Histopathologic lesions associated with seizures are found in a variety of disease conditions. The histopathology of temporal lobe epilepsy (TLE) is the most extensively investigated. In TLE with hippocampal sclerosis, several lines of evidence implicate the hippocampus as the predominant focus of seizure origin and maintenance In sclerotic hippocampi, two major pathological processes are observed. (1) The reorganization of the neural circuitry of the dentate gyrus that favors the hyperexcitability of dentate granule cells. These changes include the loss of populations of subgranular hilar interneurons, hilar mossy cells and granule cells. Additionally there is sprouting of granule cell mossy fiber recurrent collaterals into the dentate inner molecular layer and the sprouting of neuropeptide Y, somatostatin and substance P containing axons throughout the molecular layer. (2) The second process consists of glial activation and proliferation throughout Ammon’s horn along with neuronal loss. These astrocytes show a number of changes -- increased expression of specific glutamate receptors, redistribution of the water transporter AQP4, increased expression of Na⁺ and Ca²⁺ ion channels with down regulation of the Kir4.1 channels. The enzymes glutamine synthetase and lactate dehydrogenase are reduced whereas a number of molecules associated with immune function are upregulated. The density of the microvasculature is increased. The “astrocytes” associated with these changes may be subcategorized into two populations -- the strongly GFAP positive astrocytes and weakly GFAP reactive cells, which resemble the GluR astrocytes also known as NG2 cells. The functions of these two subpopulations may favor the creation of a high extracellular glutamate and K+ containing environment in the sclerotic hippocampus, which in turn may trigger seizure spread through a fairly normal subiculum. These changes may even provide an excitable substrate through which the hyperexcitability of dentate granule cells may spread out of the hippocampus to generate seizures.

INTRODUCTION

Histopathological lesions that are associated with seizures are described in several neurological disease states. Such histopathological lesions are found in developmental disorders, neoplasms, microbial diseases, cerebrovascular diseases, trauma, and immune-mediated disorders, and in disorders primarily related to seizures such as in temporal lobe epilepsy (TLE). General descriptions of these lesions have been the subject of several reviews. ^{1, 2} Temporal lobe epilepsy, a major seizure disorder which affects over 40 million people worldwide, has received the most study in relation to its histopathology, and the histological lesion is thus best understood in relation to epilepsy. This chapter will review the state of our knowledge in the histopathology of TLE.

Pierre Gloor provides an excellent review of the historical studies of TLE. ³ However, some of the more significant of these studies bear revisiting for our current appreciation of the histopathology of TLE. The earliest systematic attempt at understanding the histopathology of TLE was by Sommer. ⁴ He reviewed all previously published papers on the pathology of epilepsy and examined (macroscopically) a few of his own cases; he estimated that pathology in Ammon’s horn was found in about 30% of cases and that the pathology was more often unilateral. Studying the histology of only one case, he described diffuse cell loss limited to a sector of the hippocampus, field H1 of Rose (area CA1), which subsequently became known as the Sommer sector. This condition, which manifests as an increased hardening of the tissue, was first noted by Bouchet and Cazauvieilh ⁵ and termed Ammon’s horn sclerosis. Bratz, ⁶ studying autopsied brains of epilepsy patients, confirmed the loss of neurons in the Ammon’s horn in about 50% of the brains, and also noted that such loss was predominantly unilateral. He provided a more complete description of a sclerotic hippocampus, with accompanying woodcuts to illustrate his findings. Bratz observed the following: almost complete pyramidal cell loss in CA1 and a sharp boundary with the subiculum which showed no cell loss; preservation of spindle shaped cells in the stratum oriens; less complete cell loss in the hilus (end folium) and dentate gyrus; preservation of pyramidal cells in area CA2; and an abundance of blood vessels in the atrophic sector (area CA1). These detailed observations have held up as accurately describing the gross histology of a sclerotic hippocampus. ^{7, 8}

