Hippocampal lesions in epilepsy: A historical review

HIPPOCAMPAL LESIONS IN EPILEPSY:A HISTORICAL REVIEW

Robert lnstitut

de

Neurobiologie

Alfred

Naquet Fessard,

CNRS

Gif

I. Introduction 11. From the 19th Century to the End of the 1950s III. From the 1970s to the Present A. Role of Generalized Seizures and Generalized Status Formation of Hippocampal Lesions B. Role of Limbic Seizures and Limbic Status Epilepticus Hippocampal Lesions IV. Conclusions: From Animal Data to Febrile Convulsions, “Temporal Lobe Epilepsy” in Humans References

sur Yvette,

France

Epilepticus

in the

in the Induction Hippocampal

of Lesions,

and

I. Inlmduction

It has been known since the 19th century that epilepsy in humans is frequently associated with lesions in different structures of the brain (Bouchet and Cazauvielh, 1825; Sommer, 1880; Pfleger, 1880). For example, epilepsy-related hippocampal, cerebellar, and neocortical damage has been reported. Without ignoring the importance of the two latter regions, this review focuses on lesions of the hippocampus (also referred to in the literature as Ammon’s horn, or cornu Ammonis). Historically, two periods may be emphasized: the first from the 19th century to the end of the 1950s and the second from the 1970s to the present. It is only in the last 50 years that there has been important progress in documenting the presence of such lesions, in understanding the mechanisms involved in their origin, and in understanding their relationship to epileptic seizures, in particular, “status epilepticus.” Despite all this progress, one is surprised by the fact that the mechanisms proposed to be responsible for certain types of epileptic seizures, that is, those that appear later in life, cannot always be demonstrated with certainty. The subject is difficult due to the multiplicity of eliciting factors involved in humans and the difficulty of extrapolating findings from animal models. As a consequence, one finds a yearly increase in the literature of convergent and contradictory data leading to different concluINTERNATIONAL NEUROBIOLOGY,

KEVIEW OF VOL. 45

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Copyright Q 2001 by Academic Press. All rights of reproduction in any form reserved. 0074.774PiOl $35.00

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sions. To be correctly informed about the progress that is being made, one needs to read the literature on the subject almost continuously. The best review cannot be complete; each author needs to make a choice and if one wants to follow the “exact” evolution of ideas in the field, one needs to read and compare different reviews published. Good examples are three recently published reviews (Meldrum, 1997; Fisher et al., 1998; McNamara, 1999); this chapter most likely includes the same omissions and defaults. It would have been an error if, in this historical review, I had not mentioned the pioneering contribution of Frank Morrell to mechanisms underlying the induction of “secondary lesions.” It is my privilege to have been his friend. I had the chance to meet him in Montreal in 1954 when we were working independently in the laboratory of Herbert Jasper. We then collaborated on two different occasions when he came to work in Marseilles, first in the laboratory of Henri Gastaut in 1956 and later in my laboratory in 1968. In 1956, the term neuronal plasticity was not “a la mode,” particularly in epilepsy research. Being in favor of the existence of the phenomenon in the emergence of different brain functions, Frank Morrell introduced the concept to explain the development of a “mirror focus” following the induction of focal cortical epileptic lesions (Morrell, 1961). As is the case with many new concepts, this one was not immediately accepted by the scientific community. But the experiments that he carried out in subsequent years and a great deal of the data reported in this historical review indicate that Morrell was right, and that neuronal plasticity plays an important role in the genesis of a secondary epileptogenic lesion.

II. From

the 19th

Century

to the End of the

1950s

After the first observations published in the 19th century, one has to wait until the 1950s to find any specific interest in the study of “temporal lobe epileptic seizures,” also referred to as “uncinate fits,” “psychomotor seizures,” and, more recently, “complex partial seizures.” Such interest was the result of information gathered after the Second World War with the development of new technologies available in clinical and experimental epilepsy, and considered to be sufficient for understanding the mechanisms underlying psychomotor seizures as well as hippocampal lesions. In retrospect, however, the data obtained with the available techniques were only descriptive and did not allow definitive answers to the questions raised with respect to humans or animals.

