About this Journal Submit a Manuscript Table of Contents
Epilepsy Research and Treatment
Volume 2012 (2012), Article ID 342928, 9 pages
Review Article

Atypical Febrile Seizures, Mesial Temporal Lobe Epilepsy, and Dual Pathology

1Département de Pédiatrie, Centre de Recherche du Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montréal, QC, Canada H3T 1C5
2Département de Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada H3C 3J7

Received 25 December 2011; Revised 2 February 2012; Accepted 7 February 2012

Academic Editor: Seyed M. Mirsattari

Copyright © 2012 Nathalie T. Sanon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Febrile seizures occurring in the neonatal period, especially when prolonged, are thought to be involved in the later development of mesial temporal lobe epilepsy (mTLE) in children. The presence of an often undetected, underlying cortical malformation has also been reported to be implicated in the epileptogenesis process following febrile seizures. This paper highlights some of the various animal models of febrile seizures and of cortical malformation and portrays a two-hit model that efficiently mimics these two insults and leads to spontaneous recurrent seizures in adult rats. Potential mechanisms are further proposed to explain how these two insults may each, or together, contribute to network hyperexcitability and epileptogenesis. Finally the clinical relevance of the two-hit model is briefly discussed in light of a therapeutic and preventive approach to mTLE.

1. Introduction

Mesial temporal lobe epilepsy (mTLE) is the most common form of partial epilepsy in humans and is generally refractory to treatment [1]. It is characterized by seizures that originate in limbic structures, namely, the hippocampus, the parahippocampal gyrus and the amygdala. In approximately 65% of people suffering from this form of epilepsy, the underlying pathology is Ammon’s horn sclerosis characterized by neuronal loss, gliosis and atrophy of the hippocampus. While mTLE classically begins in teenagers and sometimes even adulthood, the initial insult is thought to be neurodevelopmental and to happen in early life, namely, after prolonged febrile seizures (FSs) [2]. Two prevailing hypotheses exist to explain the possible relationship between prolonged FS, hippocampal sclerosis, and mTLE. The first hypothesis states that hippocampal sclerosis predisposes to prolonged FS and mTLE. The second, supported by a wide body of recent evidence, suggests that prolonged FS may in fact arise from an already predisposed brain due to anatomical and/or genetic alterations, but it is the prolonged FS that leads to hippocampal sclerosis and mTLE later in life [3].

To study the pathophysiology of mTLE, several animal models have been developed in the past two decades. Experimental animal modeling stands on the important assumption that understanding fundamental mechanisms of action will help us in the elaboration of more effective treatments and therapeutic strategies for human diseases. The translational impact of experimental evidence from the study of FS and mTLE has been limited by the complexity of these clinical conditions, more specifically their uncertain causal relationship. However, recent clinical data appear to support the fact that prolonged FS, more specifically febrile status epilepticus, directly leads to hippocampal injury and mTLE [4]. Here, we will review several animal models that have been developed to study the putative biological substrate and risk factors behind the development of mTLE in humans. We will focus on two important developmental risk factors, namely, prolonged febrile seizures and cortical malformations as we propose a two-hit model of mTLE. To conclude we will discuss the impact of these findings on future clinical management.

2. Animal Studies

2.1. Animal Models of Febrile Seizures

Febrile seizures (FSs) are a common neurological disorder that usually involves 2 to 5% of children between the age of 6 months and 6 years old with a peak incidence in toddlers of 12 to 18 months [57]. FSs can be separated into two categories: simple and atypical. Simple FSs are generalized and brief seizures (lasting <15 min) that do not recur within 24 hours. Atypical FSs are prolonged (>15 min), recurrent within 24 hours, or lateralized seizures or express more than one of these characteristics. In contrast to simple FSs that generally have no long-term consequences, prolonged FSs, more specifically febrile status epilepticus (lasting >30 min), have been associated with mTLE [3, 5, 810]. Based on retrospective clinical studies, it has been shown that up to 30 to 60% of patients with mTLE have a past history of prolonged FSs [2, 7, 1113]. In one important yet controversial series, children with atypical febrile seizures showed an eightfold increased risk of developing epilepsy compared to those with simple FSs and controls [14]. Thus, one needs to understand what causes some individuals to experience prolonged FSs in order to try to prevent them. To study this, several animal models have been elaborated to mimic fever and FSs.

