Mesial temporal sclerosis: Pathogenesis and significance

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Review Article

Mesial Temporal Sclerosis: Pathogenesis and Significance

Zhao Liu, PhD, MD, Mohamad Mikati, MD, and Gregory L. Holmes, MD

Mesial temporal sclerosis (MTS) is a common pathologic finding in patients with temporal lobe epilepsy. Rarely MTS can be detected in children during the first decade of life, but is not commonly found until adolescence. Although the etiology of MTS remains controversial, there is now a considerable amount of evidence demonstrating that MTS is both a result and a cause of seizures. Clinical studies suggest that prolonged seizures or complicated febrile seizures may result in MTS. A variety of epileptogenic agents admin- istered to adult animals have resulted in MTS and spontaneous recurrent seizures. The mechanism of the lesions is due to excessive excitability secondary to release of excitatory amino acids, primarily glutamate. Glutamate, acting at a number of subreceptors on the postsynaptic membrane, leads to prolonged depolar- ization of neurons and results in the entry of cytotoxic amounts of calcium. Interestingly, the same agents that produce MTS in adult animals do not produce MTS in immature animals. Clinical and experimental evidence suggests that although prolonged seizures or complicated febrile seizures can place a child at risk for MTS, a period of time is required for the lesions to develop fully.

Liu Z, Mikati M, Holmes GL. Mesial temporal sclerosis: Pathogenesis and significance. Pediatr Neurol 1995; 12:5- 16.

Introduction

Partial seizures of temporal lobe origin are common in both children and adults. Although seizures may arise from any area of the temporal lobe, in the majority of patients seizures arise in mesial structures (i.e., hippocampus, amygdala). The most common pathologic lesion seen in adult patients with temporal lobe seizures is mesial

temporal sclerosis (MTS). MTS is the sole pathology found in two-thirds or more of patients with temporal lobe epilepsy [1,2]. MTS is characterized by selective neuronal loss and reactive gliosis in the hippocampus and other mesial temporal structures [1]. There is increasing evidence that the foundation of MTS occurs in children. Al- though the close relationship between MTS and temporal lobe epilepsy has been recognized for over a century, the precise pathophysiologic role of MTS and its relationship to mechanisms of seizure genesis remain unclear. In this review, the pathologic features of MTS are described, clinicopathologic correlations discussed, and the theories regarding etiology reviewed.

Clinical Features

The clinical features of mesial temporal lobe epilepsy in 67 patients were recently reviewed by Williamson et al. [2] and French et al. [3] at Yale. This was a unique series in that all patients had seizures recorded with intracranial electrodes and underwent successful temporal lobectomies. Although 54 (81%) had histories of convulsions during early childhood or infancy, habitual seizures began at the mean age of 9 years. All patients had complex partial seizures and one-half also had secondarily generalized seizures. All but 3 patients from the Yale series had auras, the most common of which was an abdominal vis- ceral sensation.

A prior history of febrile seizures is common in patients with mesial temporal lobe epilepsy. In the Yale series, 54 of 67 patients (81%) had histories of convulsions during early childhood or infancy; 52 of these 54 had associated fever. There was typically a long interval between the initial seizure and nonfebrile seizure onset (mean: 7.5 years). In addition, long seizure-free intervals were common, with or without the use of medications, after the onset of nonfebrile seizures. These findings were similar to those reported by Ounsted et al. [4] who, in a study of

From the Department of Neurology, Harvard Medical School, Children's Hospital, Boston, Massachusetts.

Communications should be addressed to: Dr. Holmes; Clinical Neurophysiology Laboratory; Hunnewell 2; Children's Hospital; 300 Longwood Avenue; Boston, MA 02115. Received June 14, 1994; accepted October 27, 1994.

© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 Liu et al: Mesial Temporal Sclerosis 5 SSDI 0887-8994(94)00122-I

100 patients with childhood-onset temporal lobe epilepsy, found that MTS was more common in patients who had silent intervals between seizure onset and the development of frequent recurrent seizures than in those who did not have silent intervals. These observations suggest that once the epileptic focus is established, the epileptic process leading to MTS is progressive.

The electroencephalographic (EEG) features of mesial temporal lobe epilepsy typically consist of paroxysmal features over the anterior temporal region. It is not un- common for bilateral temporal lobe abnormalities to be seen, even in patients who eventually have successful temporal lobectomies [2]. Because the primary pathology is in mesial structures, it is also common for the patient to have normal interictal EEGs. During simple partial seizures it also is quite common for the EEG to demonstrate no abnormalities. As the seizure evolves and the patient develops alteration of consciousness there usually are detectable EEG changes.

Although it is clear, based on magnetic resonance imaging (MRI) [5] and pathologic examination [6], that MTS can occur in children, the incidence of MTS in children with temporal lobe epilepsy is not known. In a study of 19 children with presumed temporal lobe epilepsy, the youngest child with MTS was 4 years [7]. In 20 children wtih temporal lobe epilepsy, Kuzniecky et al. reported MTS in 60% of children with temporal lobe resection; however, only 2 of 10 children were younger than age 12 years [6]. In 14 patients between the ages of 3-22 years who presented with posterior temporal epilepsy, Duch- owny et al. found only 1 patient who had MTS [8]. This was the oldest patient in the series (age 22 years) who had been having seizures since age 3 years [5].

Anatomy of Hippocampus and Mesial Temporal Lobe

The hippocampus lays in the mesial aspect of the temporal lobe and is covered by the parahippocampal gyms. The hippocampus consists of the dentate gyms, Ammon's horn, and the subiculum. In mammals, the hippocampus is comprised of 2 C-shaped, interlocking principal cell layers: the granular cell layer of the dentate gyrus and the pyramidal cell layer of Ammon's horn. Ammon's horn is divided into 4 subfields: CA1 to CA4. Area CA4 corre- sponds to the polymorphic zone of the dentate gyrus. Areas CA3 and CA2 together correspond to the region inferior and area CA1 to the region superior (Figs. 1A, 1B). CA3 has been divided into 3 regions (i.e., CA3a, CA3b, CA3c) with CA3a corresponding to CA2. The subiculum is distally replaced by the pre- and parasubiculum and the adjacent entorhinal cortex ventrally and the restro- splenial cortex dorsally.

The basic cytoarchitecture of the hippocampus consists of dentate granular cells and pyramidal neurons. Granular cells of the dentate region exist in a single layer with apical dendrites oriented toward the stratum moleculare.

Cd "~

I I

A ~REGIO INFERIOR

B

Figure 1. (A ) Schematic drawing of hippocampal formation consisting of the dentate gyrus (D.G.), CA1-CA4 pyramidal cell layers, and the subiculum (Sub). The pyramidal cell layer is divided into CA1 and CA2 (the regio superior) and CA3 and CA4. Fibers that originate in the entorhinal cortex travel via the perforant pathway (pp) and terminate in the dentate molecular layer with dendrites of granule cells of the dentate gyrus. The dentate granule cells give rise to mossy fibers (mf) which synapse with CA3 pyramidal cells. The CA3 pyramidal cell axons (Schaf- fer collaterals, s.c.) terminate on the dendrites of CA1 pyramidal cells, whose axons in turn project to the subiculum (h.f. = hippocampal fis- sure; fimb = fimbria). (B) Photomicrograph of coronal section of rat dorsal hippocampus. Bar: 450 txm.

The curvature of the dentate gyrus encompasses the hilus area which contains the polymorphic cell layer of CA4 and proximal part of pyramidal cell layer of CA3. This region is also called the end folium or hilum. CA3 area contains the largest pyramidal neurons with apical dendrites extending into stratum radiatum. Although the CA2 area, like the CA3 area, contains large pyramidal neurons, in contrast to CA3, CA2 does not receive mossy fiber input from the dentate gyms. CA 1 area consists of small pyramidal cells extending from CA2 to the subiculum. The subiculum begins with a single-layer structure near CA1 and progressively becomes a multilayered structure as the periallocortex is approached. Within the molecular layer of the subiculum the perforant pathway courses to the hippocampus from the entorhinal area. The presubiculum and parasubiculum are poorly defined layers that merge with the entorhinal and subicular areas. The entorhinal cortex extends from anterior to the amygdala to the level of the lateral geniculate body.