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Moreover, pathologists emphasized neuronal death rather than remodeling in the involved structures, although some of them recognized the role of proliferating astrocytes in scar tissue. For many neurophysiologists, neurologists, and neuropathologists, it was important, following the descriptions by Stauder (1935) and by Gibbs et al. (1937), to determine precisely: (1) the exact clinical and electroencephalographic symptomatology of temporal lobe epileptic seizures; (2) the relation between these defined seizures and the ones known to start in different structures of the rhinencephalon, in humans and animals; and (3) the relation between seizures of temporal lobe origin and the existence of hippocampal lesions. The symptoms of epileptic seizures induced in the cat by electrical stimulation of the amygdala and the hippocampus, and the relationship of the seizures to the symptomatology of temporal lobe seizures in humans, was rapidly demonstrated. This, however, was not the case for the existence of hippocampal lesions. Such lesions were not always present, but when they existed, the question raised was: Do epileptic seizures cause hippocampal lesions or are they secondary to them? To explain the relation between seizures of temporal lobe origin and hippocampal lesions, different theories were proposed during three colloquia organized in Lisbon (Colloquium, 1953), Marseilles (Colloquium, 1954), and Bethesda (Baldwin and Bailey, 1958) and in the years to follow. It is worth summarizing these symposia to analyze in detail the theories proposed as an explanation of the results obtained during this period. In brief, one may quote the following hypothesis for the origin of hippocampal lesions: In humans it was proposed that “from the description of the histological changes, it is clear that the secondary lesions in the cornu Ammonis have all the characteristics of the sequelae of anoxia or of disturbances of the circulation” (Gastaut et al., 1959). These authors admitted also that “the chain of pathogenic events is complex and much, at present, remains conjectural,” that hippocampal lesions may precede or follow the onset of temporal lobe seizures, and that such lesions may coexist, being independent, or may even be absent in patients presenting with psychomotor seizures. When hippocampal lesions preceded the onset of seizures, they were considered to be a possible consequence of local ischemia caused by compression of the arteries at the base of the brain or of other vessels in contact with bone or with the tentorial membrane of the falx (Lindenberg, 1955). This compression of the vessels was considered to be the result of an acute rise in unilateral intracranial pressure provoked by different factors such as: (1) closed head trauma (contre-coup mechanism); (2) obstetrical trauma (in agreement with the concept of incisural sclerosis put

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forward in Earle et al., 1953; as well as views expressed by Gastaut, Scholz, and Meyer; see Gastaut et al., 1959); or (3) focal edema associated with status epilepticus and temporary hemiplegia, due particularly to a phlebitis infectious in origin. This edema was considered to be responsible for temporal herniation through the tentorium and for the compression of some vessels providing the vascular supply of this territory (Green et al., 1957; see also Beaumanoir and Roger, 1999). When associated with the onset, some years later, of temporal lobe seizures, this particular syndrome was called “hemiconvulsions-hemiplegia-epilepsia” or HHE syndrome (Gastaut et al., 1957: 1959-1960). When hippocampal lesions followed “generalized” seizures, they were considered to be a consequence of disturbances in cerebral circulation during and after epileptic convulsions. This theory introduced by Pfleger (1880) was based on the fact that some brain structures are more sensitive to anoxia (“pathoclyse” of Vogt of the Sommer sector of Ammon’s horn) induced by seizures. This anoxia was attributed either to angiospasm (Spielmeyer, 1927) or to selective anoxia of this most vulnerable part of the hippocampus during seizures (Scholz, 1956). Many authors supported such theories, insisting that the “primum movens” of temporal lobe seizures was frequent idiopathic grand ma1 seizures or “generalized status epilepticus” (Sano and Malamud, 1953; Malamud, 1966; Weller and Norman, 1955). Some authors, however, insisted that Ammon’s horn sclerosis occurred mainly in epileptics with the onset of seizures before the 12th year, and that in such cases the sclerosis was a consequence not only of a greater number of grand ma1 attacks, but also of birth injury or of an initial severe status epilepticus (Meyer et al., 1954; see also Meldrum, 1997). In contrast, others claimed that in idiopathic, long-standing epilepsy, there is no correlation between the number and severity of seizures and the occurrence of hippocampal lesions (Adams, 1962). According to Adams, seizures and brain lesions were related to the causative factor and the mechanism of the disease, but one did not cause the other. When lesions occurred, they were probably related to circulatory collapse, arterial hypotension, cardiac arrest and so on, resulting in a grave disparity between the level of cerebral metabolism and the oxygen supply. During this period, no explanation was proposed for the lack of correlation seen between seizures and secondary hippocampal lesions. Gastaut et al. (1959) insisted that they had never seen a lesion of the cornu Ammonis in patients who suffered only from periodic grand mal, even if this occurred at short intervals over a long time. Similarly, no lesions were seen in patients after the most extensive electric shock treatment (Corsellis and Meyer, 1954). In addition, Morel and Wildi (1956) and Adams (1962) re-

