuous seizure activity lasting at least 1 h or repeated seizures without
a return to normal consciousness between convulsive
attacks. Some studies use 30 min as the minimum time
for a diagnosis of SE and others use no specific duration
but refer to descriptions such as “prolonged seizures’’
or “greater than two successive seizures.” Because the
degree of brain damage can increase with the duration
of the seizure, it is likely that the tendency to accept
DEFINITION OF SE
The definition of SE in the World Health Organization’s Dictionary of epilepsy is “a condition characterized by an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as
Address correspondence and reprint requests to Dr. C. G . Wasterlain at Neurology Service ( 1 27). VA Medical Center, 16 I 1 I Plummer Street, Sepulveda, CA 9 1343, U.S.A.
s3 7
S38
C. G. WASTERLAIN ET AL.
shorter durations and fewer seizures in the definition
of SE is in part responsible for the more benign outcomes reported recently (Aicardi and Chevrie,
1970,1983; Chevrie and Aicardi, 1978; Maytal et al.,
1989).
CLINICAL TYPES OF SE
There are as many types of SE as there are types of
seizures. It is clear that major motor SE can lead to
permanent pathological damage and altered physiological function in certain brain regions. The pathophysiological changes seen in complex partial, simple
partial, and absence SE are much less clear. In complex
partial SE, intellectual sequelae have been documented
(Treiman and Delgado-Escueta, 1983), but there is a
paucity of neuropathological data. The outcome of absence SE is quite controversial (Doose, 1983). Epilepsia
partialis continua is universally accepted as having a
very benign prognosis, and by definition does not
spread to other brain areas, yet in children is often a
symptom of serious, progressive brain disease. Even in
adults it is occasionally followed by a Todd-like loss
of motor function in the involved territory, and there
is no documentation of the fate of motor neurons in
the affected cortex.
NEUROLOGICAL SEQUELAE OF SE
SE can cause brain damage, but can also result from
it, and it has been difficult to separate the two, particularly in humans. Scholz (1959) described “post-ictal
brain damage” that could be attributed to the convulsion itself. Aminoff and Simon ( 1980)documented the
severe clinical sequel e associated with SE in the modern era. They found Jt at 28 of their 98 patients experiencing generalized major motor SE had serious outcomes. Of those, only 10 had sequelae that were clearly
related to SE itself. Two patients died, six developed
diffuse encephalopathy with “varying degrees of intellectual impairment,” and two developed cerebral atrophy on computed tomography scans with spastic
quadriparesis in one. Of the six patients, with permanent clinical sequelae, SE lasted more than 2 h in five.
Of the group that made a complete recovery, only 9
of 49 had seizures lasting for more than 2 h.
PATHOLOGIC FINDINGS IN SE
Human studies
In the first report of brain damage in patients with
epileptic seizures, Bouchet and Cazauvielh ( 1825) presented findings on 18 autopsied patients. Eight had
hippocampal abnormalities by gross inspection (six had
hippocampal sclerosis and two had hippocampal softening). Four of the 18 patients had cerebellar softening.
Epilepsia. Vol. 34. Suppl. 1. 1993
The first detailed description of the neuropathological findings in the brains of epileptic patients was published over 100 years ago (Sommer, 1880). In that
study, Sommer described the pattern of damage in the
hippocampus called Ammon’s horn sclerosis (AHS),
sometimes referred to as hippocampal sclerosis, which
is characterized by a loss of the CA 1 subpopulation of
hippocampal pyramidal cells. This landmark paper focused subsequent studies of the neuroanatomical substrates involved in epilepsy on the hippocampus and
anatomically related structures of the limbic system.
The pattern of damage described by Sommer has been
found with some modifications (less selectivity, greater
CA3 damage) in the brain of many chronic epileptic
patients and in those having experienced prolonged
SE. Controversy has continued since the first description of AHS as to whether this pattern of damage is
the cause of epilepsy or its result (Meldrum and Corsellis, 1984). Sommer believed that the sclerotic lesion
was unequivocally the causal factor for epilepsy. Pfleger
described in the same year ( 1880)the presence of hemorrhagic lesions in the mesial temporal lobes of patients
dying shortly after SE. Hi: attributed the resulting neuronal necrosis to metabolic or local circulatory disturbances caused by the seizures (Pfleger, 1880).
Norman ( 1964) described the postmortem findings
in 1 1 children, ages 1 to 6 years, after episodes of SE.
The principal histologic lesion was seen in neurons and
consisted of the “ischemic nerve cell change” described
by Spielmeyer ( 1927). This pathological change was
characterized by eosinophilia on hematoxylin and eosin
staining. The cell bodies were narrowly triangular, except in the thalamus, where they were more rounded
and shrunken. The nuclei were strongly basophilic and
triangular in shape. Norman (1964) found that the
Sommer sector (H 1 or CA 1) was “always involved”
and the end folium (H3-H5 or CA3 and dentate hilus)
was “frequently affected.” However, H2 (CA2), “the
resistant sector,” was preserved in every case. Of the
11 patients, 9 had ischemic neuronal change in the
thalamus, 6 in the amygdala, 5 in the striatum, and 5
in the cerebellum.
Margerison and Corsellis ( 1966) found AHS in 6575% of patients with temporal lobe epilepsy. Based on
the patterns of damage that they saw, they proposed
two different types of AHS. The classical type showed
loss of neurons in the H1 sector and the end folium
type showed neuronal loss in H 1 (CA 1) and H3 (CA3)
in addition to a lesser degree of loss of granule cells
(Fig. 1).
More recently, Corsellis and Bruton (1983) examined
the brains of 20 patients who died during or shortly
after an attack of SE. The most vulnerable part of the
brain was the hippocampus. Some brains showed the
PA THOPH YSIOLOG Y OF STA TUS EPILEPTICUS
s39
FIG. 1. Resected human temporal lobes showing (a) a normal hippocampal formation, (b) classical Ammon’s horn sclerosis (cell loss in
H1 and H3. sparing H2), (c)total hippocampal sclerosis, and (d)end-folium sclerosis (cell loss in H3 and dentate hilar cells only). Reproduced
from Bruton (1988) with permission.
presence of acute cerebral chang4, characterized by an
“almost complete loss of neurons in the Sommer sector.’’ These acute changes contrasted with the chronic
changes of classical hippocam pal sclerosis characterized
by “scar tissue” and atrophy. In all six patients who
died in infancy, there were acute cerebral changes. The
two adolescent children showed no acute changes. Of
the 12 adults, 3 of the 5 classified in the symptomatic
epilepsy group had acute cerebral changes, whereas
only 2 of the 7 in the cryptogenic group showed the
acute changes. These authors also reported the presence
of damage to Purkinje cells in the cerebellum, and acute
neuronal necrosis of many cortical neurons, “particularly in the middle cortical layers,” as w’ell as damage
in the thalamus and in some cases the corpus striatum.