The entorhinal cortex consists of 6 layers which are classified as the superficial layers (I-III) and deep layers (IV-VI). The entorhinal cortex has relatively large cells in

6 PEDIATRIC NEUROLOGY Vol. 12 No. 1

layer II which tend to cluster in islands. Layer III contains large pyramidal cells. The underlying white matter is called the angular bundle and forms the perforant pathway, composed of axons from layers II and III.

The major excitatory input into the hippocampus is by way of the perforant pathway. Fibers that originate in the entorhinal cortex terminate in the outer two-thirds of the dentate molecular layer with dendrites of granule cells of dentate gyrus. The latter cells create mossy fibers, which synapse with CA3 pyramidal cell dendrites in the stratum lucidum. The third link in the polysynaptic excitatory pathway through the hippocampus is provided by CA3 pyramidal cell axons (Schaffer collaterals) terminating on the dendrites of CA 1 pyramidal cells, whose axons in turn project to the subiculum and entorhinal cortex. CA3 pyramidal cells emit additional excitatory collaterals to the lateral septum and to the contralateral hippocampus and intrinsic collaterals that run longitudinally to more septal or temporal parts of CA3. Therefore, the hippocampus is a unidirectional system of synapses with extensive input and output. There is substantial evidence that glutamate and aspartate are transmitters in all of the excitatory pathways described above.

The excitatory pathway is modulated by several inhibitory interneurons, such as the basket cell, oriens-alveus, and lacunosum-moleculare interneurons. Basket cells, lo- cated in the pyramidal layer and inferior to the stratum oriens, receive excitatory synapses from hippocampal afferent fibers in the stratum radiatum, stratum oriens, and from collaterals of pyramidal cell axons and synapse with the pyramidal cells. Oriens-alveus and lacunosum- moleculare interneurons receive excitatory afferents in the stratum radiatum, the alveus and pyramidal cell axon collaterals, and synapse with pyramidal cell. Therefore, the afferent fibers may excite these inhibitory interneurons before exciting afferent synapses, creating feed-forward inhibition.

Historic Aspects of Mesial Temporal Sclerosis

Ammon's horn sclerosis was first described as a visible and palpable temporal lobe change by Bouchet and Caza- uvieil in 1825 [9]. These authors reported that in 16 au- topsies of patients with epilepsy, 8 had lesions in the hippocampus by gross inspection; 6 had increased consis- tency of the tissue, while 2 had hippocampal softening. Other reports then followed, demonstrating that hardening and reduction in size of Ammon's horn was a common finding at the autopsy of patients with epilepsy.

In 1880, Sommer reviewed previous reports and estimated that about 30% of patients with epilepsy have pathologic lesions that affect Ammon's horn [10]. He was the first to describe the pathologic changes histologically and noted that pyramidal cell loss in the hippocampus was not diffuse, but restricted to certain sectors. Pyramidal cell loss in CA1 was greater than that of the end folium (CA3- CA4) and the granular cells of the dentate gyrus. He em-

phasized the prominence of cell loss in area CA1 and this area was subsequently called "Sommer's sector." Som- mer also indicated that Ammon's horn sclerosis may rep- resent the site of seizure origin.

A detailed description of the microscopic features of Ammon's horn sclerosis was presented in 1899 by Bratz [11]. He confirmed that Ammon's horn sclerosis is commonly encountered at autopsy of patients with epilepsy. He estimated the incidence of this lesion to be 50% among patients with epilepsy. During this era, Ammon's horn sclerosis was not considered to be related to any particular form of epilepsy.

Stauder was the first to correlate Ammon's horn sclerosis with the occurrence of complex partial seizures of temporal lobe epilepsy, reporting in 1936 that damage to Ammon's horn was present in 29 of 36 patients with proved temporal lobe epilepsy [12]. This finding led him to the conclusion that the symptoms, especially the unique auras, of temporal lobe epilepsy resulted from hippocampal injury.

The discovery of EEG made it possible to identify abnormal electric discharges in epileptic patients. The work of Jasper et al. in Montreal demonstrated that certain types of seizures, called psychomotor seizures at that time, documented EEG signs of epileptogenic dysfunction in the temporal region [13]. Therefore, for the first time, electrical abnormalities involving the temporal lobes could be identified with some accuracy. This led to the surgical removal of such lobes in order to relieve refractory seizures. The earliest operations followed the method de- signed by Penfield in which variable amounts of the temporal lobe were removed in small fragments. This method made subsequent anatomic and neuropathologic assess- ment of the temporal lobe difficult.

Falconer et al. developed the method of en bloc resection which helped greatly with the subsequent anatomic and histologic examination of the incised temporal lobe [14]. The increase in the number of surgical procedures resulting from this new approach made surgical specimens available for subsequent neuropathologic studies.

Margerison and Corsellis [15], in an autopsy study of temporal lobe epilepsy, verified Stauder's [12] finding when they found about 65% of the resected temporal lobes contained identifiable abnormalities. This abnormality was most commonly a hardened or sclerotic hippocampus similar to that reported earlier in postmortem studies of patients with chronic idiopathic epilepsy who had no surgical interventions. They observed 2 major types of hippocampal sclerosis: "classical Ammon's horn sclerosis" and "end folium sclerosis." Classic Ammon's horn sclerosis was defined as atrophy of the hippocampal formation associated with loss of neurons and gliosis in CAI-CA4 and the dentate gyrus. The end folium sclerosis was defined as neuronal loss and gliosis confined to the end folium or CA3-CA4. Patients with end folium sclerosis have later onsets of seizures than do patients with Am- mon's horn sclerosis.

Liu et al: Mesial Temporal Sclerosis 7

In 1968, Falconer and Taylor published a report in which the term "mesial temporal sclerosis" was proposed [16]. The authors reported that cell loss in the Sommer's sector was associated with some degree of gliosis of the amygdala. With increasing severity of the pathology, other parts of the hippocampus also demonstrated cell loss. The uncus and the amygdala region were similarly affected in a patchy manner and definite gliosis appeared in these structures and in the white matter of the temporal lobe. With further extension of damage, neuronal loss in all these structures increased and extended to the adjacent cortex, such as the hippocampal and fusiform gyri. In some patients the damage involved the cortex, either the entire cortex or second and third layers selectively. This process, although mainly affecting the mesial gray matter in the temporal lobe, may spread widely throughout the lobe leading to generalized atrophy and gliosis of both cortex and gray matter. MTS appears to be the best term to describe the known pathologic substrate of temporal lobe epilepsy.

Mesial Temporal Sclerosis: Cause of or Result of Seizures?

Although it is commonly accepted that temporal lobe epilepsy is associated with MTS, there is controversy regarding whether MTS is the cause of seizures or the end result of recurrent or prolonged seizures. As will be discussed, there is some evidence that seizures, especially recurrent or prolonged, can lead to MTS. Evidence also suggests that once MTS develops it can lead to recurrent simple or complex partial seizures.

Clinical Studies. Pfleger found the presence of hemor- rhagic lesions in the mesial temporal lobes of patients dying shortly after status epilepticus [17]. He attributed the resulting neuronal necrosis to metabolic or local cir- culatory disturbances caused by seizures. There are indi- cations that prolonged febrile seizures are related to the development of MTS [18,19]. Scheibel et al. reported morphologic features in hippocampal neurons from brain of patients with epilepsy, which suggested to them that neuronal deterioration and death resulted from ongoing processes related to repeated seizures [20]. Studies using quantitative neuroanatomic methods suggested that severity of neuronal loss correlates to the frequency and dura- tion of generalized tonic-clonic seizures [21].

Other studies however, demonstrated that the extent of MTS correlated poorly with seizure history. Bratz found that only some of his patients with seizures resulting from tumors, localized infection, or other localized brain dis- eases had hippocampal sclerosis, suggesting that seizures do not consistently result in MTS [ 11 ]. Quantitative neuroanatomic studies by Babb et al. do not support the con- tention that MTS is caused by seizures [22]. In their study of 70 patients with epilepsy, the authors used MRI volumetric measurements of amygdala and hippocampal for-

mation. In 91% of 45 patients with temporal lobe epilepsy without foreign tissue lesions, there were significant re- ductions in size of the amygdala and/or hippocampus co- inciding with the side of the EEG seizure onset. There was no correlation between seizure frequency or length of time the patient had epilepsy with volumetric measurements. Based on studies using volumetric analysis of the temporal lobes, Cendes et al. proposed that degree of MTS is related to the initiating event as opposed to recurrent seizures [ 18,19].