Whether hippocampal pathology is specially associated with TLE is still a topic of considerable discussion. To date, several lines of evidence suggest that the hippocampus does play an important role in TLE. Positron emission tomography (PET) studies demonstrate that the most significant hypometabolism is seen in the lateral temporal and medial temporal regions, with the degree of hypometabolism correlating with the severity of hippocampal pathology. ⁹ Hippocampal cell densities are significantly related to the amount of hypometabolism in the thalamus and basal ganglia in TLE patients. ¹⁰ Further, anteromedial temporal lobectomy, with removal of the hippocampus and amygdala, controls seizures and leads to improvement of the pre-operative hypometabolism in the remaining areas of the temporo-limbic network (e.g. inferior frontal temporal lobe, ipsilateral temporal neocortex and medial thalamus). ¹¹ Stauder ¹² was the first to associate hippocampal sclerosis with TLE. He made a list of ictal symptoms and signs attributable unequivocally to temporal lobe disease (olfactory and gustatory auras, sensory aphasia and paraphasia, vertigo, auditory hallucinations or illusions and dreamy states) and correlated these with the postmortem pathology of 53 cases of “genuine epilepsy.” Sixty eight percent of the brains showed hippocampal sclerosis, of which 80% had definite and another 11% probable symptoms of “genuine epilepsy,” whereas none of those without hippocampal sclerosis showed symptoms. Falconer ¹³ who developed the technique of en bloc resection of the temporal lobe for treatment of drug-resistant epilepsy, found a high correlation of good surgical outcome with mesial temporal sclerosis in the resected temporal lobe. Further, intracranial EEG recordings in patients with TLE associated with hippocampal sclerosis show that seizures originate in the sclerotic hippocampus. ¹⁴ More recently, a multicenter study of seizure outcome after medial temporal resective surgery reports that hippocampal atrophy (sclerosis) and a history of absence of tonic-clonic seizures were the sole predictors of remission of seizures 2 years after surgery. ¹⁵

Bratz ⁶ suggested that the hippocampal pathology in TLE cannot be assumed to be a consequence of seizures but must play a pathogenetic role. Whether hippocampal sclerosis is the cause or a consequence of seizures, has remained a topic of lively debate over the years. Several more recent observations indicate that hippocampal sclerosis is probably not a consequence of seizures. MRI volume measurements show that the degree of hippocampal atrophy is not correlated with the duration and severity of seizures. ¹⁶ Some patients with multiple daily seizures since infancy do not have hippocampal sclerosis. ¹⁷ Likewise, a study of post-mortem hippocampi from patients with poorly controlled seizures has confirmed a subgroup with an absence of significant neuronal loss despite decades of seizures. ¹⁸ Additionally, hippocampi surgically removed from a large series of patients with temporal lobe epilepsy show that in about 15% of them (paradoxical temporal lobe epilepsy) there is no hippocampal sclerosis or evidence of extra hippocampal mass lesions, though their seizure semiology and history is indistinguishable from those with hippocampal sclerosis. ⁷ Thus, seizures themselves do not result in hippocampal sclerosis. A more detailed and careful investigation of the histopathology of the sclerotic hippocampus and its relationship to the pathogenesis of human TLE is important, and since the 1980’s there has been resurgence in investigations of the histopathology of the hippocampus in TLE. This renewed effort was ignited by a wider use of the technique of en bloc resection of the hippocampus by neurosurgeons ^{19, 20} and the availability of new methods for histological analysis. This chapter will attempt to summarize this considerable body of recent literature, various aspects of which have been the subject of other detailed reviews. ^{7, 21, 22}

HISTOPATHOLOGICAL VARIATIONS IN TLE HIPPOCAMPUS

In their now classic study, Margerison and Corsellis ²³ examined the brains of 55 epileptic patients postmortem, in which clinical and electroencephalographic assessments of seizures during life were available. The hippocampi of this group showed varying degrees of histological change. Thirty five percent of the hippocampi showed no evidence of neuronal loss bilaterally while the remainder showed varying degrees of hippocampal sclerosis, ranging from classical hippocampal sclerosis (40%) to end folium sclerosis (25%). With the advent of surgery for the control of intractable epilepsy, further analyses of excised hippocampi were undertaken. Bruton ²⁴ identifies a variety of hippocampal pathologies using neuronal and myelin stains. ²³ More recently, in another surgical series the use of neuronal cell counts with immunohistochemical stains for neurotransmitters, has led to the identification of several variations in the histopathology of the hippocampus in patients with medically intractable TLE. ^{7, 25} Based on conventional histopathologic criteria, hippocampi were divided into two groups – those without classical hippocampal sclerosis (compared to autopsy controls from neurologically normal subjects) and those with hippocampal sclerosis (Figure 1). Those without classical hippocampal sclerosis had a small loss (<25%) of neurons throughout the hippocampus, with hippocampal volumes similar to autopsy controls and none of the immunohistochemical changes observed in the sclerotic hippocampi. However, these non-sclerotic hippocampi are divisible into two sub-groups based on epilepsy etiology: the mass-associated TLE group (MaTLE) had an extrahippocampal temporal lobe mass lesion (low grade gliomas, cavernomas), as opposed to a group described as “paradoxical” temporal lobe epilepsy (PTLE) in which such mass lesions were absent and there was no history of febrile seizure or other identifiable etiological factors. Distinctive patterns correlating neuronal densities of the dentate gyrus and all areas of Ammon’s horn, electrophysiologic measures, and power spectral densities further differentiate these sclerotic and non-sclerotic groups. ^{7, 25, 26} The hippocampi with hippocampal sclerosis (MTLE) show more extensive neuronal loss and some distinctive histopathological features. These features could be grouped under two broad categories: First, features associated with the neural reorganization of the dentate gyrus; and the second, the proliferation of astrocytes accompanying neuron loss in the Ammon’s horn (Cornu Ammonis; CA), especially noticeable in area CA1. The details of these changes are described in the sections below.