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ported that some of their epileptic patients did not show hippocampal lesions, whereas such lesions were also found in people without epilepsy. Turning to the animal literature, psychomotor seizures very similar to those seen in humans were demonstrated in adult cats either using electrical stimulation (Gastaut et al., 1951, 1952a,b; Naquet, 1953) or by producing rhinencephalic scars (Gastaut et al., 1953; Gastaut and Roger, 1955; Roger, 1954). At that time, only cats could be used because of the stereotaxic equipment available. These techniques were then used to investigate the role of the hippocampus in this type of epilepsy and the eventual lesions associated with it (Gastaut et al., 1959; Naquet et al., 1962). Although different models were used, the data obtained and their interpretation were more or less concordant. These results demonstrated the following: Hippocampal damage is not a necessary requirement for the initiation of psychomotor seizures, but if such damage exists in association with a neighboring lesion, then it promotes seizures. An ischemic mechanism may be at the origin of secondary lesions and of grand ma1 attacks, but the severity of status epilepticus is associated with anoxic sequelae much less frequently than had been previously suggested (Gastaut et al., 1959). Cerebral edema (never comparable to that associated with HHE syndrome in terms of its intensity and its bilaterality) or status epilepticus may be responsible for secondary lesions. In the case of status, these lesions appear more readily if the animal is sacrificed later in the course of its evolution. Moreover, these lesions do not always coincide in time with the initial lesion responsible for the seizures. They can be secondary to the onset of the initial lesion when this primary lesion induced focal status epilepticus. l

l

l

These results “bring in question the responsibility of a status in determining hippocampal lesions by means of any kind of mechanisms”; in such cases, a hypoxic mechanism different from an ischemic one was proposed for their origin (Naquet et al., 1962). It was difficult at this time to go further with the investigation of the mechanisms responsible for such damage because in freely moving cats, it was impossible to induce generalized status with metrazol to see if it was responsible for secondary lesions in the hippocampus (Gastaut et al., 1959). Some years later, the role of status epilepticus in the initiation of hippocampal lesions was reconsidered and it was proposed that, among other complex factors, status epilepticus may act through circulatory or blood pressure changes and concomitant metabolic modifications (Naquet et al., 1962).

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NAQUET

the 1970s

to the Present

It is only in the 1970s that experiments aimed at studying the relationship between hippocampal lesions and epilepsy were initiated again. The progressive development of new technologies led to a better description of the nature of hippocampal lesions, the conditions under which they appeared, and the mechanisms responsible for them. The emphasis here is on animal experiments, but some important data published in humans are added at the end of this review.