Another finding that supports the concept that MTS leads to seizures as opposed to being a result of seizures is the observation that removal of only the damaged portion of hippocampal formation is sufficient to reduce the incidence or abolish further seizures. If MTS were only a consequence of seizures, removal of such a small area would not be expected to reduce seizure frequency. In addition, epileptiform activity is frequently confined only to the hippocampus, again suggesting that MTS is a cause of the seizures.

Experimental Studies. Recent studies using animal models clarified some aspects of the controversy. Several lines of experimental evidence support that seizures can cause MTS. Systemic and intracerebral injections of the excitotoxin kainic acid (KA) or cholinergic agonists (i.e., pilocarpine) in rats and mice result in intense seizure ac- tivities in the limbic pathways which resemble human complex partial seizures in both behavioral and EEG features. The morphologic sequelae of these seizures are rem- iniscent of MTS in human temporal lobe epilepsy: selective cell loss and gliosis in sectors CA1 and CA3 of the hippocampus with variable sparing of sector CA2 and granule cells of dentate gyrus [23-25]. This neuronal damage is still observed when systemic hypotension, hypoxia, and metabolic disturbances are prevented by mechanical ventilation and neuromuscular blockade, suggesting that neuronal damage following seizures is dissociated from systemic metabolic disturbances related to behavioral seizures [26]. More recently, quantitative study using an un- biased stereologic estimation method demonstrated that the degree of neuronal loss in sectors CA1 and CA3 was closely related to the severity of status epilepticus following pilocarpine injection [27].

Sloviter demonstrated that prolonged intermittent or continuous stimulation of the entorhinal-hippocampal fibers in rats essentially replicates the pattern of brain damage obtained with convulsant drugs [28]. This model has the following advantages: drug side effect is avoided, seizure site is controlled precisely, and effects of motor convulsions on other physiologic variables are controlled by urethane anesthesia. Therefore, the damage in this model is solely attributed to seizure activity. Studies in the kindling model of epilepsy also demonstrated that even repeated, brief, sporadic seizures induce local structural alterations in pathways of the hippocampus, including neuronal loss, axonal sprouting, and regeneration of synaptic


connection patterns [29]. These observations demonstrate thatdamage is related to the seizures per se and not to an hypoxia-ischemic mechanism.

Experimental studies also support the viewpoint that MTS is an important factor for the development of subsequent seizures. Spontaneous recurrent seizures (SRS) are frequently observed following seizure-induced structural damage in several animal models [30,31]. These seizures are typically partial in onset with secondary gener- alization. They are based on EEG and behavioral features and begin in the hippocampus or amygdala.

Although the mechanism by which MTS causes seizures is not yet clear, recent neuropathologic studies provided some clues. It has been demonstrated that in parallel with the progressive loss of pyramidal neurons during seizures, the mossy fiber pathway from granule cells of the dentate gyms undergoes reorganization of the synaptic connections [29,32,33]. Because the net effect of such reorganization appears to be excitatory, it is possible that the structural alterations following MTS may be a factor that result in recurrent seizures.

From experimental data, it appears that prolonged seizures constitute one factor that causes MTS. It is also clear that MTS itself leads to recurrent seizures. The possible explanation is that prolonged seizures themselves induce neuronal loss which, in turn, leads to formation of new synaptic connections that can express abnormal hyperexcitability and results in seizures. Therefore, a vicious cycle can emerge that may underlie the inexorable progres- sion of a seizure disorder in some patients, culminating in seizures refractory to available medications.

Pathogenesis of Mesial Temporal Sclerosis

Excitotoxic Amino Acid Receptors and Mesial Temporal Sclerosis

Excitatory amino acids (EAAs) L-glutamate and L-aspartate are the most abundant amino acids in brain. Given the high concentration and widespread distribution of these substances in the central nervous system, it is not surprising that EAAs play an important role in normal neuronal functions, as well as contribute to cellular abnormalities of certain pathologic conditions. Since the first discovery by Lucas and Newhouse in 1956 that glutamate had toxic effect on newborn mouse retina neurons [34], a large body of evidence has accumulated demonstrating that exposure of neurons to glutamate for a brief period causes delayed cell death [35].

Studies have demonstrated that the delayed cell death induced by glutamate is also produced by calcium iono- phores and attenuated by N-methyl-o-aspartate (NMDA) antagonists, suggesting that the cell death is caused by the Ca 2 + influx through the activation of NMDA receptors [35]. Recent studies demonstrated that non-NMDA receptor activation is also necessary for glutamate-induced neuronal damage [361. Voltage-operated Ca 2÷ channels may

be the pathway by which lethal Ca 2 ÷ accumulation occurs in the slow neurotoxicity brought about by activation of non-NMDA ionotropic receptors [37].

In recent years, interest has developed in the potential role of excitotoxic effects of amino acid receptors both in epileptogenesis and seizure-induced pathology. KA, an analogue of excitatory amino acid glutamate, has been documented to induce seizures and subsequent neuronal damage in hippocampal CA3 [25]. Sloviter and Dempster demonstrated that neuronal injury induced in the hippocampus by stimulation of the perforant path shares many of the characteristics of excitotoxic injury [38]. These re- suits suggest that neuronal injury following seizures may be mediated by an excitotoxic mechanism. Several lines of evidence support this mechanism.

1. Glutamate-Induced Neuronal Injury Resembles Sei- zure-Induced Injury. Administration of glutamate and its analogues is associated with marked swelling of neuronal dendrites and cell bodies, with sparing of adjacent axons and presynaptic nerve terminals [39,40]. Similar histologic findings following seizures are produced by KA and the cholinergic agonist pilocarpine. More recently, Holmes et al. demonstrated that intrahippocampal infusion of glutamate and quisqualate produces similar neuronal injury as that following seizures induced by KA and pilocarpine [41]. These findings support the hypothesis that the excessive amounts of glutamate and aspartate that may be released during seizures result in neuronal damage.

2. EAA Released in Excessive Amount During Seizures. Recently, in vivo microdialysis and high-performance liq- uid chromatography (HPLC) were used to identify and measure the dialysate concentrations of amino acids during seizures. Several lines of evidence reveal that extracellular levels of glutamate and aspartate are markedly increased during seizures in both human and animal models. During and Spencer reported that in 6 patients with complex partial epilepsy, the concentrations of glutamate were higher in epileptogenic hippocampus before seizures and there was a sustained increase in extracellular glutamate in the epileptogenic hippocampus during seizures [42]. Carlson et al. used intracerebral microdialysis com- bined with EEG recording in patients who had epilepsy surgery [43]: They found that marked elevations of aspartate (79-fold), glutamate (15-fold) dialysate concentrations occurred in association with the onset of seizures. In another study, Ronne-Engstrom et al. also observed dramatic increases of extracellular glutamate and aspartate concentrations in association with focal seizures in 7 patients with medically intractable epilepsy [44]. These results suggested that a rise in extracellular EAAs may play an important role in the mechanism of seizure-related brain damage in human epileptic focus.

In experimental studies, Dodd and Bradford reported enhancement of glutamate release from cobalt epileptic lesions was approximately 3-fold greater than that from nonepileptic lesions [45]. In addition, epileptogenic le-


sions revealed a marked reduction in glutamine release compared to controls. Lehmann found that the seizures induced by kainic or folic acid were accompanied by pro- nounced elevations of extracellular alanine and phospho- ethanolamine in the hippocampus [46]. Extracellular glutamate was slightly elevated (50-70% over baseline values). Lallement et al. noted a sustained increase in the extracellular glutamate level occurred in the amygdala and hippocampus following soman-induced seizures [47,48]. Minamoto et al. reported that the extracellular concentrations of glutamate and aspartate were increased during amygdaloid kindling [49]. The values of glutamate and GABA were increased 3-4 times in C2-C3 stages in comparison with the values in control animals. After reaching C5 stages, these values were increased 3-7 times. Re- cently, Millan et al. demonstrated that there were large and sustained increases in extracellular hippocampal aspartate (250%) and glutamate (55%) levels following pilocarpine-induced seizures in rats pretreated with glutamate uptake inhibitor [50]. The authors also found that perfusion of the dorsal hippocampus with pilocarpine via a dialysis probe resulted in a transient 2.5-3-fold increase in extracellular aspartate and glutamate levels.