2.1.1. Hyperthermia as a Model of Febrile Seizures

Several experimental paradigms have been used to mimic the increase in core body temperature occurring during episodes of fever. Multiple studies have artificially evoked hyperthermia-induced seizures (HSs) to determine how FSs are generated. The most stable and most accepted model is hyperthermia-induced by hot dry air [11, 1517]. HSs have been provoked in rats by many other methods such as exposure to an infrared lamp [18], infrared rays [19], microwaves [20, 21], a heated pad [22], or warm water [23]. However, the use of these apparatus was restricted because of high morbidity, mortality, and clinical variability. In contrast, models of HSs induced by exposure to heated dry air develop highly stereotypical generalized seizures that are reproducible and easy to characterize, with minimal or no mortality [2, 3, 7, 9, 11, 12, 15, 17, 24]. Like in humans, this model leads to the development of age-specific seizures that, when brief, do not lead to the development of spontaneous seizures later in life. However, when seizures are prolonged, up to 33% of naive rats develop electroclinical seizures in adulthood [11, 24]. The original studies have reported changes in hippocampal excitability, gene expression, and network effects but without the typical changes observed in mTLE such as neuronal loss, mossy fiber sprouting, or neurogenesis [2527]. However, in these models, the duration of the seizure is determined by the duration of the exposure to high temperature rather than by individual vulnerability.

2.1.2. Lipopolysaccharide- (LPS-) Induced FSs

Many experimental models have used hyperthermia to induce convulsions as a model to study FSs [15, 18, 28, 29]. This is because most of the developing animals experience seizures when they reach a high core temperature and because hyperthermia and fever share common mechanisms to elicit seizures such as the release of cytokines including interleukin-1β (IL-1β) [11, 27, 30]. This particular cytokine seems key to generate FSs in young rats based on the evidence that rats lacking the interleukin-1 receptor type I (IL-1R1) gene exhibit a much higher temperature threshold necessary to develop FSs [11, 27]. In the hippocampus, IL-1 receptors are expressed in high density [31] and their stimulation triggers a cascade of downstream effects through mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling. This could alter gene expression and transform normal neuronal circuitry into a proconvulsive epileptic network [5, 8, 32]. However, even if the IL-1β pathway seems to be a crucial and shared mechanism of both hyperthermia and fever, its activation may not fully or appropriately imitate FSs as fever reflects a regulated increase of body temperature resulting from a broader immune challenge. The common precipitating event in both simple and prolonged FSs is an infection with a bacterial or viral agent. This induces a febrile response, which involves the elaboration of several inflammatory cytokines that include not only interleukin-1β but also IL-6 and tumor necrosis factor (TNF) α. These cytokines, released by activated leukocytes, lead to the production of prostaglandins such as cycloxygenase-2/3 and prostaglandin E2 in the preoptic nuclei of the hypothalamus. This then results in an upregulation in thermostatic set point for body temperature and then fever [33, 34]. However, apart from the fibrogenic properties of inflammatory cytokines, there is increasing evidence that they play a direct role in the generation of FSs. Clinical studies have shown that peripheral leukocytes obtained from children with FSs show an exaggerated IL-1β release to a challenge with lipopolysaccharide (LPS) [3537] or viral RNA [38]. Injection of bacterial lipopolysaccharide (LPS) in vivo in animals is another interesting experimental approach to study the role of proinflammatory cytokines in fever challenge at the systemic level. However, the rise in temperature is somewhat limited and is not sufficient to induce seizures in naive animals. Heida et al. were the first to demonstrate a causal relationship between IL-1β and FSs in an experimental model of FSs using LPS [28, 30]. In this study immature rats were first injected with LPS, which produced a mild fever without a seizure but by giving a subconvulsive dose of kainite, seizures are induced in 50% of pups pretreated with LPS [28]. IL-1β is thought to lead to the generation of FSs through its effects on inhibition, by reducing GABAA receptor currents [39], or through promoting glutamatergic mediated excitatory effects, by increasing calcium conductance through N-methyl-d-aspartate (NMDA) receptors [40].

2.1.3. Viral Mediation of Febrile Seizures?

Some clinical studies have pointed that the human herpes virus 6 (HHV-6) could be a putative link between FSs and mTLE. Some studies suggest that HHV-6 infection happens prior to the occurrence of FSs. Other studies found HHV-6 DNA in brain tissue removed during surgery for mTLE [41, 42]. However, only a minority of primary HHV-6 infections may be associated with FSs [5, 43, 44]. Another virus of the herpes family, the Herpes simplex virus type 1 (HSV-1), causes the limbic seizures by reducing dynorphin expression in the dentate gyrus of hippocampus in rats, leading to seizures [45, 46]. Inherited dynorphin promoter polymorphisms are associated with temporal lobe epilepsy and febrile seizures in human. In animals, the dynorphin system in the hippocampus regulates excitability. These findings show a vulnerability of hippocampal dynorphin during herpes infection, and this may highlight a neurochemical basis for limbic seizures following viral infections.