One of us (D.G.F.) has reviewed the findings from
three patients who died 11-27 days after the onset of
nonconvulsive SE lasting from 2.5 h to 3 days (unpublished observations). None of the three had preexisting epilepsy and all had systemic variables monitored carefully because the onset of SE occurred in
the hospital. In all three, SE caused neuronal loss in
the hippocampus (CA 1-CA3 and hilus), amygdala,
piriform cortex, dorsomedial thalamic nucleus, cerebellum, and cerebral cortex, despite an absence of con-
vulsive seizure activity. The spatial distribution of the
damage was strikingly similar to that produced by animal models of limbic SE, in which damage occurs
primarily in interconnected limbic structures with high
densities of glutamate receptors (see next section and
sections on “Excitotoxic mechanisms” and “Excitotoxic neuronal injury is calcium-mediated”). These
patients, all of whom were treated vigorously (one required pentobarbital anesthesia for 4 days), underscore
the importance of stopping electrographic seizure activity quickly, even in cases of nonconvulsive SE, to
avoid widespread, irreversible neuronal damage.
Animal models of SE
Extensive data from animal models show that convulsions greatly accelerate brain damage, but that the
latter can result from nonconvulsive focal or generalized seizures.
Convulsive, tonic-clonic SE rapidly leads to severe
brain damage
In adolescent baboons with convulsions, the classical
studies of Meldrum and co-workers showed that
bicuculline-induced SE was associated with fever, hypotension, hypoxia, and acidosis (Meldrum and Horton, 1973) (also, see the section on “Systemic compliEpilepsia, Vol. 34. Suppl. I . 1993
S40
C. G. WASTERLAIN ET AL.
cations of SE” for a discussion of these factors). Extensive neuronal necrosis was found in the neocortex,
hippocampus, amygdala, thalamus (occasionally), and
cerebellum (the latter was related to fever and shock,
not to the seizures) (Meldrum and Brierley, 1973).
Generalized SE in nonconvulsive, well-oxygenated
animals produces brain damage
Paralyzed, 02-ventilated baboons with electrographic
seizure discharges for over 3 h showed neuronal necrosis in the neocortex and hippocampus, proving that
electrographic seizures can damage the brain in the
absence of behavioral convulsions and systemic complications (Meldrum et al., 1973). Similarly, flurothylinduced seizures in 02-ventilated rats produced brain
lesions, including “hypermetabolic” infarction of the
substantia nigra (Nevander et al., 1985). These experimental data imply that the treatment of SE should
not simply aim at controlling convulsions, but should
also stop electrographic seizure discharges, since the
latter is capable of inducing significant brain damage.
Focal seizures can induce neuronal necrosis
Focal penicillin seizures in the &ex cause distant
thalamic lesions in synaptically connected sites (Collins
and Olney, 1982), probably by an excitotoxic mechanism (Clifford et al., 1989). Electrical stimulation of
the perforant path for 2-24 h leads to ipsilateral necrosis
of hilar interneurons and CA3 pyramidal cells (Sloviter,
1983). This necrosis closely resembles that caused by
intraventricular injection of glutamate or aspartate
(Sloviter and Dempster, 1985). These results suggest
that endogenous glutamate and/or aspartate release
may be responsible for seizure-induced damage and
that overstimulation alone injures glutamatoreceptive
neurons.
Limbic seizures also cause brain lesions
Limbic SE can be induced by kainic acid (Olney et
al., 1974), cholinomimetics (Honchar et al., 1983; 01ney et al., 1983a; Turski et al., 1983), and other methods (McIntyre et al., 1982,1986; Buterbaugh et al.,
1986; Strain and Tasker, 199 1). Limbtc SE causes neuronal necrosis in the hippocampus, amygdala, piriform
cortex, entorhinal cortex, lateral septum, thalamus,
neocortex, and substantia nigra. The neuronal damage
depends on synaptic activation (Ben-An, 1985), probably via a glutamatergic, calcium-mediated mechanism
(see the sections on “Excitotoxic mechanisms” and
“Excitotoxic neuronal injury is calcium-mediated’’ for
details).
Selective vulnerability in SE
Some neurons are highly vulnerable to damage from
SE (e.g., CAI and CA3 pyramidal cells and dentate
Epilepsia, Vol. 34, Suppl. 1. 1993
hilar neurons), whereas others are relatively resistant
(e.g., CA2 neurons and dentate gyrus granule cells).
The biochemical basis of these differences in vulnerability varies with the cell type, physiological properties,
membrane and cytoplasmic proteins, and stage of
development.
Vulnerability is influenced by the type of
neurotransmitter receptors on the cell membrane
CA3 pyramidal cells are very vulnerable to seizureinduced damage in humans (Mouritzen-Dam, 1980)
and in animal models of SE (see the section on “Animal
models of SE”). Their vulnerability to kainic acidinduced seizures is very low at birth in the rat and
appears with the ontogenetic development of kainate
receptors on their membranes (Ben-Ari, 1985).
N-methyl-D-aspartate (NMDA) receptors mediate
excitotoxic neuronal injury (see the sections on “Excitotoxic mechanisms” and “Excitotoxic neuronal injury is calcium-mediated”) and are abundant on vulnerable CAI neurons (Monaghan et al., 1989). SEresistant dentate granule cells also have abundant
NMDA receptors, but they may be able to survive calcium influx better than CA l neurons because their cytoplasm contains large amounts of the calcium-binding
protein calbindin D28K (Wasterlain et al., 1990).
Metabolic factors correlate with vulnerability
Brain regions with the highest metabolic rates during
SE are prone to neuronal necrosis (Ingvar and Siesjo,
1990). Other metabolic factors, such as lactic acid accumulation during SE, also correlate with vulnerability
(Ingvar et al., 1987).
SpeciJic neuronal types are selectively
vulnerable in SE
In many models of SE, including kainic acid, cholinergic, electrical, and other types of chemical or mixed
SE, and in human brain, a predictable hierarchy of
vulnerability is seen: somatostatin-containing hilar interneurons > CA3 neurons > CA1 neurons > dentate
granule cells > GABA- or GAD-containing neurons
(Ben-An, 1985; Sloviter, 1987; Babb et al., 1989).