3. Regions of Hippocampus Most Vulnerable to Dam- age Contain Highest Concentrations of EAA Receptors in Mammalian Brain. Based on an excitotoxic mechanism, it would be expected that Sommer's sector and sector CA3 of the hippocampus are vulnerable to damage because both are rich in EAA receptors. Quantitative autoradiographic studies demonstrated that Sommer's sector of the hippocampus contains the highest density of L-(3H) glutamate binding sites in brain [51]. It was also demonstrated that CA3 and hilus regions contained abundant KA receptors [52]. Given the fact that these regions are most vulnerable to damage, it can be surmised that seizure-induced neuronal damage is associated with powerful activation of NMDA receptors in Sommer's sector and KA receptors in CA3. These receptors, when powerfully activated by ap- propriate ligands during seizures, allow a considerable influx of Ca 2÷ ions into the postsynaptic pyramidal neurons. The increased intracellular Ca 2+ will trigger a cas- cade of reactions resulting in cell death in these regions.

4. Damage in Hippocampus Displays Topographic Pro- file that Dovetails With Pattern of Distribution of Ca 2 + - Binding Protein in Hippocampal Formation. The increase in intracellular calcium that occurs as a result of excitatory amino acid receptor activation has been suggested to be the initiating factor in seizure-induced neuronal death [53]. However, although all hippocampal neurons are presumably excited during seizures, some cell populations are more vulnerable than others. It has been hypothesized that differences in the vulnerability of hippocampal neurons to seizures may be related to absence or presence of cytoplasmic calcium-binding proteins that buffer free intracellular Ca 2÷ [54]. Recent studies demonstrated that the distribution of calcium-binding protein perfectly matches the pathologic profile of hippocampal sclerosis

[55,56]. This protein is absent in pyramidal neurons of the vulnerable sectors CA1 and CA3, but is abundantly present in those of resistant sector CA2 and granule cells of the dentate gyms, and axons of mossy fibers. This finding suggests that neuronal damage following seizures is Ca 2+-mediated [57].

5. Seizure-Induced Neuronal Damage Prevented by Both NMDA and Non-NMDA Blocker. In models of status epilepticus, protection from neuronal necrosis has been obtained with both NMDA and non-NMDA antagonists. Pretreatment with MK-801, an NMDA antagonist, reduces KA-induced spontaneous recurrent seizures [58]. In unpublished work from our laboratory, NBQX, a non- NMDA glutamate antagonist, also reduced the damage elicited by KA.

Energy Metabolism Defects and Mesial Temporal Sclerosis

It is known that prolonged seizures are often accompanied by changes in cerebral blood flow and changes in brain metabolism. Changes in cerebral blood flow are an adaptation to the seizure and its increased metabolic de- mands. The onset of seizures may abolish autoregulation of cerebral blood flow which becomes pressure-dependent [59]. During the early course, seizure raises systemic blood pressure and results in a large increase in blood flow, which has a protective effect by delivering more oxygen and glucose to brain. As the seizure develops, blood flow decreases as blood pressure falls. The late decrease in blood flow reduces the supply of oxygen and glucose to brain. Seizures result in metabolic changes, including a large increase in cerebral metabolic rate for glucose and oxygen [60], moderate decrease in ATP [61], and lactate accumulation [62]. Other systemic changes following seizures include ischemia, hypoxia, hypother- mia, hypertension, and hypoglycemia [59]. Seizure- induced systemic and metabolic changes were demonstrated to cause massive increases in arachidonic acid concentration, diacylglycerol-mediated activation of protein kinase C, calcium-mediated changes in calmodulin kinase II, and generation of free radical [63]. These factors may play a role in the mechanism of neuronal injury.

Recent experimental studies demonstrated that seizures can cause MTS in the absence of hypotension, hypox- emia, and hypoglycemia. When systemic hypotension, hypoxia, and metabolic disturbances are prevented by mechanical ventilation and neuromuscular blockade in a model of drug-induced status epilepticus in primates, neuronal damage is still observed in the hippocampus, thalamus, and cortex [64]. Intense epileptic activity in the hippocampus induced by repeated activation of afferent pathways with high-frequency stimulation in anesthetized, paralyzed rats also induced neuronal loss in the hippocampus and hilus of the dentate gyrus [38]. These results suggest that seizure-induced neuronal damage can be dissociated from systemic metabolic disturbances related to behavioral seizures. However, the role of energy and met-


abolic defects in the pathogenesis of MTS should not be discarded. It is likely that excitotoxic and energy defect mechanisms are synergistic in producing MTS.

Gene Expression and Mesial Temporal Sclerosis

Seizure activity induces rapid increases in levels of mRNA and proteins that are encoded by the immediate- early genes c-fos, c-jun, jub-B and nerve growth factor I-A (NGFI-A) [65,66]. The significance of expressions and function of these genes is unknown.

Recently, several studies suggested that gene expression may be involved in seizure-induced cell death. Using a fos-lacZ transgenetic mouse, Smeyne et al. reported that continuous expression of fos following doses of KA appears to be a harbinger of death [67]. They reported that following doses of KA-induced status epilepticus, a rapid and transient expression of fos-lacZ was found in the nucleus of neurons, as has already been described for c-fos expression in other seizure models. At 4 days posttreatment, and peaking at about 7 days posttreatment, fos-lacZ expression reappeared in specific regions of the limbic system: CA1, CA3, and to a lesser extent CA4 of the hippocampus, as well as the dorsal medial nucleus of the amygdala. This pattern of fos-lacZ expression is coinci- dent with the map of neurotoxicity described for KA. In contrast to the nuclear localization detected in the first wave, [3-galactosidase was detected throughout the cyto- plasm, an event consistent with loss of integrity of the nuclear membrane. At that time, marked disorganization, pyknosis, and neuronal loss were noted in the CA1 and CA3 pyramidal cell layers of the hippocampus. By l0 days, only a few, sporadic, [3-galactosidase-positive cells were observed in the hippocampus and amygdala. These data suggest that an induction of fos-lacZ occurred before the onset of cell death in neurons of the limbic system that are susceptible to KA-mediated excitotoxicity [67]. Con- sidering that [3-galactosidase activity was detected in cells of the medial-edge epithelium undergoing programmed cell death during development, expression of fos-lacZ may signal neuronal death following seizures.

More recently, Rocamora et al. reported that unilateral intrahippocampal injection of 120 nmol of quinolinic acid induced seizures together with local neurodegeneration in specific cell layers [68]. In situ hybridization histochemistry was used to analyze the spatial-temporal pattern of expression of neurotrophin-3. A long-lasting, specific stimulation of this messenger RNA expression was observed in ipsilateral CA 1 and CA4 local degenerating cell layers, suggesting that this neurotrophin factor is involved in the quinolinic acid-mediated neurodegeneration process [68].

Mesial Temporal Sclerosis, Synaptic Reorganization, and Epileptogenesis

How could MTS lead to epilepsy? Several possible mechanisms have been postulated based on evidence of experimental studies. Among them, the sprouting mecha-

nism has attracted recent attention [32]. Sprouting mechanisms suggest that degeneration of neuronal pathways evokes growth in nearby undamaged pathways. Aberrant synaptic conditions, termed sprouting or reactive synap- togenesis, form in response to the loss of hippocampal neurons and produce hyperexcitability that either provokes or facilitates abnormal discharges.

Evidence of synaptic reorganization following lesions has been demonstrated in both human and animal models. In the rat model of KA-induced seizures, following cell loss in the CA3 and hilus, the mossy fiber pathway from granule cell of the dentate gyms undergoes reorganization of its synaptic connections. The sprouting of mossy fiber axons is readily observed with the Timm method, a histochemical technique that selectively stains mossy fiber axon terminals because of their high zinc content [69]. These sprouting axons establish morphologically intact synapses in the inner molecular layer that are likely excitatory in nature [70]. Reorganization of mossy fiber synapses was also observed in models of generalized seizures [71], tottering mouse [72], and during kindling of limbic structures, including perforant path, amygdala, and olfac- tory bulb [73]. Evidence of synaptic reorganization in epileptic human temporal lobe has also been identified with the use of several histologic markers of the mossy fiber pathway, including Timm histochemistry [74].