Overall the evidence summarized here indicates that prolonged FSs contribute to epileptogenesis rather than being simply a marker of an epileptic tendency. In addition, the duration of the FSs seems to be an important factor of the development of subsequent epilepsy in the nonpredisposed brain. These findings suggest that preventing prolonged FSs could be a key therapeutic goal. However, it has recently been shown that prolonged FSs are often unrecognized in the emergency room [10]. Therefore, early identification of children at risk for prolonged FSs and epileptogenesis could be a better strategy to prevent mTLE.

2.2. Animal Models of Cortical Malformation

In order to understand how underlying cortical malformations may be implicated in epileptogenesis and developmental delay, various animal models were developed. A good animal model for malformation of cortical development should display (1) hyperexcitable brain regions and (2) macroscopic as well as microscopic structural abnormalities that are similar to the human pathology [47]. Many of these models have been yielding interesting results.

2.2.1. MAM Chemical Lesion Model

Methylazoxymethanol acetate or MAM is a teratogenic alkylating neurotoxin which specifically blocks mitosis of neuroepithelial cells actively dividing during development, without affecting the postmitotic cells. When administered to pregnant rats (intraperitoneal injection at embryonic day 15 (E15)) [48], MAM causes multifocal cerebral malformations in the rat pups including microcephaly, cortical thinning, loss of lamination, and cortical and hippocampal heterotopia [49, 50]. The heterotopic neurons displayed hyperexcitable properties, and these animals showed a diminished seizure threshold to various proconvulsant agents such as kainic acid [48, 51] or hippocampal electrical kindling [52]. Interestingly, no long-term spontaneous recurrent seizures (SRSs) were generally reported in this model, although Harrington et al. [54] described some electrographic seizures in 2 out of 11 MAM-treated animals. Some of the molecular and cell mechanisms of MAM-induced hyperexcitability include altered cell firing due to smaller calcium-activated potassium (K+) currents affecting membrane potential after-hyperpolarization [53, 54], lack of fast A-type Kv4.2 K+ currents on heterotopic neurons [55], modification of N-methyl-D-aspartate receptor subtype 2A/B (NR2A/B) expression in heterotopic neurons [56], and diminution in inhibitory synaptic activity in heterotopic neurons [57] suggesting profound changes of heterotopic neurons. The MAM model has the advantage of having a specific effect on neuroepithelial cells, not affecting astrocytic cells and not affecting cells from other organs which have a different ontogenic precursor [58]. However, in order for the MAM administration to be reliable, the first day of gestation must always accurately be identified. In any case, this model yields a more diffuse cortical dysplasia than what is observed clinically [59] and does not show spontaneous recurrent seizures alone [47]. Nonetheless, MAM-treated pups are more susceptible to the epileptogenic effects of prolonged FSs with all animals developing epilepsy [60].

2.2.2. In Utero Irradiation Model

The in utero irradiation model is obtained by exposing pregnant rats at E17 to radiation doses as low as 100 centiGray (cGY) to as high as 225 cGy of external gamma radiation from a linear accelerator source [61, 62]. The irradiated cortex shows diffuse cortical dysplasia, similar to the MAM model, along with microcephaly characterized by a 50% diminution in cortical thickness [63], agenesis, hypoplasia, and the presence of heterotopic neurons, sign of a severe migrational abnormality [64]. Indeed, at E17 layer II/III cortical neurons are still migrating and are therefore most severely affected by the radiation [65]. Treated animals have been shown to display interictal epileptiform activity visible in the cortex as well as in the hippocampus; however, spontaneous recurrent seizures occurred only in a subset of irradiated animals, depending on the radiation dose. The manifestations of these clinical seizures was quite typical of limbic seizures including staring, facial twitches, wet dog shakes, and limb clonus [61, 64, 66]. Looking at the network and cellular levels, slices obtained from radiation-treated animals are more excitable as seen by spontaneous and evoked field potentials in slices of neocortex [62]. Furthermore, electrophysiological recordings have shown that the excitatory activity in slices coming from irradiated animals is greater relative to untreated controls and that the inhibitory activity is diminished [26], which may be explained by a diminution in activity of somatostatin and parvalbumin containing inhibitory interneurons in the irradiated group [67]. Therefore, an imbalance between excitation and inhibition is involved in the neocortical hyperactivity leading to the presence of epileptiform events in this model. The in utero irradiation model has the advantage of being noninvasive to the offspring, which induces less stress; however, it yields a diffuse type of cortical dysplasia distinct from the typical clinical situation [64]. In any case, studies looking at the vulnerability of irradiated pups to FSs have, to our knowledge, not yet been done.

