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. 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