Cahan et al. measured the density of NMDA and KA receptors using receptor autoradiography from 5 patients undergoing lobectomy and compared the findings with 6 specimens obtained postmortem [75]. A 2-fold increase in the density of NMDA receptors and an increased density of KA receptors were found in entorhinal cortex in epileptic specimens. Loss of NMDA and KA receptor density was apparent in the sclerotic regions, CAI and CA3, but not in other areas of the hippocampus or dentate gyrus. These findings suggested that damage in the hippocampus may result from the presence of aberrant excitatory cir- cuits in the entorhinal cortex.

Although attractive, the sprouting hypothesis cannot explain all physiologic changes that occur in the hippocampus following a prolonged seizure. Using field potential recordings in vivo in KA-treated rats Sloviter found a reduction in hippocampal inhibition and increased excitability prior to sprouting [76]. It has been proposed that loss of hilar, GABAergic neurons may be the important feature of altered excitability. Sloviter proposed that, following a prolonged seizure, loss of hilar cells may deaf- ferent inhibitory neurons, rendering them "dormant" and thereby disinhibiting an enlarged expanse of the granule cell layers [33]. Recurrent seizures would then ultimately produce the full pattern of hippocampal and mesial temporal sclerosis by further destroying cells within the seizure circuit.

Predisposing Factors of Mesial Temporal Sclerosis

Status Epilepticus. Status epilepticus (SE) is defined as continuous or repetitive seizures without periods of inter-

Liu et al: Mesial Temporal Sclerosis I I

vening consciousness lasting for 30 min or longer. SE is a neurologic emergency that may rapidly lead to brain damage or death [77]. The influence of SE in the pathogenesis of MTS has been studied extensively. Corsellis and Bru- ton examined brain tissue of 20 patients who died during or shortly after SE. The most vulnerable part of brain was the hippocampus [78]. Wasterlain et al. reported that in 3 patients who died 11-27 days after the onset of noncon- vulsive SE lasting from 2.5 hours to 3 days, SE caused neuronal loss in the hippocampus (CAI-CA3 and hilus), amygdala, piriform cortex, dorsomedial thalamic nucleus, cerebellum, and cerebral cortex [79]. Corsellis and Bruton found that 25 patients had one or more recorded episodes of SE before lobectomy [78]. Sixteen of these patients had sclerotic Ammon's horns.

Meldrum et al. reported that bicuculine-induced SE was associated with extensive neuronal necrosis in the neocortex, hippocampus, amygdala, thalamus, and cerebellum [64]. Paralyzed, O2-ventilated baboons with EEG seizure discharges for over 3 hours exhibited neuronal necrosis in the neocortex, hippocampus, proving that EEG seizures can damage the brain in the absence of behavioral convulsions and systemic complications. Electrical stimulation of the perforant pathway for 2-24 hours leads to ipsilateral necrosis of the hilar interneurons and CA3 pyramidal cells [28]. In addition, SE induced by KA [40] and cholinomimetics [80] caused neuronal necrosis in the hippocampus, amygdala, piriform cortex, entorhinal cortex, lateral septum, thalamus, neocortex, and substantia nigra.

An important variable appears to be the age at which status occurs. Many clinical studies suggested that MTS is produced early in life, presumably as a result of a prolonged seizure, particularly if the child were febrile at the time. Both Zimmerman [81] and Ounsted et al. [4] reported that typical MTS is induced when status epilepticus occurs at ages 3-7 years. Before and after this age range the pathologic consequence may not be the same. Cav- anagh and Meyer et al. [82] emphasized that MTS was seen more commonly in those adults whose seizures began before age 4 years. They also found that a first seizure experience of status epilepticus was more strongly associated with MTS, especially when such a seizure occurred in early infancy.

In experimental animals there is accumulating evidence to suggest that the extent of hippocampal damage following prolonged seizures is highly age-dependent. For ex- ample, KA administration to immature rats in our laboratory [30,83] and others [84,85] demonstrated that despite causing higher mortality rates in young rats, convulsant dosages of KA lead to fewer long-term sequelae than in older animals. In rats younger than 20 days, KA-----despite causing severe seizures--is associated with no discernible hippocampal damage or deficits in memory, learning, or behavior [83]. In addition, Sperber et al. reported that although KA caused more severe seizures in the PI5 rats than in adults, these seizures did not produce mossy fiber

sprouting or changes in paired-pulse excitation in hippocampal slice preparations in rats tested 2-4 weeks after status epilepticus [85]. Status epilepticus produced by continuous electrical hippocampal stimulation in the immature animal is also associated with fewer histologic lesions and behavioral abnormalities in immature animals than in mature animals [86]. Likewise, pilocarpine administration, which produces severe seizures in both immature and mature animals, results in fewer behavioral abnormalities and less histologic damage in the immature animal than in the mature animal [87,88]. These experimental data challenge the clinical dictum that prolonged seizures in the young child lead to MTS.

One possible reason the immature brain is less vulnerable to prolonged seizures is that the immature brain has fewer or functionally immature EAA receptors. However, there are studies demonstrating that KA and NMDA receptors are present at birth and increase dramatically during the first few weeks of life. Miller et al. studied the ontogeny of KA binding sites in rat forebrain using in vitro receptor autoradiography [89]. Specific binding of KA was detectable in the hippocampus by postnatal day 1. In the CA3 region, binding of KA increased progressively with age, peaking at postnatal day 21. Insel et al. also found specific binding of NMDA and quisqualic acid to receptors at postnatal day 1 in the hippocampus and striatum with the adult pattern of binding to NMDA receptors emerging by postnatal day 14 [90]. Physiologic development of EAAs parallel biochemical maturation. The population spike elicited by NMDA application to CA 1 cells of the hippocampus peaks at 10 days, with long-term po- tentiation peaking at about 15 days of age in the rat [91- 93[.

Furthermore, some EAAs produce greater neurotoxicity in the immature brain than in mature brain [94-97]. McDonald et al. found that NMDA neurotoxicity is greater following injection in the corpus striatum of 7-day-old rats than in adults [94]. NMDA toxicity in vivo transiently peaks near postnatal day 7 in rats with the severity of the developing brain to direct intrastriatal infusion of equimo- lar NMDA approximately 60 times greater at this age compared to adults. The severity of brain injury produced by infusion of NMDA at ages 1, 14, 21, and 28 days was comparable to that produced by NMDA in adults, whereas intermediate levels of injury are present at 4 and 10 days of age and peak levels are present at age 7 days. Likewise, when given by a single injection, amino-3-hydroxy-5- methyl-4-isoxazole propionic acid and quisqualic acid have greater toxicity in immature animals than in mature animals [96,97]. In unpublished data from our laboratory, we found that KA, when infused by osmotic pump, also causes lesions similar in size to those of the mature brain.

Therefore, it appears that the immature brain is as sensitive, if not more sensitive, to the direct effects of EAAs; brain damage following prolonged seizures is significantly less extensive in immature animals than in mature ani-


mals. One possible reason for this apparent discrepancy is that less glutamate is released from presynaptic terminals during prolonged seizures than in mature brain. This hypothesis is supported by the finding that glutamate concentrations in the immature rat brain are low [98], as are concentrations of glutamate-related enzymes [99-101]. Hippocampal slices from immature rats have a low presynaptic release of EAAs [102] and low sodium-dependent high-affinity uptake of glutamate and aspartate into presynaptic terminals and into glial cells [103]. Ribak and Navetta found that mossy fiber synapse development in the subgranular layer of the hilus did not reach adult levels until P21 and in the deep hilus until P30 [104]. They suggested that immaturity of the mossy fibers, with subsequent decreased release of glutamate in rats younger than 20 days, could explain the lack of cell loss following prolonged seizures. However, animal data must be inter- preted cautiously. There is increasing evidence that prolonged febrile seizures can lead to mesial temporal sclerosis. In addition, Mathem et al. found that in surgically resected hippocampi from children with extrahippocampal seizures and structurally nonatrophic brains, cell loss could be found in the fascia dentata, CA4, and CA2 [105]. In addition, even in children younger than 2 years of age mossy fiber sprouting could be seen.