Figure 1

Photomicrographs of coronal sections of the hippocampus from a non-sclerotic (A) and sclerotic (MTLE) hippocampus stained with Cresyl Violet. (A) The non-sclerotic hippocampus is from a temporal lobe epilepsy patient with an extrahippocampal mass lesion (more...)

REORGANIZATION OF THE DENTATE GYRUS IN SCLEROTIC HIPPOCAMPUS

Changes in Neurotransmitter Receptors

Associated with the reorganization of neurons and neural circuits in the dentate gyrus of the sclerotic hippocampus (MTLE) are several changes in the distribution of neurotransmitter receptors within the dentate gyrus as compared to non-sclerotic surgically removed hippocampi (MaTLE and PTLE) and neurologically normal autopsy controls. These changes are summarized in Table 1. Several receptor subtypes that mediate glutamatergic transmission are changed. The AMPA type receptor GluR 1 and GluR2/3 subunits are increased on the apical dendrites of the granule cells throughout the IML while the GluR2/3 subunits are also increased on the granule cell bodies. ⁵⁵ Such an increase in glutamate receptors may facilitate the excitation of granule cells through glutamatergic inputs such as the recurrent collaterals from mossy fibers or glutamatergic inputs from surviving hilar mossy cells (which terminate in the IML), and entorhinal inputs (which synapse on dendrites in the outer ML). ²² Up regulation of these AMPA type receptor subunits on the thorny excrescences of mossy cells ⁵⁶ suggests a facilitation of glutamatergic transmission from remaining granule cells through surviving mossy cells. The role of the metabotropic receptor subtypes (Table 1), which are also upregulated in the molecular layer and the granule cell layer, ^57–59 is unclear at present but may modulate excitatory and/or inhibitory effects. ⁶⁰ Concomitant with up regulation of these glutamate receptors, there is also evidence of upregulation of inhibitory receptors. Thus, the GABA_A receptor subtypes α1 and α2 ⁶¹ along with GABA_B receptors ^{62, 63} are upregulated on the granule cells somata, with the GABA_A α2 subtype significantly upregulated also on the proximal portion of the granule cells dendrite in the IML. ⁶¹ GABA_A and GABA_B receptor subtypes are also upregulated in the hilus, though their exact cellular location is unclear. ⁶¹ The receptors for somatostatin are upregulated in the granule cell layer and dentate molecular layer, particularly the IML as well as the hilus, ^{64, 65} and are consistent with the sprouting of somatostatin containing axons into these regions. ⁴⁰ Likewise, the NPY-Y2 receptors are upregulated on the granule cell layer and the IML as well as the hilus, ^{65, 66} consistent with the sprouting of NPY positive axons in these regions. The dopamine D2 receptors are upregulated in the granule cell layer and IML ⁶⁷ while VIP receptors are upregulated in the granule cell layer and hilus. ⁶⁸ Several of these receptor changes -- somatostatin, NPY-Y2, GABA, dopamine D2 and some of the mGluR receptors may be involved in increasing the inhibition of the excitability of surviving granule cells. ⁶⁹ It thus appears that in the sclerotic hippocampus, along with processes that facilitate hyperexcitability, there are also several reorganizational changes that seem to reestablish inhibition, though perhaps inadequately.

TABLE 1

Neurotransmitter Receptor Localization in the Dentate Gyrus of the Sclerotic (MTLE) Hippocampus.