A. ROLE OF GENERALIZED EPILEPTICUS

SEIZURES AND GENERALIZED STATUS IN THE FORMATION OF HIPPOCXMPAL LESIONS

The role of generalized seizures and generalized status epilepticus (Meldrum and Horton, 1971) in the development of hippocampal lesions was examined using new animal models and different experimental conditions. Generalized seizures in the form of status epilepticus were induced by injection of bicuculline in baboons and produced stereotyped patterns of hippocampal damage (Meldrum and Brierley, 1973; Meldrum et al., 1974; see also Naquet et al., 1982; Meldrum, 1997). These results demonstrated that such status does not induce temporal herniation, and that there is a good correlation between the occurrence and severity of ischemic cell change in the hippocampus and the duration of electrographic seizure discharge (the threshold for damage was around 90 min). It was proposed that other factors caused by seizures, such as the duration of hyperpyrexia, the occurrence of hypoglycemia, and the duration of arterial hypotension, may have played a role in the induction of such lesions. In experiments in which such changes were largely eliminated by muscular paralysis with artificial ventilation, it was possible to demonstrate that hippocampal pathology was the result of focal seizure activity, rather than systemic changes modifying the local supply of oxygen and glucose (Meldrum et al., 1973). These results were confirmed in a series of experiments in rats using different techniques, in particular, those that measured oxygen consumption (Siesjo and Abdul-Rahman, 1979; Pinard et al., 1987). The studies showed that status epilepticus, irrespective of the compound used to induce it, was associated with sustained enhancement of cerebral blood flow and cerebral metabolic rate for oxygen utilization. For the time being, most investigators appear to agree with the concept that “continuous seizure activity for tens to hundreds of minutes . . ., has been shown to kill neurons, even in well oxygenated animals” (McNamara, 1999).

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LESIONS IN EPILEPSY

Generalized seizures resulted in neuronal retraction and rarefaction in the vulnerable sector of the hippocampus only when they were frequently induced (e.g., 66 seizures in 7% months at the rate of 2 or 3 per week) by intermittent light stimulation in very photosensitive Pupio papie (Riche et al., 1971). It was already known, however, that this form of generalized seizures was cortical in origin and did not automatically involve the hippocampus (Fischer-Williams et al., 1968). Generalized seizures induced very frequently (e.g., more than 26 seizures in one day) in P. papio shortly after injection of allylglycine led to some symmetrical neuronal loss in the end folium and a similar but asymmetrical change in Sommer’s sector (Meldrum et al., 1974). These changes were less severe than those associated with sustained seizures induced by bicuculline, but were more substantial than those induced by intermittent light stimulation alone in the naturally photosensitive baboon. Such experiments supported the concept that the intensity, the repetition at short intervals, and the duration of the seizure discharge itself influence the occurrence of acute brain damage in the hippocampus by a mechanism independent of systemic physiological changes. The question of the equal severity of the abnormal electrical discharge in all brain regions was first raised without an answer (Naquet et al., 1982). Later, it was demonstrated that bicuculline produced limbic seizures at threshold doses and generalized seizures at higher doses (Meldrum, 1997), accompanied by very strong activation of limbic metabolic activity (Siesjo and Abdul-Rahman, 1979). These results demonstrated indirectly that secondarily generalized seizures induced by bicuculline should be considered different from generalized seizures generated by other compounds or stimuli. Since generalized seizures and generalized status do not always bring the same brain structures into play, it is not surprising that an explanation can be found for the existence or absence of hippocampal lesions.

B. RULE <)F LIMBIC INDUCTION

SEIZURES AND LIMBIC OF HIP~OCAMPAL LESIONS

STATUS EPILEPTICUS

IN THE

The extensive study of the role of limbic seizures and limbic status in creating hippocampal lesions started at the beginning of the 1980s. The development of neurophysiological, neuroanatomical, and neuroimaging technologies also led to a further understanding of the mechanisms involved in the creation of an epileptogenic cicatrix following repetitive hippocampal seizures.