Febrile Seizures. Prolonged febrile seizures have been implicated as a major predisposing factor in the development of temporal lobe epilepsy and MTS [4,14,106,107]. Postmortem studies in children who died as a consequence of febrile seizures demonstrated the typical pattern of neuronal loss in the hippocampus that characterizes MTS [4,81]. Bruton reported that in 55 patients with temporal lobe epilepsy who had histories of febrile seizures in infancy, no less than 50 of these patients had sclerotic Am- mon's homs [108].

Falconer compared 2 groups of patients with complex partial seizures who had temporal lobectomies performed for medically intractable seizures: those with and without mesial temporal sclerosis [109]. Histories of prolonged febrile seizures were more common in the first group. Rocca et al., in a population-based case-control study of risk factors for complex partial seizures, found that febrile seizures were significantly more common in the medical records of patients (20%) than in those of controls (2%) [107]. In most patients the preceding febrile seizures were complicated: prolonged, focal, recurrent, or occurring at a young age.

Although there does appear to be an overrepresentation of complex partial seizures following complicated febrile seizures, it should be noted that other seizure types, including generalized tonic-clonic [110] or absence [111] seizures can occur after febrile seizures. Febrile seizures appear to be linked to subsequent epilepsy through a presumably preexisting lower seizure threshold, either genetically determined or secondary to an acquired lesion. Rocca et al. [110] argued that a preexisting brain lesion is

likely to be more common in febrile seizures followed by complex partial seizures, while a genetically determined susceptibility to seizures is probably more common in febrile seizures followed by generalized seizures [110].

There is increasing evidence that complicated febrile seizures can be associated with febrile seizures. In a series of 67 patients with mesial temporal lobe epilepsy followed at Yale by French et al. [3], 54 (81%) had histories of convulsions during early childhood or infancy, 52 of whom had associated fever. Grattan-Smith et al. [5], in a review of MRI scans from 53 children with medically refractory temporal lobe epilepsy, found that hippocampal sclerosis was present in 30 children (57%). MTS was frequently associated with a history of prior neurologic in- suits, primarily febrile seizures, while other MRIs that detected lesions in patients with temporal lobe epilepsy were not highly related to prior neurologic insults.

The mechanisms by which febrile convulsions may produce MTS are not clearly understood. Excessive Ca 2÷ influx through the activation of NMDA and KA receptors during seizures has been suggested as one mechanism re- sponsible for seizure-induced neuronal damage. Enhanced energy demand and relative insufficiency of substrate de- livery during febrile seizures may result in a rapid lower- ing of tissue adenosine triphosphate (ATP) content. The decrease in neuronal ATP may inhibit the ATP-dependent calcium extrusion pump across the neuronal plasma membrane and thus aggravate intracellular calcium accumulation. A recent study from our laboratory revealed that hyperthermia markedly aggravates seizure-induced neuronal damage in the hippocampus [ 112].

Birth Injury. At one time there was controversy regarding the relationship between birth injury and temporal lobe epilepsy. Penfield and Jasper speculated that MTS was the consequence of parturitional birth injury, perhaps the result of excessive molding of the newborn head, resulting in compression of internal carotid and posterior cerebral artery branches at the incisural edge, leading to localized anoxic infarction within the territories of these vessels. In due course these damaged areas matured into epileptic lesions [113]. The term "incisural sclerosis" was used to describe this pathologic process [114]. The theory of incisural sclerosis was questioned when it was found that most patients with MTS did not have a history of birth injury [4].

A recent experimental study by Lowenstein et al. did find that fairly mild head trauma could lead to hippocampal damage [115]. Using a model of fluid-percussion injury, the authors found that neurons of the dentate hilus were vulnerable to brief, unilateral impact to the extradu- ral surface of brain. One week after trauma, there was a dramatic reduction in hilar neurons ipsilateral to the impact, and a milder but significant decrease in neurons on the contralateral side as well. This neuronal loss was highly selective because adjacent dentate granule and pyramidal neurons appeared to be relatively unaffected. Fur-


thermore, the loss of hilar neurons was associated with abnormal hyperexcitability in the dentate gyms. There- fore, these findings provide a potential mechanistic link between human head injury and subsequent development of MTS.

Summary

It is now clear that MTS is the major pathologic finding in complex partial seizures of temporal lobe origin, con- stituting more than two-thirds of all cases. Although the etiology of MTS is not yet clearly understood, there is considerable evidence suggesting that MTS is caused by seizures. Several mechanisms have been implicated. Among them, an excitotoxic model is well documented in both humans and animals. Other mechanisms include seizure-associated energy metabolism defects and seizure- induced gene expression which signals neuronal death. Evidence also supports the belief that MTS can lead to synaptic reorganization which can express abnormal hyperexcitability and result in more seizures. Therefore, a vicious cycle has emerged which may underlie the pro- gression of seizures in some patients.

This work was supported by NINDS (NS27984) and the Stephen Linn Fund (G.L.H.). The drawing in Figure 1 was by Peter Roman.

References

[1] Babb T, Brown W. Pathological findings in epilepsy. In: Engel 1, ed. Surgical treatment in epilepsy. New York: Raven Press, 1987;511- 40.

[2] Williamson PD, French JA, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroen- cephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann Neurol 1993;34:781-7.

[3] French JA, Williamson PD, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993;34:774-80.

[4] Ounsted C, Lindsay J, Norman R. Biological factors in temporal lobe epilepsy. Clinics in developmental medicine, No. 22. London: William Heinemann Medical Books, 1966;1-131.

[5] Grattan-Smith JD, Harvey AS, Desmond PM, Chow CW. Hip- pocampal sclerosis in children with intractable temporal lobe epilepsy: Detection with MR imaging. AJR 1993;161:1045-8.

[6] Kuzniecky R, Murro A, King D, et al. Magnetic resonance imaging in childhood intractable partial epilepsies: Pathologic correlations. Neurology 1993;43:681-7.

[7] Cross JH, Jackson GD, Neville BGR, et al. Early detection of abnormalities in partial epilepsy using magnetic resonance. Arch Dis Child 1993;69:104-9.

[8] Duchowny M, Jayakar P, Resnick T, Levin B, Alvarez L. Pos- terior temporal epilepsy: Electroclinical features. Ann Neurol 1994;34: 427-31.

[9] Bouchet C, Cazauvieil H, Epilepsie et l'alienation mentale. Arch Gen Med 1825;9:510-42.

[10] Sommer W. Erkrankung des ammonshorns als aetiologisches moment der epilepsien. Arch Psychiatr Nervenkr 1880;10:631-75.

[ l l l Bratz E. Ammonshornbefund bei epileptischen. Arch Psychiatr Nervenkr 1899;31:820-36.

[12] Stauder KH. Epilepsie und schl~ifenlappen. Arch Psychiatr Nervenkr 1936;104:181-212.

[13] Jasper H, Pertuisset B, Flanigin H. EEG and cortical electro-

grams in patients with temporal lobe seizures. Arch Neurol Psychiatr 1951 ;65:272-90.

[14] Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and pathogenesis of temporal lobe epilepsy. Arch Neurol 1964;10:233-48.

[15] Margerlson JH, Corsellis JAN. Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 1966;89:499-530.

[16] Falconer MA, Taylor DC. Surgical treatment of drug-resistant epilepsy due to me sial temporal sclerosis. Arch Neurol 1968;19:353-61.

[17] Plleger L. Beobachtungen tiber schrumfung und sklerose des amonshorns bei epilepsie. Allgemeine Z Psychiatr 1880;36:359-65.

[18] Cendes F, Andermann F, Gloor P, et al. Atrophy of mesial structures in patients with temporal lobe epilepsy: Cause or consequence of repeated seizures? Ann Neurol 1993;34:795-801.

[19] Cendes F, Andermann F, Dubeau F, et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: An MRI volumetric study. Neurology 1993; 43:1083-7.

[20] Scheibel ME, Crandall PH, Scheibel AB. The hippocampal- dentate complex in temporal lobe epilepsy. A Golgi study. Epilepsia 1974; 15:55 -80.

[21] Mouritzen-Dam AM. Epilepsy and neuron loss in the hippocampus. Epilepsia 1980;21:617-29.

[22] Babb TL, Lieb JP, Brown WJ, Pretorius J, Crandall PH. Dis- tribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 1984;25:721-8.