CHANGES IN AMMON’S HORN AND THE ROLE OF ASTROCYTES

GENE EXPRESSION IN SEIZURE FOCUS

In recent years, several high throughput gene expression analyses of hippocampal tissue from TLE patients have been reported. ^{112, 121, 122} The most interesting of these studies are those that have compared the expression patterns in sclerotic hippocampi with those of non-sclerotic hippocampi. Unbiased hierarchical cluster analysis of expression data reveals that the gene expression patterns of sclerotic hippocampi from TLE patients usually cluster closely together suggesting that they have molecular characteristics distinguishable from other TLE subtypes (Figure 2). ^{112, 122} While there is variability among studies on the specific genes that are selectively expressed, there is considerable agreement on some of the functional groups of genes that are differentially expressed in the sclerotic hippocampus. In our own laboratory, we compared the CA1 region from TLE patients with hippocampal sclerosis (medial temporal lobe epilepsy with sclerosis, MTLE) with those from two groups of patients without sclerosis (MaTLE and PTLE, see ⁷). Comparison of this study with other studies is published elsewhere. ¹¹² On examination of the genes selectively expressed in all MTLE hippocampi, increased expression of genes belonging to three important categories are recognized – astrocyte associated genes, immune and inflammatory response genes, and genes associated with the endothelial cell-astrocyte interface.

Figure 2

The comparison of the gene expression patterns in 20 hippocampi from patients with TLE. The dendrogram was obtained by unsupervised hierarchical cluster analysis using Gene Spring software. The analysis included all genes expressed in a microarray analysis (more...)

Among the astrocyte related genes upregulated in MTLE are: (1) those associated with astrocyte morphology -- GFAP is associated with astrocyte process extension, paladin (KIAA0992) regulates astrocyte shape, and plectin 1 (PLEC1) serves as a structural protein. The genes ezrin, radixin and moesin control three closely related proteins (ERM proteins), which constitute the machinery for association of actin filaments to the plasma membrane. (2) the CD44 family of surface glycoproteins whose cytoplasmic domain is directly associated with the ERM proteins. (3) the extracellular matrix proteins tenascin (TNC) and chondroitin sulphate phosphoglycan 2 (CSPG2). (4) S100A6 and S100B - members of a family of proteins involved in Ca²⁺ regulation with AHNAK being a target for S100B.

In addition to the molecules associated with the microvasculature described above (see above, “astrocytes and vasculature”), the ligands CCL3 and CCL2 for the chemokine receptors CCR1 and CCR2 found on the microvasculature ¹²³ are increased in MTLE. CCL4 is also upregulated on astrocytes. ^{112, 122} The binding of these ligands to their receptors on blood vessels may influence their permeability and perhaps leakage during seizures.

Several genes involved with immune and inflammatory responses are also upregulated. These include those regulating chemokines and their receptors, cytokines and their receptors, signal transduction proteins, transcription factors, transcription factor related genes, and class II major histocompatibility complex genes. The particular genes belonging to these categories are listed in Lee et al. ¹¹² Many of these immune and inflammatory factors are probably produced by astrocytes. ^{124, 125} Indeed, immunohistochemical localization of interleukin (IL)-1β and IL-1R in sclerotic hippocampi reveals their expression on astrocytes in areas of prominent gliosis and neuronal loss (CA1 – CA3 and hilus) particularly in perivascular end feet. ¹²⁶ Likewise, immunohistochemical localization of complement C1q, C3c, C3d, and C5b – C9 show that C1q, C3c and C3d are localized in astrocyte-like cells only in sclerotic hippocampi. C5 – C9 are not on astrocytes. Experimental studies in animals indicate that molecules such as IL-1β and complement are closely associated with seizure generation. ¹²⁷