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It was known at the end of the 1970s that intracerebral injection of kainic acid (KA) could provoke neuronal damage at the site of injection or indirectly in the hippocampus (Olney et al., 1974; Olney, 1978; Nadler et al., 1978; Wuerthele et al., 1978). Almost at the same time it was demonstrated that amygdaloid injection of KA in the rat induced behavioral and electrographic symptoms corresponding to a “secondarily generalized status epilepticus.” If the duration of the status was long enough (between 2 and 6 h), it was followed by secondary lesions of the hippocampus (Ben-Ari et al., 1979a, 1981; see also Best et al., 1994; Lothman and Collins, 1981; Nadler, 1981). Transection of the perforant path (Ben-Ari et al., 1980) diminished the epileptic consequence of the injection of KA in the amygdala (i.e., seizures and secondary hippocampal lesions). If the status was blocked by an injection of diazepam within 2 h of the onset of the seizures, hippocampal lesions did not appear (Ben-Ari et al., 1979b). On the other hand, if the evolution of the status was not modified, some of the animals presented with recurrent secondary spontaneous seizures (Cavalheiro et al., 1982; Pisa et al., 1980). Similar effects of intraamygdaloid injection of KA were observed in other species, one of them being the baboon (Naquet et al., 1982). Following intraamygdaloid KA injection, P. papio developed clinical and electrographic limbic status (without any sign of generalization from the clinical and electroencephalographic points of view) and severe secondary hippocampal lesions (Menini et al., 1980). Subsequent to this period, a number of experiments have been undertaken to investigate the mechanisms responsible for the secondary lesions induced by KA and other compounds such as pilocarpine (Turski et al., 1989; Leite et al., 1990). The role of these agents in the induction of seizures has been widely discussed (Ben-Ari, 1981, 1985; Meldrum, 1997; Fisher et al., 1998). The importance of the primary lesions induced by such compounds made the results obtained by their use difficult to extrapolate to humans; however, hippocampal lesions were also described, to a lesser extent, using other models. Among the latter one may include: (1) the prolonged electrical stimulation of the principal input to the hippocampus, which induces a selective loss of hilar cells analogous to that described in humans (Margerison and Corsellis, 1966) and sometimes damage to CA3 neurons (Sloviter, 1983, 1987; Sloviter and Damiano, 1981); and (2) kindling stimulations that are associated with a loss in neuronal density in the hilus (Cavazos et al., 1994; Sutula et al., 1988). These results, obtained in adult animals, demonstrated the role that limbic status epilepticus may play in the generation of a secondary localized hippocampal lesion. They also showed that these secondary lesions may become, with time, epileptogenic. The mechanisms responsi-