[23] Ben-Ari Y, Tremblay E, Ottersen OP, Meldrum BS. The role of epileptic activity in hippocampal and 'remote' cerebral lesions induced by kainic acid. Brain Res 1980;191:79-97.

[24] Mikati MA, Holmes GL, Chronopoulos A, et al. Phenobarbital therapy modifies seizure related brain injury in the developing brain. Ann Neurol 1994;36:425-33.

[25] Nadler JV. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 1981;29:2031-42.

[26] Meldrum BS. Metabolic factors during prolonged seizures and their relation to nerve cell death. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter R J, eds. Advances in neurology. Vol. 34. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;261-75.

[27] Liu Z, Nagao T, Desjardins CG, Gloor P, Avoli M. Quantita- tive evaluation of neuronal loss in the dorsal hippocampus in rats with long-term pilocarpine seizures. Epilepsy Res 1994;17:237-47.

[28] Sloviter RS. "Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophys- iological and light microscopic studies. Brain Res Bull 1983;10:675-97.

[29] Sutula TP. The pathology of the epilepsies: Insights into the causes and consequences of epileptic syndromes. In: Dodson WE, Pel- lock JM, eds. Pediatric epilepsy: Diagnosis and treatment. New York: Demos, 1993:37-44.

[30] Stafstrom CE, Thompson JL, Holmes GL. Kainic acid seizures in the developing brain: Status epilepticus and spontaneous recurrent seizures. Dev Brain Res 1992;65:237-46.

[31] Cavalheiro EA, Leite JP, Bortolotto ZA, Turski WA, Ikonomidou C, Turski L. Long-term effects of pilocarpine in rats: Struc- ture damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 1991;32:778-82.

[32] McNamara JO. Cellular and molecular basis of epilepsy. J Neurosci 1994;14:3413-25.

[33] Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol 1994;35:640-54.

[34] Lueas DR, Newhouse JP. The toxic effects of sodium L-glutamate on the inner layers of the retina. Arch Ophthalmol 1957;58:193- 201.

[35] Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330: 613-22.


[36] Koh J-Y, Goldberg MP, Hartley DM, Choi DW. Non-NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci 1990;7: 693-705.

[37] Weiss JH, Hartley DM, Koh J, Choi DW. The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science 1990;247:1474-9.

[38] Sloviter RS, Dempster DW. "Epileptic" brain damage is rep- licated qualitatively in the rat hippocampus by central injection of glutamate or aspartate but not by GABA or acetylcholine. Brain Res Bull 1985;15:39-60.

[39] Oiney JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J Neuropathol Exp Neurol 1971;30:75-90.

[40] Olney JW, Rhee V, Ho OL. Kainic acid: A powerful neuro- toxic analogue of flutamate. Brain Res 1974;77:507-12.

[41] Holmes GL, Thurber ST, Liu Z, Stafstrom CE, Gatt AM, Mikati MA. Effects of quisqualic acid and glutamate on subsequent learning, emotionality, and seizure susceptibility in the immature and mature animal. Brain Res 1993;623:325-8.

[42] During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993:341: 1607-10.

[43] Carlson H, Ronne-Engstrom E, Ungerstedt U, Hillered L. Sei- zure related elevations of extracellular amino acids in human focal epilepsy. Neurosci Lett 1993;140:30-2.

[44] Ronne-Engstrom E, Hillered L, Flink R, Spannare B, Ungerstedt U, Carlson H. Intracerebral microdialysis of extracellular amino acids in the human epileptic focus. J Cereb Blood Flow Metab 1992;12:873-6.

[45] Dodd PR, Bradford HF. Release of amino acids from the ma- turing cobalt-induced epileptic focus. Brain Res 1976;111:377-88.

[46] Lehmann A. Alterations in hippocampal extracellular amino acids and purine catabolites during limbic seizures induced by folate injections into the rabbit amygdala. Neuroscience 1987;22:573-8.

[47] Lallement G, Carpentier P, Collet A, et al. Involvement of glutamatergic system of amygdala in generalized seizures induced by soman: Comparison with the hippocampus. C R Acad Sci 1991 ;313:421-6.

[48] Lallement G, Carpentier P, Collet A, Pernot-Marino I, Baubi- chon D, Blanchet G. Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus. Brain Res 1991;563:234-40.

[49] Minamoto Y, ltano T, Tokuda M, et al. In vivo microdialysis of amino acid neurotransmitters in the hippocampus in amygdaloid kin- dled rat. Brain Res 1992;573:345-8.

[50] Millan MH, Chapman AG, Meldrum BS. Extracellular amino acid levels in hippocampus during pilocarpine-induced seizures. Epi- lepsy Res 1993; 14:139-48.

[51] Monaghan DT, Cotman CW. Distribution on N-methyl-D- aspartate sensitive L-[3H]glutamate binding sites in rat brain. J Neurosci 1985;5:2909-19.

[52] Cotman CW, Monaghan DT. Anatomical organization of excitatory amino acid receptors and their properties. In: Schwarez R, Ben- Ari Y, eds. Excitatory amino acids and epilepsy. New York: Plenum Press, 1986;237-52.

[53] Connor DJ, Langlais PJ, Thai LJ. Behavioral impairments after lesions of the nucleus basalis by ibotenic acid and quisqualic acid. Brain Res 1991:555:84-90.

[54] Freund TF, Ylinen A, Miettinen R, et al. Pattern of neuronal death in the rat hippocampus after status epilepticus. Relationship to calcium binding protein content and ischemic vulnerability. Brain Res Bull 1992;28:27-38.

[55] Sloviter RS, Sollas AL, Barbaro NM, Laxer KD. Calcium- binding protein (Calbindin-D28K) and paralbumin immunocytochemis- try in the normal and epileptic human hippocampus. J Comp Neurol 1991;308:381-96.

[56] Gloor P. Historical background and an overview from a mod- em perspective. In: Liiders H, ed. Epilepsy surgery. New York: Raven Press, 1991;689-703.

[57] Meldrum B. Excitotoxicity and epileptic brain damage. Epi- lepsy Res 1991;10:55-61.

[58] Holmes GL, Stafstrom CE, Thompson JL, Chronopoulos A, Thurber S. Effects of MK-801 on seizure susceptibility following kainic acid-induced status epilepticus. Epilepsia 1990;31:634.

[59] Meldrum BS, Nilsson B. Cerebral blood flow and metabolic rate early and late in prolonged epileptic seizures induced in rats by bicuculline. Brain 1976;99:523-42.

[60] Chapman AG, Meldrum BS, Siesj6 BK. Cerebral metabolic changes during prolonged epileptic seizures in rats. J Neurochem 1977; 28:1025-35.

[61] Howse DC. Cerebral energy metabolism during experimental status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;209-16.

[62] Ingvar M, Folbergrova J, Siesj6 BK. Metabolic alterations underlying the development of hypermetabolic necrosis in the substantia nigra in status epilepticus. J Cereb Blood Flow Metab 1987;7:103-8.

[63] Bazan NG, Turco R, Moreli de Liberti S. Free arachidonic acid and membrane lipids in the central nervous system during bicuculline- induced status epilepticus. In: Delgado-Escueta AV, Treiman DM, Wasterlain CG, Porter RJ, eds. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;305-10.

[64] Meldrum BS, Vigouroux RA, Brierley JB. Systemic factors and epileptic brain damage. Prolonged seizures in paralysed artificially ventilated baboons. Arch Neurol 1973;29:82-7.

]65] Gall C, Lauterborn J, Isackson P, White J. Seizures, neuro- peptide regulation, and mRNA expression in the hippocampus. Prog Brain Res 1990;83:371-90.

[66] Morgan JI, Curran T. Stimulus-transcription coupling in the nervous system: Involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 1991;14:421-51.

[67] Smeyne RJ, Vendrell M, Hayward M, et al. Continuous c-fos expression precedes programmed cell death in vivo. Nature 1993;363: 166-9.

[68] Roeamora N, Massieu L, Boddeke HWGM, Mengod G, Pala- cios JM. Neuronal death and neurotrophin gene expression: Long-lasting stimulation of neurotrophin-3 messenger RNA in the degenerating CAI and CA4 pyramidal cell layers. Neuroscience 1993;53:905-8.