SUBICULUM

The subiculum is the region of the hippocampal formation from which major efferent pathways originate ¹²⁸ and is involved in the spread of electrical activity from the hippocampus to other parts of the brain generating behavioral activity. Even in sclerotic hippocampi in MTLE patients, the subiculum remains largely intact with no detectable neuron loss. ^{8, 129, 130} However, Cohen et al. ¹³¹ report that the subiculum of the sclerotic hippocampus initiates spontaneous interictal discharges that originate in a minority of subicular neurons, including interneurons and a subset of GABAergic pyramidal neurons in the subiculum and its transitional area with CA1. This paradoxical behavior of GABAergic neurons, which are normally inhibitory but behave as excitatory cells in the subiculum, has found an explanation in recent research. This switch of GABAergic neurons from inhibitory to excitatory relates to relative expression of two Cl cotransporters – Na⁺K⁺, 2Cl cotransporters such as NKCC1, which accumulate Cl⁻ in the cell, and Cl⁻ extruding K⁺, Cl co-transporters like KCC2. Alterations in the balance of NKCC1 and KCC2 determine the switch from hyperpolarizing to depolarizing effects of GABA. Immunohistochemical localization and quantitative RT-PCR analysis mRNA extracted from subiculum have suggested that greater than 20% of NKCC1-expressing pyramidal neurons in the sclerotic subicular/CA1 transitional zone not only lacked KCC2 but exhibited increased NKCC1. This pattern contrasts with about 95% co-localization in non-sclerotic patients. ^132–134 Increased Cl⁻ in cells produces depolarization when GABA-mediated chloride channels are opened. Thus, it is suggested that altered Cl⁻ transport renders GABA neurons aberrantly excitable, contributing to the precipitation of seizures. ¹³⁴ However, Wozny and coworkers ¹³⁵ provide evidence, also obtained from slices of surgically removed hippocampal tissue, that interictal spontaneous activity is seen not only in sclerotic hippocampi but also non-sclerotic hippocampi. Thus, the subiculum of the sclerotic hippocampus may not be involved in a epileptogenesis uniquely in sclerotic hippocampus. this region of the hippocampal formation may be a more generally excitable zone than other regions.

ENTORHINAL CORTEX

The entorhinal cortex (EC) is a principal source of efferents to the hippocampus, with major projection to the dentate gyrus (perforant pathway) and CA1 (temporo-ammonic pathway). Abnormal epileptiform activity has been recorded from this region. ^{136, 137} Histopathological studies of this region in TLE patients report neuronal loss and gliosis in layer III and, to a lesser extent in layer II of the anterior portion of the medial entorhinal cortex of the sclerotic hippocampus. ¹³⁸ However, other studies have reported a more variable pattern of neuronal loss ¹³⁹ or no detectable loss. ¹⁴⁰ Nevertheless, gliosis is a finding common to the EC in both sclerotic and non-sclerotic hippocampus. ¹⁴⁰ Primary cultures from the EC (parahippocampus) of patients with a sclerotic hippocampus had increased Ca2+ release and Ca2+ oscillations in astrocytes. ⁸³ If Ca2+ release is associated with glutamate release, these cells may trigger hyperexcitation of EC neurons and thus spread activity through the hippocampus. More needs to be learned about the role of these glial cells in the EC region.

PROBABLE PATHOPHYSIOLOGICAL MECHANISMS OF SEIZURE GENERATION

The probable pathophysiological mechanism of seizure generation must take into account the complex histopathological picture sketched above. Prominent features of this histopathology – a reorganized dentate gyrus, a neuronally depleted and gliotic Ammon’s horn with an essentially intact and even spontaneously active subiculum -- constitute the epileptogenic hippocampus.

Broadly, two sets of processes that have distinct histological substrates may be identified. The first set of processes are based in the dentate gyrus and may be important at least in the early genesis of the epileptic focus, before the loss of dentate granule cells is extensive. In this presumed early phase of pathogenesis, several cellular changes may underlie the development of hyper-excitable granule cells. These processes involve morphological remodeling of surviving granule cells, selective loss of hilar interneurons, sprouting of new axonal projections, and adaptive changes in neurotransmitter receptor distribution, representing a reorganization of the neural circuits within the dentate gyrus. An attempt to integrate these changes and hypothesize how they may result in granule cells hyperexcitability is given in de Lanerolle & Lee (²², see Figure 1).

Despite the existence of such hyperexcitable granule cells, unanswered is the question of how such hyperexcitability passes from the granule cells to the subiculum to generate behavioral seizures, since the neural pathways connecting the two are interrupted due to extensive neuronal loss in the CA1 area early in pathogenesis. One hypothesis is that in the sclerotic region NG2 like cells, which are depolarizable and excitable, provide a substrate for the spread of waves of depolarization from the dentate gyrus to the subiculum. An alternative though less likely possibility is that the neural networks in the stratum oriens, which are very resistant to loss, provide a sufficient substrate for spread of neural excitation from dentate to subiculum.