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ble for each of these events and their sequence are described in the following sections. 1. Cell Death During epileptic seizures there is an excessive release of excitatory amino acids (Dodd and Bradford, 1976). Glutamic acid is a neurotransmitter (N-methyl-n-aspartate (NMDA), o-amino-5-hydroxy-3-methyl-4isoxazolepropionic acid (AMPA), and kainate being the three major glutamate ionotropic receptors) with both neuroexcitatory and neurotoxic effects in mammalian neurons (Nadler et al., 1980). During seizures, this release of excitatory amino acids may cause neuronal damage leading to cell death analogous to that seen in I&induced seizures (Olney et al., 1974). This damage is most extensive in hippocampal regions, where, in the rat brain, the largest number of glutamate binding sites have been described (Monoghan and Cotman, 1985). The acute and selective neuronal death was attributed to the excessive release of Ca2+ entering neurons and the following succession of events (Meldrum, 1983; Sloviter and Dempster, 1985). Calcium enters the dendrites principally through activation of NMDA receptors (Evans et al., 1983; Griffiths et al., 1983). The mitochondria within focal dendritic swellings and in somata show massive calcium loading and progressive dilation. These changes may progress to necrotic cell death, “ischemic cell change” in vulnerable neurons, or fully reversible changes within about 10 min of seizure cessation (Griffiths et al., 1984). This selective seizure-mediated brain damage may be prevented by administration of noncompetitive NMDA antagonists (Rothman and Olney, 1987). Cell death has also been attributed to an increase in the permeability of the AMPA receptor ionic channel to calcium. In the normal animal, the presence of GluR2, one of the subunits of the AMPA receptor, renders the ionic channel impermeable to calcium. The reduction in its expression following KA-induced status epilepticus has been proposed to lead to neuronal damage (Friedman et al., 1994; Pollard et al., 1993). The induction of cellular death during status epilepticus has also attributed to other factors such as: (1) a decrease in inhibitory transmission due to a decrease in the expression of y-aminobutyric acid (GABA)-A and benzodiazepine receptor mRNA (Friedman et al., 1997; Titulaer et al., 1995a,b); and (2) modulation by free radicals, nitric oxide (Bauknight et al., 1992; Cheng and Sun, 1994; Montecot et al., 1998), zinc (Gall et al., 1991; Fujikawa, 1996), or calcium-binding proteins (Sloviter et al., 1991). Selective neuronal death is generally thought to be an acute phenomenon, but there is also evidence indicating that cells undergoing less stress may die with a significant delay due to apoptosis (Wasterlain et al., 1993; Pollard et al., 1994; Sloviter et al., 1996).

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2. From Cell Death to Epileptogenic Hi@ocampal

Cicatrix

This particular topic is in constant evolution. Many fascinating results have been published suggesting that the increase in the level of epileptogenicity of the hippocampus is due to the restructuring of the intrinsic networks of this structure and resultant hyperexcitability (Meldrum, 1997; Fisher et al., 1998; McNamara, 1999). One theory links aberrant axonal sprouting to the development of epilepsy. Hippocampal damage has been shown to be associated with sprouting on hippocampal glial and neuronal cells, particularly the mossy fiber axons of dentate granule cells reinnervating parts of sclerotic lesions (Nadler et al., 1980; Tauck and Nadler, 1985). In KA-treated animals, mossy fiber sprouting involves the formation of novel excitatory terminals by granule cell axons, either in the inner third of the molecular layer or in the dendritic fields of the CA1 pyramidal neurons (Ben-Ari and Represa, 1990; Represa et al., 1989). This aberrant mossy fiber sprouting is electrophysiologically functional and hyperexcitable (Tauck and Nadler, 1985) and is associated with the development of chronic seizures in KAtreated rats (Mathern et al., 1993). Synaptic reorganization of mossy fibers was also noted after pilocarpine kindling and after metrazol injection (Sutula et al., 1988; Golarai et al., 1992; Mello et al., 1993; Represa et al., 1993; Okasaki et al., 1995). Nerve growth factors may influence sprouting (Meldrum, 1997). For example, neurotrophins induce sprouting of cholinergic and mossy fiber systems (Holtzman and Lowenstein, 1995; Represa et al., 1994) and influence the kindling process. In contrast, antibodies to nerve growth factor (NGF) delay kindling and block sprouting (Van der Zee et al., 1995); however, the comparison between KA sprouting and the sprouting induced by kindling indicates that they are not identical. The mossy fiber sprouting observed after KA injection is predominant on or in the vicinity of cells expressing E-NCAM in late-developing or adult animals. Such reexpression of E-NCAM was not demonstrated in kindled animals (Le Gal La Salle et al., 1992). Summarizing data published in recent years, McNamara (1999), in a concluding paragraph on the subject, proposed that “the occurrence of mossy fiber sprouting in a sclerotic hippocampus with extensive loss of neurons led to the hypothesis that the stimulus that initiates mossy fiber sprouting is death of susceptible neurons, with axons of the surviving neurons (i.e., the granule cells) filling in vacated synapses.” Another theory is based on the role of “dormant basket cells” in epileptogenesis (Sloviter, 1991; Bernard et al., 1998; Fisher et al., 1998). Inhibitory basket cells may survive seizure activity while, in the