[69] Danseher G. Histochemical demonstration of heavy metals. A revised version of the sulphide silver method suitable for both light and electronmicroscopy. Histochemistry 1981 ;71 : 1-16.

[70] Tauck D, Nadler JV. Evidence of functional mossy fiber sprouting in the hippocampal formation of kainic acid-treated rats. J Neurosci 1985;5:1016-22.

[71] Golarai G, Paroda I, Sutula T. Mossy fibers synaptic reorganization induced by repetitive pentylenetetrazol seizures. Soc Neurosci Abstr 1988;14:882.

[72] Stanfield BB. Excessive intra- and supragranular mossy fibers in the dentate gyms of tottering (tg/tg) mice. Brain Res 1989;480:294-9.

[73] Sutula T, Harrison C, Steward O. Chronic epileptogenesis induced by kindling of the entorhinal cortex: The role of the dentate gyms. Brain Res 1986;385:291-9.

[741 Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 1989;26:321-30.

[75] Cahan LD, Geddes JW, Choi BH, Cotman C. Excitotoxic amino acid receptors in human complex partial epilepsy. Stereotact Funct Neurosurg 1990;54-55:21-4.

[76] Sloviter RS. Possible functional consequences of synaptic reorganization in the dentate gyms of kainate-treated rats. Neurosci Lett 1992;137:91-6.

[77] Aicardi J, Chevrie J-J. Consequences of status epilepticus in infants and children. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Advances in neurology. Vol. 34. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;115-25.

[78] Corsellis JAN, Bruton CJ. Neuropathology of status epilepticus in humans. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter R J, eds. Status epilepticus. New York: Raven Press, 1983; 129-39.


[79] Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophys- iological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34(suppl 1):$37-53.

[80] Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Caval- heiro EA. Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy. Synapse 1989;3:154-71.

[81] Zimmerman HM. The histopathology of convulsive disorders in children. J Pediatr 1941;13:859-90.

[82] Cavanagh JB, Meyer A. Aetological aspects of Ammon's horn sclerosis associated with temporal lobe epilepsy. Br Med J 1956;2: 1403-7.

[83] Stafstrom CE, Holmes GL, Chronopoulos A, Thurber S, Thompson JL. Age-dependent cognitive and behavioral deficits following kainic acid-induced seizures. Epilepsia 1993;34:420-32.

[84] Aibala BJ, Mosh6 SL, Okada R. Kainic-acid-induced seizures: A developmental study. Dev Brain Res 1984;13:139-48.

[85] Sperber EF, Haas KZ, Stanton PK, Mosh6 SL. Resistance of the immature hippocampus to seizure-induced synaptic reorganization. Dev Brain Res 1991;60:88-93.

[86] Thurber S, Chronopoulos A, Stafstrom CE, Holmes GL. Be- havioral effects of continuous hippocampal stimulation in the developing rat. Dev Brain Res 1992;68:35-40.

[87] Cavalheiro EA, Silva DF, Turski WA, Calderazzo-Filho LS, Bortolotto ZA, Turski L. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Dev Brain Res 1987;37:43-58.

[88] Hirsch E, Baram TZ, Snead OC III. Ontogenic study of lith- ium-pilocarpine-induced status epilepticus in rats. Brain Res 1992;583: 120-6.

[89] Miller LP, Johnson AE, Gelhard RE, Insel TR. The ontogeny of excitatory amino acid receptors in the rat forebrain--II. Kainic acid receptors. Neuroscience 1990;35:45-51.

[90] Insel TR, Miller LP, Gelhard RE. The ontogeny of excitatory amino acid receptors in rat forebrain--I. N-methyl-D-aspartate and quisqualate receptors. Neuroscience 1990;35:31-43.

[91] Harris KM, Teyler TJ. Developmental onset of long-term po- tentiation in area CA1 of the rat hippocampus. J Physiol 1984;346:27-48.

[92] Hammon B, Heinemann U. Developmental changes in neuronal sensitivity to excitatory amino acids in area CAI of the rat hippocampus. Dev Brain Res 1988;38:286-90.

[93] Ben-Ari Y, Cherubin E, Krnjevic K. Changes in voltage de- pendence of NMDA currents during development. Neurosci Lett 1988; 94:88-92.

[94] McDonald JW, Silverstein FS, Johnston MV. Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988;459:200-3.

[95] McDonald JW, Johnston MV. Pharmacology of N-methyl-D- aspartate-induced brain injury in an in vivo perinatal rat model. Synapse 1990;6:179-88.

[96] McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Res 1992;583:54-70.

[97] McDonald JW, Trescher WH, Johnston MV. The selective ionotropic-type quisqualate receptor agonist AMPA is a potent neuro- toxin in immature rat brain. Brain Res 1990;526:165-8.

[98] Campochiaro P, Coyle JT. Ontogenic development of kainate

neurotoxicity: Correlates with glutamatergic innervation. Proc Natl Acad Sci USA 1978;75:2025-9.

[99] Barea MA, Toledano A. Histochemical electron microscopic study of the enzyme glutamate dehydrogenase (GD) in post-natal developing cerebellum. Cell Mol Biol 1982;28:187-95.

[100] Rothe F, Schmidt W, Wolf G. Postnatal changes in the activity of glutamate dehydrogenase and aspartate aminotransferase in the rat nervous system with special reference to the glutamate transmitter metabolism. Dev Brain Res 1983;11:67-74.

[101] Kvanne E, Svenneby G, Torgner IAA, Drejer J, Schousboe A. Postnatal development of glutamate metabolizing enzymes in hippocampus from mice. Int J Dev Neurosci 1985;3:359-64.

[102] Minc-Golomb D, Levy Y, Kleinberger N, Schramm M. D-[3H]Aspartate release from hippocampus slices studied in a multiwell system: Controlling factors and postnatal development of release. Brain Res 1987;402:255-63.

[103] Schmidt W, Wolf G. High-affinity uptake of L-[3H]glutamate and D-[3H]aspartate during postnatal development of the hippocampal formation: A quantitative autoradiographic study. Exp Brain Res 1988; 70:50-4.

[104] Ribak CE, Navetta MS. An immature mossy fiber innervation of hilar neurons may explain their resistance to kainate-induced cell death in 15-day-old rats. Dev Brain Res 1994;79:47-62.

[105] Mathern GW, Leite JP, Pretorius JK, Quinn B, Peacock WJ, Babb TL. Children with severe epilepsy: Evidence of hippocampal neuron losses and aberrant mossy fiber sprouting during postnatal granule cell migration and differentiation. Dev Brain Res 1994;78:70-80.

[106] Annegers JF, Hauser WA, Elveback LR, Kurland LT. The risk of epilepsy following febrile convulsions. Neurology 1979;29: 297-303.

[107[ Rocca WA, Sharbrough FW, Hauser WA, Annegers JF, Schoenberg BS. Risk factors for complex partial seizures: A population- based case-control study. Ann Neurol 1987;21:22-31.

[108] Brnton CJ. The neuropathology of temporal lobe epilepsy. New York: Oxford University Press, 1988;1-158.

[109] Falconer MA. Genetic and related etiologic factors in temporal lobe epilepsy. A review. Epilepsia 1971; 12:13-31.

[110] Rocca WA, Sharbrough FW, Hauser WA, Annegers JF, Schoenberg BS. Risk factors for generalized tonic-clonic seizures: A population-based case-control study in Rochester, Minnesota. Neurology 1987;37:1315-22.

[111] Rocca WA, Sharbrough FW, Hauser WA, Annegers JF, Schoenberg BS. Risk factors for absence seizures: A population-based case-control study in Rochester, Minnesota. Neurology 1987;37: 1309-14.

[112] Liu Z, Gatt A, Mikati M, Holmes GL. Effects of temperature on kainic acid-induced seizures. Brain Res 1993;631:51-8.

[113] Pentieid W, Jasper HH. Epilepsy and functional anatomy of the human brain. Boston: Little, Brown, 1954;1-896.

[114] Earle KM, Baldwin M, Penfield W. Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth. Arch Neurol Psychiatr 1953;69:27-42.

[115] Lowensteln DH, Thomas MJ, Smith DH, Mclntosh TK. Se- lective vulnerability of dentate hilar neurons following traumatic brain injury: A potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 1992;12:4846-53.


Mesial temporal sclerosis: Pathogenesis and significance

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