Misdirected regeneration may explain the
epileptogenicity of SE-induced lesions
Lesions of vulnerable neurons during SE denervate
their target zones, and regenerative efforts by surviving
neurons can result in misdirected circuitry, which either
enhances excitation or reduces inhibition in specific
regions. The “granule cell” and the “dormant basket
cell” hypotheses (Sutula et al., 1989; Sloviter, 1991)
were proposed to explain the reason that “seizures beget
seizures,” based on such modifications of hippocampal
circuitry.
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”).
S41
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
S42
C. G. WASTERLAIN E T AL.
understood. Nitric oxide is a major vasodilator of cerebral vessels, but its exact role and that of direct innervation of the cerebral vasculature by cerebral neurons remain uncertain.
Early increases in CBF protect the brain
The onset of seizure activity abolishes the autoregulation of CBF, which becomes pressure-dependent
(Posner et al., 1968; Meldrum and Nilsson, 1976;
Ingvar and Siesjo, 1983). Because SE raises the systemic
blood pressure to extremely high levels, this results in
large increases in CBF, delivering more oxygen and
glucose to the brain .
Late changes in CBF are detrimental
Late in the course of SE, the blood pressure falls
progressively, for a multitude of reasons: severe lactic
acidosis may develop and decrease the responsiveness
of peripheral vessels to circulating catecholamines; the
levels of catecholamines themselves may fall; and peripheral catecholamine receptors may get desensitized
(Wasterlain, 1974; Morin and Wasterlain, 1983). The
CBF, which is now pressure-dependent, falls witiil6e
blood pressure, reducing the supply of glucose and oxygen to the brain (Meldrum and Nilsson, 1976; Ingvar
and Siesjo, 1990).
Changes in brain metabolism during SE
We lack the space to review the extensive and elegant
work done in this area. We can only illustrate a few
basic principles.
SE causes large increases in cerebral metabolic rate
for glucose and oxygen
The largest increases in cerebral metabolic rate that
can be measured occur during SE (Chapman et al.,
1977). It is likely that the bulk of the increase in metabolic rate is used for ionic pumping across membranes
that repolarize repeatedly during seizures. The increase
in glycolysis is usually slightly greater than the increase
in respiration, resulting in rises in brain lactate concentration.
Neuronal necrosisfrom SE is associated with
moderate falls in ATP
Even in longlasting SE, as long as histological
changes are largely reversible, only minimal falls in
ATP and energy reserves are seen (DuEy et al., 1975;
Meldrum and Nilsson, 1976; Chapman et al., 1977;
Folbergrovi et al., 1981). The regions in which SE leads
to neuronal necrosis invariably show significant falls
in ATP and energy reserves (Howse, 1983; Ingvar et
al., 1987). The role of moderate energy failure in cell
injury is not known. It could limit neuronal reuptake
of excitatory amino acid transmitters and glial uptake
of the same compounds, and impair the function of
Epilepsia, Vol. 34, Suppl. I. 1993
the calcium pump or calcium-sodium exchange
through inhibition of the sodium pump. All of these
factors would eventually result in a decreased ability
of the cell to lower its cytoplasmic free calcium (see
the section on “Excitotoxic neuronal injury is calciummediated”).
Hypermetabolic necrosis is associated with lactate
accumulation
Hurothyl-induced SE in well-oxygenated rats leads
to necrosis of the substantia nigra, associated with the
accumulation of large amounts of lactic acid, which
may be instrumental in the infarction of that brain
region (Ingvar et al., 1987).
The transition from early to late SE is often one from
adaptive to maladaptive mechanisms
During a single nonconvulsive seizure, increases in
CBF more than compensate for the increased metabolic
needs of the brain (Posner et al., 1969). After a variable
period, generally between 30 and 120 min, maladaptive
changes tend to develop, such as a mismatch between
blood flow and glucose utilization (Ingvar and Siesjo,
1983), self-sustaining Seizures (Wasterlain, 1974), fall
in blood pressure, and inability of the brain to utilize
available oxygen (Kreisman et al., 1983). Protein synthesis becomes profoundly inhibited (Dwyer anti Wasterlain, 1984) and histological changes begin to appear.
MECHANISMS OF NEURONAL INJURY
Excitotoxic mechanisms
Recent interest concerning mechanisms of neuronal
damage from a variety of causes has focused on the
role played by the excitatory amino acid transmitter
glutamate. The excitatory effect of glutamate on central
neurons has been known for years (Hayashi, 1954;
Curtis and Watkins, 1960), as has its potential neurotoxic effect (Lucas and Newhouse, 1957; Olney,
1969). During the 1970s, Olney and his collaborators
(1974, 1979) studied the neurotoxic effects of exogenous administration of glutamate analogues in vivo
and in the in vitro chick embryo retinal preparation.
The most extensively studied of these analogues, kainic
acid, was found to damage limbic structures primarily
and to do this by inducing limbic SE in the rat (BenA n et al., 1980; Schv.rob et al., 1980; Lothman and
Collins, 1981).
Glutamate-induced neuronal injury resembles SEinduced injury
Ultrastructural studies revealed that administration
of glutamate and its analogues was associated with
marked swelling of neuronal dendrites and cell bodies,
sparing adjacent axons and presynaptic nerve terminals
(Olney, 1971; Olney et al., 1971). Similar electron-mi-
PA THOPH YSIOLOG Y O F STA TUS EPILEPTICUS
croscopic findings following seizures were produced by
the structural glutamate analogue, kainic acid (Olney
et al., 1979), by continuous electrical stimulation of
the perforant path for 2 h (Olney et al., 1983b), by
repeated intraventricular injections of glutamate or aspartate for 1 h (Sloviter and Dempster, 1985) and by
the muscarinic cholinergic agonist, pilocarpine, given
alone or in combination with lithium chloride (Clifford
et al., 1987). At the light-microscopic level, a similar
distribution of neuronal damage (limited primarily to
limbic structures) was found from seizures induced by
kainate (Olney et al., 1979;Ben-An et al., 1980;Schwob
et al., 1980; Lothman and Collins, 1981), and by pilocarpine or lithium/pilocarpine (Honchar et al., 198
Turski et al., 1983;Clifford et al., 1987). These findi gs
have led to the hypothesis that excessive amounts of
glutamate and aspartate are released during limbic SE
and that this results in neuronal damage (Olney et al.,
1983a.b; Olney, 1985; Sloviter and Dempster, 1985).