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same region, other cells (excitatory dentate mossy cells, neuropeptide Y, somatostatin-immunoreactive neurons) do not survive (Sloviter, 1991, 1994). Some of these neurons normally excite the inhibitory GABAcontaining basket cells, Although these basket cells may survive the excitotoxic effects of seizure activity, they lie dormant in the sense that they are hypofunctional because of a loss of excitatory input. Without this normally present inhibition, otherwise normal excitatory input can lead to excessive firing of granule cells, neuronal death, and, over time, the formation of an epileptic focus (McNamara, 1994). 3. The Phenomenon of “Death and Birth by Seizure”’ It has been demonstrated that 40 electrically induced seizures are sufficient to initiate apoptosis of a tiny fraction of neurons in the dentate gyrus (Bengzon et al., 1997). These dentate granule cells are generally considered to be less susceptible to “death by seizure” than their neighbors in the hippocampus (CA3, CA1 pyramidal cells, and mossy cells of the dentate hilus). The discrepancy between these data is the consequence of a specific property of these granule cells: their neurogenesis persists even into adulthood. Seizures induced by diverse stimuli increase the rate of granule cell proliferation by a particular type of plasticity, namely, “birth by seizure” (Parent et al., 1997, 1998). The observation that the number of granule cells seems to remain constant in most epilepsy models may be explained by the two competitive processes of apoptosis and neurogenesis. Moreover, although newly born granule cells contribute to mossy fiber sprouting, a recent study has demonstrated that the older, preexisting granule cell population appears to be the main source of sprouted mossy fibers that grow into the molecular layer (Parent et al., 1998). 4. Relationship between Hippocampal Lesions and Prolonged Seizures in Developing Animals Several studies have shown that immature rats may respond differently than adults to prolonged seizures and that the pathological data obtained in the two age groups may not always be similar. As is the case in adult rats, immature rats exposed to KA develop repetitive seizures or true status epilepticus (Albala et al., 1984; Tremblay et al., 1984); however, unlike those in adults, KA- or pilocarpine-induced seizures (l-2 h of severe tonic-clonic convulsions) are generally not followed by hippocampal lesions in rats less than 18 days of age (Nitecka et al., 1984; Okada et al., 1984; Sperber et al., 1991; Holmes and ‘See McNamara

(1999)

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Thompson, 1988; Liu et al., 1996; Cavalheiro et al., 1987). When they are 18 days old, reversible neuronal and glial abnormalities are observed. At 35 days, however, KA-induced seizures are clearly associated with neuronal cell loss in the hippocampus. Different hypotheses have been proposed to explain why immature rat brains are or are not protected from KA-induced seizure damage. Friedman and colleagues have suggested that the immaturity of the central nervous system may prevent the decrease in the expression of GluR2 during status epilepticus that is seen in the adult (Friedman et al., 1994). The brain would thus be protected from calcium-induced neuronal destruction and the imbalance between inhibitory and excitatory neuronal transmission (Friedman et al., 1994). Another hypothesis is that the immature brain may be better able than the mature brain to handle certain metabolic products, such as the increase in neurotoxic lactate brought about by KA-induced seizures (Sperber et al., 1992). The observation that seizures induced in immature rats may be followed by hippocampal damage in certain models has raised some problems that have not yet been well explained. For example, after intracerebral injection of pilocarpine and probably as a consequence of its significant toxicity, neuronal injury has been observed after seizures in some rats as young as 2 weeks of age (Sankar et al., 1997). Also, intraventricular injection of corticotropin-releasing hormone induced hippocampal seizures in adult and immature (as young as 12 days of age) rats (Ehlers et al., 1983; see also Baram and Schultz, 1991). This was followed by degeneration of pyramidal cells in the CA3 region, as well as mossy fiber sprouting (Baram and Ribak, 1995; Ribak and Baram, 1996). Finally, neuronal migration disorders induced by in utero exposure to methylazoxymethanol provoked an increased susceptibility to febrile seizures, KA-induced seizures, and hippocampal lesions in 14-day-old infant rats (German0 et al., 1996). All these data demonstrate the complexity of factors that may influence the occurrence of hippocampal secondary lesions following repetitive seizures or true status epilepticus in immature animals.