It is notable that in several surgically removed hippocampi, the dentate gyrus is almost completely devoid of granule cells and Ammon’s horn is very gliotic; yet such hippocampi may take part in seizure generation in these patients. Seizures have been shown to originate from such hippocampi ¹⁴ and in vivo dialysis studies demonstrate elevated extracelluar glutamate ictally in such foci. ^{105, 141} In such hippocampi, the subiculum remains intact; however, the evidence, as discussed above, that the subiculum by itself is responsible for epileptic activity is weak. Alternative explanations must therefore be considered, such as astrocyte and astrocyte-related mechanisms. The unique properties of astrocytes in the hippocampal seizure focus are reviewed above, and an attempt to integrate these properties in the pathophysiology of epilepsy is provided in de Lanerolle et al. ⁸⁰ Astrocytes may contribute to vascular permeability and increased extracellular glutamate and K+ levels in the sclerotic hippocampus, which in turn may contribute to the hyperexcitability of the subiculum resulting in epileptic activity.

SPECULATION ON FUTURE CHALLENGES IN THE AREA

Our knowledge of the histopathology of temporal lobe epilepsy has advanced significantly over the recent past. However, we are still engaged largely in descriptive pathology. One of the major challenges for the future is to understand the functional significance of the various changes observed. Of primary importance is an understanding of the functional biology of astrocytes and astrocyte-like cells in the sclerotic hippocampus. We have advanced several hypotheses regards their role, but these need experimental testing. What is the proportion of GluR- and GluT-like astrocytes? How do they contribute to the increased extracellular glutamate and K+ concentrations observed at the sclerotic seizure focus? Much of our information of their role in these mechanisms has come from the study of astrocytes from embryonic animal tissue, and very little from the study of adult astrocytes from human foci. Do these abnormal astrocytes provide an excitable substrate for the spread of neural excitation from the dentate to the subiculum? Understanding the biology of astrocytes in TLE sclerotic foci would be very useful in providing insight into the epileptogenic mechanisms of other seizure foci such as mass lesions, tubers in tuberous sclerosis complex, and many of the neocortical epilepsies in which astrocytes may be a major constituent.

Our understanding of the functional implications of the anatomical changes in the dentate gyrus in the human also remains sketchy. Though much attention has been given to certain aspects such as the functional significance of granule cell sprouting and glutamatergic and GABAergic mechanisms regulating granule cell function in the sclerotic hippocampus, there is far less experimental analysis of the significance of other changes such as the new neuropeptidergic inputs to granule cells and the changed distribution of the several receptors. Studies that attempt to correlate the time course of functional changes resulting from dentate gyrus reorganization and abnormal astrocytes in the sclerotic human hippocampus are essential for the better understanding of the causative mechanisms of human TLE.

IMPACT ON FINDING CURES AND REPAIRS FOR EPILEPSIES

The current antiepileptic drugs and other repair strategies have focused attention almost exclusively on neurons as the primary cell type involved in mechanisms underlying epilepsy. The existence of a large group of patients with drug refractory epilepsy is evidence that more effective therapeutic measures are required. The activity of the currently available antiepileptic drugs broadly target glutamatergic and GABAergic mechanisms, though they may have other effects as well. They are mediated through three main mechanisms – blockade of voltage-gated sodium and calcium channels that limit glutamate release; blockade of glutamate receptors, and the potentiation of GABAergic inhibition, through increasing GABA availability or modulation of GABA receptors. ^{142, 143} The histopathology of the epileptic hippocampus reviewed above, which shows that there is extensive loss of neurons in the hippocampus, suggests why current antiepileptic drugs, which focus on modulating functions of neurons, may be ineffective. New therapeutic agents should target astrocytes and astrocyte-like cells instead of neurons, as these cells are the primary constituents of the sclerotic hippocampus. Cell replacement strategies might consider transplantations of human stem cells that may develop into normal astrocytes that may restore a more normal extracellular glutamate concentration in the seizure focus, and compensate for the abnormal astrocytes.

ACKNOWLEDMENTS

We thank Ms. Ilona Kovacs our histology associate over the past 25 years, whose outstanding expertise has contributed greatly to all of the studies from our laboratory. We also thank our many collaborators who contributed to the studies from our laboratory reported in this paper, especially Drs. Michael Brines, Tore Eid, Jung Kim, Matthew Phillips, Sanjoy Sunderasen, John Tompkins, Subu Magge and Edward O’Connor.

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