2
Five subtypes of the glutamate receptor have been
described to date
Interest in excitotoxic mechanisms of brain damage
was accelerated by the development of antagonists to
glutamate analogues, which are ligands that bind to
different subtypes of the glutamate receptor. This permitted the identification of specific receptor subtypes
that mediate not only normal electrophysiological responses to activation by specific agonists, but also increased activation of these receptors by a hypothesized
excessive release of the endogenous ligand, most likely
glutamate, as might occur during SE.
To date, five excitatory amino acid receptor
subtypes have been described, based upon radioligand binding or the depolarizing effects of the following agonists: NMDA, kainate, a-amino-3hydroxy-5-methylisoxazole-4-propionic
acid (AMPA),
L-2-amino-4-phosphonobutyrate(AP4), aqd trans- 1aminocyclopentane- I ,3-dicarboxylic acid (ACPD)
(Monaghan et al., 1989). Recent cDNA cloning and
base sequencing of non-NMDA ionotropic receptors
indicate that AMPA and kainate bind to different subunit classes of the cDNA-cloned non-NMDA type of
glutamate receptor (Hollman et al., 1989; Boulter et
al., 1990; Keinanen et al., 1990; Egebjerg et al., 1991;
Werner et al., 1991). This possibility is also supported
by pharmacologic data (Barnard and Henley, 1990).
AP4 may bind to an autoreceptor that acts presynaptically to inhibit glutamate release (Monaghan et al.,
1989). Activation of the ACPD receptor, also called
the metabotropic receptor, stimulates inositol polyphosphate (IP) metabolism, which has complex intracellular consequences (Monaghan et al., 1989). The
NMDA, AMPA, and kainate receptors enclose ion
'
s43
channels that are relatively specific for calcium
(NMDA) and sodium (AMPA and kainate), and have
consequently been referred to as ionotropic receptors.
By way of contrast, stimulation of the metabotropic
receptor activates the IP second essenger pathway
intracellularly, and through the fonration of IP3results
in the release of calcium into the cytoplasm from endoplasmic reticulum stores (Nahorski, 1988).
NMDA-receptor antagonists reduce brain damage
from SE
The NMDA receptor has been more extensively
studied than the other receptor subtypes, largely because potent and selective antagonists, such as 2-amino5-phosphonopentanoicacid (AP5) (Davies et al., 198l),
have been available for up to 10 years. When the competitive NMDA-receptor antagonist 2-amino-7-phosphonoheptanoic acid (AP7) is microinjected into the
amygdala, neurons are protected from SE-induced
damage, despite full 3-h pilocarpine-induced seizures
that damage neurons in other brain regions and in the
contralateral, buffer-injected amygdala (Fujikawa,
1988). Similarly, when AP-5 is injected into the ventricles superior to the hippocampus, CAI neuronal
damage induced by kainate seizures is ameliorated
(Lason et al., 1988). In addition, the noncompetitive
NMDA-receptor antagonists, ketamine and MK-80 1,
protect against damage from kainate- and pilocarpineinduced SE (Fariello et al., 1989; Fujikawa et al., 19893;
Hudson and Buterbaugh, 1989; Clifford et al., 1990;
' Fujikawa, 1990), and from bicuculline-induced focal
seizures (Clifford et al., 1989). It was found in all of
these studies that NMDA-receptor antagonists do not
eliminate electrographicseizure discharges, so the neuroprotective effect of these compounds occurs independently of an antiepileptic effect.
The expected increased glutamate in SE has been
dificult to document
The neurotoxic effect of exogenous glutamate and
aspartate and the neuroprotective effect of NMDA-receptor antagonistslend strong support to the hypothesis
that excessive presynaptic glutamate release during SE
is the cause of the selective postsynaptic neuronal necrosis that occurs. To test this hypothesis directly in
vivo, investigators have combined implantation of
small-diameter brain dialysis probes, which allow sampling from the extracellular space, with high-performance liquid chromatography (HPLC), to identify and
measure the dialysate concentrations of amino acids
(Ungerstedt et al., 1982; Benveniste, 1989). Studies of
two animal models of SE have failed to demonstrate
any elevations of extracellular glutamate or aspartate
in hippocampus or amygdala during seizures (Lehmann et al., 1985; Fujikawa and Cheung, 1991). HowEpilepsia, Vol. 34, Suppl. 1. 1993
s44
C. G. WASTERLAIN ET AL.
ever, intra-amygdala folate injection resulted in limbic
seizures in the rabbit and a 50-7596 increase in hippocampal glutamate during 2-h seizures (Lehmann,
1987). Soman-induced SE produced a slight increase
in extracellular glutamate in the piriform cortex (20%
above control levels) after 60-min seizures, but this was
not maintained thereafter during 4-h seizures (Wade
et al., 1987).However, none of the microdialysis studies
to date has provided histological confirmation of neuronal damage in the dialyzed area.
The lack of a significant and sustained rise in extracellular glutamate and aspartate during SE has been
attributed to efficient neuronal and astrocytic uptake
of these neurotransmitters, so that although the’ turnover probably increases, their concentration remain
relatively constant. Moreover, it is likely that average
extracellular concentrations of glutamate and/or aspartate do not reflect an increased release of these neurotransmitters at synaptic terminals, which in turn activates an increased number of postsynaptic receptors.
f
Excitotoxic neuronal injury is calcium-mediated
It was first shown in hepatocyte cultures that cell
death is dependent on the presence of extracellular calcium ([Ca”],) (Schanne et al., 1979). This led to the
hypothesis that intracellular calcium ([Ca2’],) accumulation causes cell death (Farber, 198l), possibly by
activating many Ca’+-dependent enzymes, such as
proteases and phospholipases, which can lead to cell
membrane breakdown, for example.
During pentylenetetrazol-induced seizures, there is
a 0.7 mM decrease in [Ca”], from baseline levels of
1.2- 1.5 mM in cat sensorimotor cortex, suggestingthat
seizures drive [Ca2+], into cells (Heinemann et al.,
1977). Calcium accumulates intracellularly in the mitochondria of CA1 neurons, in CA3 basal dendrites,
and in some CAI, CA3, and dentate hilar cell bodies
during 2 h of bicuculline- or L-allylglyqine-induced seizures (Griffithset al., 1983). However, the excess [Cazf]i
and acute dendrosomatic swelling produced by 1.5 h
of L-allylglycine-induced SE disappeared 60 min after
the seizures stopped, indicating that the seizure interval
was not long enough to result in irreversible damage
(Griffiths et al., 1984).