IV. Conclusions:

From

Animal Data to Febrile Convulsions, Hippocampal “Temporal lobe Epilepsy” in Humans

lesions,

and

The results obtained in the last 20 years in animal models have clarified some of the mechanisms responsible for the development of hippocampal lesions. Material covered in the reviews already mentioned

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(Meldrum, 1997; Fisher et al., 1998; McNamara, 1999) and other studies in humans (see other chapters in this volume) have shown that there is generally a close relation between the results obtained in animals and those described in humans. Precise clinical history of the patients, application of new neuroimaging techniques to the in uivo visualization of the hippocampus, and up-to-date neuroscience technologies applied to surgical tissue are demonstrating these homologies. The epileptogenic role of hippocampal lesions secondary to seizures early in life (resulting from genetic or acquired predispositions) in leading to intractable temporal lobe seizures later in life is suspected but not clearly demonstrated. The following questions still remain without an answer: Do the animal experiments explain the origin of all temporal lobe seizures in humans? Do the models used most commonly in rats permit, without restriction, an extrapolation to human data? Has the emphasis placed on the importance of the hippocampus in this animal overshadowed the role of other cortical structures, particularly in primates? Does the classification of human febrile convulsions allow us to predict which one(s) will be followed by hippocampal lesions? In the evaluation of a child who has had a prolonged febrile convulsion, what may be systematically added if one wishes to gather useful, prospective information that might lead to a better understanding of the potential role of febrile seizures in epilepsy? As a form of conclusion, it seems interesting to analyze from my own perspective only one additional publication relevant to humans. VanLandingham et al., (1998) presented magnetic resonance imaging (MRI) results in 27 children who had had experienced complex febrile convulsions. Twelve infants with generalized complex febrile convulsions had a normal MRI. Seven infants with focal or lateralized complex febrile convulsions also had a normal MRI. The remaining six infants had abnormal MRIs. Among them, “4 had significantly longer seizures than other infants and had MRI changes suggesting acute edema with increased hippocampal T2-weighted signal intensity and increased volume predominantly in the hippocampus in the hemisphere of seizure origin.” The authors concluded there was acute edema of these hippocampi, possibly secondary to increased neuronal firing, and resultant excitotoxic neuronal injury or unrecognized hypoxic or ischemic injury secondary to seizures. Furthermore, “histories of perinatal abnormalities and developmental abnormalities were frequent in these infants.” In their discussion, the authors insisted that “a fraction of complex febrile

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convulsions may be related to pre-existing brain dysfunction and, in addition, that focal prolonged or repetitive complex febrile convulsions themselves can produce an acute insult to the hippocampus that may involve hippocampal atrophy in a small number of infants.” These results and their interpretation by the authors are very interesting. The authors confirmed the work of many others: a close correlation may exist between prolonged febrile convulsions and secondary lesions of the hippocampus. They further showed, without any explanation, that this is not the rule. They demonstrated indirectly that some questions raised in the 1950s are still without an answer. But the data presented suggest that in the future, it may be possible (with further refinement of techniques of molecular genetics and neuroimaging) to see how the hippocampus “reacts ” in time to febrile convulsions. This will allow us to understand why in some cases of complex febrile convulsions the hippocampus remains normal whereas in other cases it may show some lesions, how such lesions develop (from edema to a scar), and why some complex febrile convulsions accompanied by hippocampal lesions may or may not be associated with temporal epilepsy. The correlation with anatomical facts will undoubtedly become more fascinating as time goes on.

Acknowledgments

The

author

thanks

Gildas

Le Gal La Salle and

Leyla

de Toledo-Morrell

for their

help.

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