A recent autoradiographic study in the rat showed
that intravenously injected 45CaZ+
accumulates unilaterally in the hippocampal CA3 region, lateral septa1
nucleus, and thalamic reticular nucleus 2 h after ipsilateral intra-amygdala kainate injection, which induced
typical limbic seizures (Tanaka et al., 1989). The Ca”
accumulation preceded light microscopic evidence of
neuronal damage in the same brain regions, which was
found 4 h but not 2 h after kainate injection. 45Cais a
marker of total tissue Caz+ content, not [CaZ+],,and
I
Epilepsia. Vol. 34. Suppl. 1. 1993
45CaZ+
could simply leak into the brain at sites of bloodbrain bamer disruption. Nevertheless, this study shows
clearly that seizure-induced Ca2+accumulation occurs
in vulnerable brain regions hours before there is histological evidence of neuronal necrosis.
It was widely assumed until recently that the damaging effect of elevated [Ca2’Ii was brought about by
Ca2+ influx through voltage-operated Ca2+ channels
(VOCCs). However, excitatory amino acids increase
[Ca2+Ii-by activating NMDA receptors, thereby
opening NMDA-receptor-operated Ca2+channels (MacDermott et al., 1986). In addition, several investigators
showed in vitro that the neurotoxicity of excitatory amino
acids is dependent on the presence of [Ca2+],(Garthwaite
et al., 1986; Choi, 1987; Rothman et al., 1987). Calcium
entry through VOCCs appears to play a smaller role than
Ca” influx through receptor-operated channels in acute
glutamate neurotoxicity (Choi, 1987).
However, then is evidence that non-NMDA receptor
activation (ionotropic and metabotropic) is also necessary for glutamate-induced neuronal damage in cultured murine cortical neurons (Frandsen et al., 1989;
Koh et al., 1990; Frandsen and Schousboe, 1991).
Voltage-operated Ca2+channels may be the pathway
by which lethal Ca2+accumulation occurs in the “slow”
neurotoxicity brought about by activation of nonNMDA ionotropic receptors (Weiss et al., 1990).
There are some data that call into question the role
played by increased free cytosolic Ca2+in producing
neuronal death. For example, in one study, [Caz+Iiin
cultured hippocampal neurons following glutamate or
kainate exposure did not correlate well with eventual
survival (Michaels and Rothman, 1990). In addition,
the large increase in free cytosolic Ca2+brought about
by metabolic inhibition of cultured hippocampal neurons with sodium cyanide did not damage those neurons (Dubinsky and Rothman, 1991). This points out
the complicated nature of intracellular Ca2+homeostasis and how little we know about the precise mechanisms by which cell death occurs.
A current formulation of the excitotoxic hypothesis,
which is applicable to SE-induced neuronal damage,
is that excessive presynaptic release of glutamate activates both NMDA and non-NMDA postsynaptic receptors, the net result of which is Ca2+entry through
the NMDA-receptor-operated ion channel and release
of Ca2+from intracellular stores, elevating the intracellular CaZ+,which in turn activates Ca2+-dependent
enzymes that irreversibly damage neurons.
Changes in membrane lipids, free radicals, second
messengers, and protein kinases
SE induces major changes in membrane phospholipids, including massive increases in arachidonic acid
PA THOPH YSIOLOGY O F STA TUS EPILEPTICUS
s45
LI and either neuronal necrosis or survival. However,
concentrations (Bazan et al., 1983),diacylglycerol-melike Vass and co-workers ( I989), they found that a sediated activation of protein kinase C, calcium-mediated
changes in calmodulin kinase 11, and possibly generk r e l y damaged region, the substantia nigra, which undergoes hypermetabolic necrosis in this model, failed
ation of free radicals that could play an essential role
to show any HSP-LI. Thus, according to these invesin the mechanism of neuronal injury. Nitric oxide mediates the action of the excitatory neurotransmitter
tigators, the most that can be said at present is that
glutamate in stimulating cyclic GMP concentrations,
HSP72 is induced in neurons that undergo metabolic
which sustain massive increases in SE (Wasterlain and
stress; although it may be neuroprotective, there is at
I
Csiszar, 1980). Nitric oxide may play a role in gluta- - present no direct evidence that this is the case.
mate-induced oxidative damage to neuro% (Bredt et
SYSTEMIC COMPLICATIONS OF SE
al., 1991). Activation of the calcium-independent form
of calmodulin kinase I1 could mediate the prolonged
The presence of systemic complications, most of
toxic effects of evanescent increases in free calcium
which are associated with convulsive activity, is a major
concentrations and play a role in delayed neuronal
determinant of the prognosis of SE, and elimination
death (Bronstein et al., 1988).The precise role of these
of such complications is one of the primary goals of
factors in neuronal injury during SE, however, must
treatment.
still be elucidated.
Hypoxia
Changes in gene expression
The sustained contraction of the diaphragm during
Seizures induce immediate-early gene expression
the tonic phase of seizurescauses apnea and hypoxemia
Seizures and other stimuli induce rapid increases in
at a time of vastly increased cerebral oxygen (0,)dethe levels of mRNA and proteins that are encoded by
mand and of competition for the available 0, between
the immediate-early genes c-fos, c-jun, jun-B, and nerve
brain, cardiac muscle, and skeletal muscle. The regrowth factor I-A (NGFI-A) (Gall et al., 1990; Morgan
sulting decrease in 0, availability to the brain is a major
and Curran, 199I). In kainate-induced seizures, for exfactor in mortality and morbidity. In a typical experample, c-fos-like proteins are expressed at seizure onset
iment, 10 rats subjected to 30 consecutive electroconfirst in the dentate gyms and then other limbic strucvulsive seizures died, but none of the 10 controls
tures; c-fos-like immunoreactivity declines to control
shocked the same way but paralyzed and ventilated
levels 48 h after kainate injection (Popovici et al., 1990).
with O2died (Wasterlain, 1974).In the classical studies
The proteins expressed may mediate the regulation of
of Meldrum and collaborators, maintaining juvenile
the neuropeptide genes for enkephalin, dynorphin,
baboons on the respirator during SE reduced mortality
cholecytokinin, and neuropeptide Y, which are differand brain damage (Meldrum and Brierley, 1973;
entially affected in the hippocampus by seizure activity
Meldrum et al., 1973). This is the reason that the first
(Gall et al., 1990). The significance of the c-fos-like
goal of treatment of SE must be to maintain or restore
protein expression and neuropeptide regulation is at
oxygen delivery to the brain by attending to respiration
present unknown. However, by changing the patterns
and blood pressure, before treating the seizures.
of gene expression, seizures could induce both transient
Lactic acidosis
and longer-term adaptive changes in the brain regions
In convulsive SE, a combination of hypoxia and inactivated by seizures.
tense muscular contractions liberates large amounts of
Heat shock proteins are expressed in response to SE
lactic acid from the muscles, resulting in some patients
SE also induces the synthesis of a 72-kDa heat shock
in profound metabolic acidosis, which can be lifeprotein (HSP72) (Vass et al., 1989; Lowenstein et al.,
threatening. In one series of SE, one-quarter of the pa1990). Vass and colleagues (1989) found that HSP72
tients had an arterial pH below 7.0 and values as low
is expressed primarily in limbic system neurons that
as 6.18 were observed (Aminoff and Simon, 1980). Exsurvive kainate-induced SE. Neurons with histological
perimental studies have already documented the fact
evidence of damage did not express HSP72. Heat shock
that profound metabolic acidosis is accompanied by
protein expression is longer lasting than that of c-fos
hypotension and shock, and that its correction with
protein; it was still present in most brain regions 5 days
bicarbonate delays or prevents shock and the failure
after kainate injection.
of CBF associated with it (Wasterlain, 1974). This is
In flurothyl-induced SE, many of the brain regions
the reason that most reviews of SE recommend obtaining arterial blood gases routinely in SE (Brown and
that are vulnerable to neuronal damage showed HSP72Hussain, I99 1) and treating severe metabolic acidosis
like immunoreactivity (HSP-LI) (Lowenstein et al.,
(pH c 7) by injecting 100 mEq of bicarbonate, followed
1990). Lowenstein and colleagues ( 1990) suggest that
there is not a one-to-one correspondencebetween HSPby further checks on blood gases.
Epilepsia, Vol. 34. Suppi. I . I993
S46
C. G. WASTERLAIN ET AL.
C 0 2 narcosis
An elevated carbon dioxide (CO,) tension is common in SE. Occasionally, patients can retain C 0 2 to
such an extent that respiratory acidosis and C 0 2 narcosis become life threatening. In one series, 13 of 18
patients in SE had C 0 2 tensions exceeding 60 mm Hg
(Aminoff and Simon, 1980). Carbon dioxide narcosis
has been documented in rats in experimental SE (Wasterlain, 1974).
H yperkalemia
During SE, muscular contractions can be so intense
as to cause rhabdomyolysis, liberating large amounts
of potassium and occasionally causing life-threatening
hyperkalemia (Glaser, 1983).
Hypoglycemia
Seizures stimulate autonomic neurons and result in
a massive neurogenic release of both insulin and glucagon (Meldrum et al., 1979). At the same time, the
release of large amounts of circulating catecholamines
elevates cyclic AMP in the liver, resulting in marked
stimulation of glycogenolysis. The net result in the early
phases of seizures is hyperglycemia. During prolonged
seizures, particularly in patients with hepatic damage
or poor glycogen stores (e.g., neonates), the hyperinsulinemia can result in profound hypoglycemia. Some
experimental studies have actually suggested that such
hypoglycemia can lesse; cerebral damage from SE
(Blennow et al., 1978, 1979), but these findings are
controversial. The possibility that hypoglycemia, by
further reducing energy stores, might add to excitotoxic
damage during SE should not be underestimated.
Early hypertension, late shock
Seizures invariably result in marked arterial hypertension, which is abolished by cord transection and
depends in part on a massive increase in adrenal output
of catecholamines and steroids (Posner et al., 1968;
Meldrum et al., 1979). This hypertension can occasionally reach levels close to those of hypertensive encephalopathy (Brown and Hussain, 199 1). It is usually
accompanied by a rise in intracranial pressure. In infants or children under sedation or curarization, this
rise in blood pressure, together with pupillary dilation
and tachycardia, may be the main features suggesting
a seizure. Since seizures abolish autoregulation of CBF,
such hypertension protects the brain by improving the
delivery of glucose and oxygen (Posner et al., 1968).
However, in prolonged SE, profound lactic acidosis is
associated with progressive arterial hypotension, which
can be partially corrected by correcting the acidosis
(Wasterlain, 1974). When the blood pressure falls, the
CBF, which is now pressure-dependent, falls with it
(Wasterlain, 1981). In other words, the same mechaEpilepsia. Vol. 34, Suppl. I , 1993
nisms that protected the brain against single seizures
have now b e c p e a liability in the presence of circulatory failure associated with the late phases of SE. It
is possible that desensitization of catecholamine receptors may also play a role in these late circulatory
changes (Morin and Wasterlain, 1983).
Cardiac arrhythmias
The simultaneous stimulation of sympathetic and
parasympathetic nerves in the hypoxic myocardium
creates a favorable setting for the development of ventricular arrhythmias, which are frequently observed in
experimental SE (Wasterlain, 1974) and are the presumed cause of death in young epileptic persons (Lathers and Schrader, 1982).
Pulmonary edema
Pulmonary hypertension can reach such high levels
that it exceeds the oncotic pressure of the blood, and
also causes a stretch injury to the capillaries, so that
the resulting pulmonary edema can either be an exudate, a transudate, or both (Simon et al., 1982). Pulmonary edema is a routine finding in young epileptic
persons who die during seizures.
Acute tubular necrosis
The intensity of muscular contractions can cause
rhabdomyolysis, and the leaky muscle membrane releases several proteins. Large amounts of myoglobin
can be detected in the urine, and can cause acute tubular necrosis (Penn et al., 1972). Creatine phosphokinase can be elevated 100-fold in blood and can also
be markedly elevated in spinal fluid (Brown and Hussain, 1991).
High-output failure
A large increase in blood pressure and cardiac output
can result in congestive failure in susceptible patients,
and can contribute to pulmonary edema as well.
Aspiration pneumonia
Autonomic stimulation can result in a large increase
in salivation and in tracheal and pulmonary secretions,
and reflux of vomitus into the airway is common, resulting in aspiration pneumonia.
H yperpyrexia
Increased muscle activity produces large amounts of
heat, and fever can reach fatal levels in the absence of
infection (Wasterlain, 1974; Glaser, 1983; Meldrum,
1983).
Leukocytosis and CSF pleocytosis
Elevated white cell counts up to 20,000/mm3 are
common even in the absence of infection. Spinal fluid
pleocytosis rarely exceeds 1OO/mm3 and is usually
transient (less than 24 h) (Aminoff and Simon, 1980).
PA THOPHYSIOLOGY OF STATUS EPILEPTICUS
Other autonomic symptoms
Vomiting, electrolyte and fluid loss, detrusor muscle
contraction resulting in urinary incontinence, fecal incontinence, increased sweating, salivation, and tracheobronchial secretions are commonly seen.
PATHOPHYSIOLOGY OF BRAIN DAMAGE
IN NEONATAL S E
Some factors that play a major role in brain damage
in adult SE are not present in the immature brain
(Tremblay et al., 1984; Represa et al., 1986). The
unique metabolic needs of the neonate and the immaturity of the blood-brain bamer (Wasterlain and
Duffy, 1976; Fujikawa et al., 1990) result in a set of
vulnerabilities unique to the neonate. The general rule
that the immature brain is not simply a small version
of the adult brain, but a different organ with unique
sets of pathophysiological mechanisms, certainly holds
true when applied to brain damage from neonatal SE.
Cerebral blood flow and metabolism in neonatal SE
Autoregulation of CBF is present at birth in most
species, including humans (Wagerle and DelivoriaPapadopoulos, 1990). The arterial hypertension and
increased CBF associated with seizure activity in the
adult are also seen in many experimental models of
neonatal seizures, and possibly in humans (Monin et
al., 1990; Wagerle and Delivoria-Papdopoulos, 1990).
Increases in local CBF were obseked during focal penicillin seizures in newborn macaque monkeys (Hosokawa et al., 1977), generalized seizures in newborn dogs
(Young et al., 1985) and piglets (Clozel et al., 1985;
Park et al., 1987; Monin et al., 1990), and were observed by positron emission tomography (PET) in an
asphyxiated human infant during a focal motor seizure
(Perlman et al., 1985). On the other hand, studies of
bicuculline-induced seizures in newborn marmoset
monkeys showed large increases in brainstem blood
flow but little or no increase in forebrain structures
(Fujikawa et al., 1986,1990). At the same time, there
is a large (two- to sixfold) increase in the glucose metabolic rate during seizures in most brain regions of the
neonate, including the cortex, in spite of its immaturity
(Fujikawa et al., 1989a 1990). During generalized seizures in marmosets, and to a lesser extent during focal
seizures in newborn macaques, this creates a mismatch
between blood flow and glucose utilization in the cortex
and hippocampus. This mismatch is associated with
profound inhibition of protein synthesis (Dwyer et al.,
1986), suggesting that it might play a role in the longterm effects of seizures on brain development. Whether
or not a similar mismatch occurs in humans has not
been established. In the marmoset, it is unique to neonates and disappears by the age of 2 months.
s4 7
Energy reserves during SE
Sacktor et al. (1966) found a decrease in energy reserves in freely convulsing 10-day-old mice. Wasterlain
and Duffy ( 1976) found no progressive decline in ATP
in SE in 4-day-old rats, but the animals were frozen
after the end of the seizures. Young and colleagues
(1989, using 31PNMR spectroscopy in newborn dogs
that were paralyzed and ventilated with oxygen during
bicuculline-induced SE, found significant decreases in
phosphocreatine (PCr), but minimal changes in ATP.
In a neonatal model of bicuculline-induced SE in the
marmoset monkey in which no hypoxemia nor hypotension occurred, marked depletions of PCr and
ATP, a profound depletion of glucose, and a marked
rise in lactate were seen in the neocortex (Fujikawa et
al., 1988). In a study of human neonates with convulsions in which 31PNMR spectroscopy was used, cerebral hemispheric PCr-Pi ratios were greater than two
standard deviations below the mean (Younkin et al.,
1986). In one infant, the ATP values of the hem'sphere
with seizure discharges were 40% of the V a l 4 of the
contralateral hemisphere without seizure activity.
However, when interpreting the results, one must take
into account the complexity of clinical situations and
the presence of previous asphyqia in those infants.
Nevertheless, taken together, the data suggest that in
at least some models of neonatal SE, and possibly in
human SE associated with neonatal asphyxia, depletion
of energy reserves does take place and may play a significant role in the genesis of brain damage associated
with seizures.
Glucose transport
In newborn rats (Wasterlain and Duffy, 1976), rabbits (Dwyer and Wasterlain, 1985), and monkeys
(Dwyer and Wasterlain, 1985; Fujikawa et al., 1988),
brain glucose falls rapidly after the onset of seizures in
spite of normal or elevated concentrations of blood
glucose. This phenomenon, which is unique to the neonate, results in calculated intracellular glucose concentrations that are often near zero. Tight junctions
are fully mature at birth in most species, and glucose
enters the brain almost entirely by facilitated transport,
to the exclusion of diffusion. The capacity of the immature blood-brain bamer for glucose transport in
newborn rats is at most 20% that of the adult (Growdon
et al., 1971; Moore et al., 197 1). The concentration of
the glucose transporter molecule, measured by cytochalasin B binding, was 1.9 pmol/mg of protein in
newborn rat cortex compared to 8.9 pmol/mg of protein in adult cortex (Morin et al., 1988). This lower
transporter concentration in the immature blood-brain
barrier and in neuronal membranes (Cremer et al.,
1979; Morin et al., 1988) appears to limit the capacity
Eprlepsia, Vol. 34. Suppl. 1. 1993
S48
C. G . WASTERLAIN E T AL.
of glucose transport in neonates to keep up with glycolytic rates increased by seizures (Fujikawa et al.,
1989a).
Lactate transport
In adult SE, hypermetabolic infarction of the substantia nigra is associated with lactic acid concentrations in excess of 20 mM(1ngvar et al., 1987). Similar
degrees of lactic acid accumulation, which is lethal for
both neurons and glia (Kraig et al., 1987; Nedergaard
et al., 199l), are not seen in the brain during neonatal
SE (Sacktor et al., 1966; Dwyer and Wasterlain, 1985;
Fujikawa et al., 1988). In fact, hyperglycemia reduces
the mortality and developmental effects of SE in newborn rats (Wasterlain and Duffy, 1976). This is probably due to the large amounts of monocarboxylic acid
camer present in the blood-brain bamer of suckling
animals, which easily transport lactate from brain to
blood (Cremer et al., 1979).As a result, lactic acid does
not accumulate to toxic concentrations in the immature brain during SE.
Excitotoxic mechanisms
Some excitotoxic mechanisms are not present in
neonates
In adult rats, kainate-induced SE produces extensive
damage to CA3 hippocampal neurons, which have numerous kainate receptors (Lothman and Collins, 1981).
In neonates, no CA3 lesiois are seen following kainateinduced SE (Nitecka et al., 1984). The appearance of
vulnerability of CA3 neurons to kainic acid seizures
coincides with the appearance of kainate receptors on
those cells (Campochiaro and Coyle, 1978; Berger et
al., 1984; Represa et al., 1986).
NMDA receptor concentrations and NMDP
vulnerability may peak in early postnatal life
In humans as well as in the rat (Barks et al., 1988),
NMDA and AMPA receptors are abundant at birth.
Their concentrations in rat cortex at postnatal day 7
and the size of the lesion induced by intracortical or
intrahippocampal injection of NMDA peak at the same
age (McDonald et al., 1988; Yang et al., 1989). Paradoxically, binding sites for the ionic channel associated
with NMDA receptors do not follow the same curve
(Morin et al., 1989).
Does neonatal SE produce excitotoxic damage?
SE in infants and children is often followed by cognitive-impairment (Aicardi and Chevrie, 1970,1983)
and cerebral atrophy and histological lesions (Fowler,
1957; Norman, 1964;Corsellis and Bruton, 1983),but
the incidence of serious complications may be decreasing (Maytal et al., 1989), and with clinical cases it is
often impossible to distinguish the effects of seizures
from those of the lesions that caused them. In experEpilepsia. Vol. 34, Suppl. I . I993
imental animals, in spite of the abundance of NMDA
receptors and of peak NMDA toxicity in neonates, no
established model of SE has resulted in excitotoxic-like
neuronal necrosis (Soderfeldt et al., 1990). The immaturity of the presynaptic apparatus may limit the
amount of glutamate released and therefore the excitotoxic injury. On the other hand, most studies have
not taken into account the lower metabolic rate of neonates and therefore the longer time that would be
expected in order for SE to produce brain damage
(Vannucci and Fujikawa, 1990). In fact, some of the
models of neonatal SE were designed to avoid neuronal
necrosis in order to observe the effect of seizures on
brain growth and development &!asterlain, 1976;
Wasterlain and Duffy, 1976). Prelisnary results in
our laboratory suggest that kainate- and flurothylinduced seizures in newborn monkeys may produce
some neuronal necrosis in neocortex and hippocampus
(unpublished findings). Thus, very immature neurons,
before they acquire receptors for excitatory amino acids, are resistant to seizure-induced damage. However,
although it is clear that NMDA and AMPA receptors
are abundant in the brains of many species, including
humans, during the perinatal period, and that the brain
at that age is quite vulnerable to exogenously administered excitatory amino acids, it is not clear whether
such damage occurs as the result of clinical or experimental neonatal seizures.
Effect of S E on brain growth and development
SE is deleterious to the brain in animals (Wasterlain,
1976;Wasterlain and D u e , 1976; Holmes et al., 1988)
and in humans (Aicardi and Chevrie, 1983), but the
significance of the association between uncontrolled
seizures and cognitive impairment is disputed (Bourgeois et al., 1983; Rodin et al., 1986). A single bout of
SE in 4-day-old rats inhibits brain growth and brain
protein synthesis and can result in a permanent reduction in brain size and brain cell number (Fig. 2)
even when those seizures do not induce any histological
damage (Wasterlain, 1976; Dwyer et al., 1986). In addition to inhibiting cell multiplication, seizures can reduce the accumulation of myelin (Dwyer and Wasterlain, 1982) and that of a variety of synaptic markers
(Jorgensen et al., 1980), suggesting that uncontrolled
seizures reduce the number of cell-to-cell connections.
In vitro, the outgrowth of axonal hippocampal growth
cones is regulated by NMDA receptors, and exposure
to excessive amounts of glutamate results in the influx
of large amounts of calcium into growth cones and in
the retraction or pruning and death of growth cones
(Mattson et al., 1988; Kater and Mills, 1991).It ispossible that such effects mediate the effect of seizures on
brain growth. If this is the case,it may have implications
s49
PA THOPHYSIOLOGY OF STATUS EPILEPTICUS
FIG. 2. Relationship between growth velocity curves for the rat brain and vulnerability of brain regions to status epilepticus (SE). After
day 4, cell multiplication declines rapidly in the forebrain but not in the cerebellum. SE-induced reduction of growth is greater in the
cerebellum (hatched bar, 31% reduction in cell number) than in the forebrain (dark bar, 18% reduction) 3 days after SE. However, the
cerebellum has erased that deficit by 30 days of age, whereas in the forebrain a significant deficit persists into adulthood (dark bar, 5%
of the number of cells in the forebrain). Reproduced from Wasterlain et at. (1990) with permission.
for the treatment (medical or surgical) of uncontrolled
seizures (even nonconvulsive) in the developing brain.
In any case, the animal models of neonatal SE demonstrate that uncontrolled seizures have the potential
of having permanent adverse effects on the brain even
when they do not cause neuronal necrosis.
CONCLUSIONS
This review of pathophysiological mechanisms leading to brain damage from SE serves both to measure
the enormous progress accomplished in the past 10
years in our understanding of SE, and to show us how
far we still have to go. We are beginning to understand
the relationship between convulsions and systemic
factors, brain metabolism and energy reserves, liberation of excitatory amino acids, and cell injury. Still,
the precise roles of these factors have yet to be defined,
and the obvious therapeutic conclusions have not yet
been drawn. We believe that the predominant mechanism of neuronal injury in SE is excitotoxic, yet the
clinical and experimental evaluation of the many
pharmacological agents that block excitotoxic mechanisms is barely beginning. Even when severe SE requires general anesthesia, ketamine, a widely available
anesthetic that blocks calcium entry through NMDAoperated ion channels, is not being utilized. In neonates, we observe severe brain damage associated with
seizures, yet we do not have experimental or clinical
data to tell us if the seizures play any role in that damage, or if the drugs that could prevent the developmental effects of seizures do not have adverse developmental consequences of their own. In the next
decade, there should be a rational effort to understand
the mechanisms of brain damage from seizures and
their therapeutic implications.
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