2.2.3. Neonatal Freeze Lesion Model

The freeze-lesion-induced cortical malformation in rats was developed by Dvorak and Feit [68] and closely resembles the polymicrogyrus observed in humans, in that it yields the formation of a four-layer neocortex rather than the typical six. To achieve this model, one-day-old rat pups are anaesthetized with isoflurane, their scalp cut at the midline and opened, and a frozen 2 mm large probe is placed on the soft cranium overlying the sensorimotor cortex for a period of ten seconds [9, 17]. It should be noted however that the probe width, the lesion duration, and the number of lesions may vary from one study to another. In all cases, contact with the frozen probe causes an immediate focal necrotic lesion, followed by neuronal migration to repair the damaged region, which explains why lesions should be done at a very young age when cells are still in a migratory state [69]. Indeed, glial fibrillary acidic protein (GFAP) as well as bromodeoxyuridine (BrdU) expressing cells were found in high levels within the dysplastic cortex suggesting the presence of still proliferating astrocytic cells [70]. The polymicrogyrus later obtained following the freeze lesion in rat is very similar to what would be observed in a focal human neuronal migration disorder [71, 72]. Fiber reorganization occurs within the cortical and subcortical layers of lesion rats as thalamocortical and corticothalamic projections are shown to be affected, possibly implicated in the process of epileptogenesis [73]. Disorganized projections were also seen by Brill and Huguenard who noted more inputs coming from infra- and supragranular cortical layers synapsing onto layer V pyramidal cells than in controls [74].

On top of the macroscopic modifications taking place in the dysplastic cortex, other changes at the molecular level occur and seem to unbalance the excitation/inhibition equilibrium favoring excitation. Looking at the expression of excitatory glutamate receptors, an autoradiography study showed that NMDA, AMPA, and KA receptor levels were elevated within the dysplastic cortex [75, 76], while they were unchanged when measures were taken in the surrounding normal cortex [77], suggesting the presence of a spatial gradient of ionotropic glutamate receptors with a greater concentration within the polymicrogyrus. Amongst the NMDA receptors, the NR2B subunit seems to be of great importance to the epileptogenicity of the lesion as the NR2B currents are functionally enhanced, and specific NR2B antagonists limit the spread of the epileptiform activity [71, 78], although it was shown that an AMPAR antagonist may block more widespread epileptiform activity measured extracellularly [79]. On the other hand, looking at inhibitory activity, the same autoradiography study showed lowered GABAA and GABAB binding within the dysplastic cortex [76] and a downregulation of GABAA inhibition has been shown electrophysiologically in the freeze model [75]. However, no interneuron cell loss was reported near or far from the lesion [80, 81]. This widespread modification in various GABAA subunits can be the cause of the decrease in inhibitory activity [82]. It is, however, also plausible that the GABAA inhibition downregulation may not be directly involved in the hyperexcitability observed, as the somatostatin-positive interneuron loss occurred after the onset of epileptiform activity in their model [83]. The freeze lesion model of TLE is relatively easy to generate with reproducible results [69]. However, despite the hyperexcitability observed in brain slices from lesion animals, there are in this model no recurrent seizures occurring spontaneously in vivo [72] which is an important prerequisite to a good experimental model of human mTLE. We have therefore developed in our laboratory a two-hit model.

2.3. Two-Hit Rat Model of TLE

When the cortical polymicrogyrus model precedes another insult, this represents a two-hit model and mimics the human condition described in our clinical series [59]. A few models, having in common a cortical polymicrogyrus as a first hit followed by another insult [17, 60, 8486], may lead to TLE development at a later age.

2.3.1. Freeze Lesion + Hyperthermia-Induced Seizure Model

In the case of the freeze lesion and HSs model, the FSs constitute the “second hit” occurring postnatally while the “first hit” is thought to occur at an early stage of brain development. Therefore, in this model, the freeze lesion is performed at P1, while the HSs are induced at P10 [17] (Figure 1).

Figure 1: Lesion and hyperthermia model of TLE. Timeline and description of the different steps of the model, their pathological correlates, and the findings at various ages in the literature.

At the time of HSs induction, the temperature necessary to induce a generalized convulsion during hyperthermia was diminished in rats with a cortical lesion compared to rats without lesion, and the latency to attain the generalized convulsion was also shorter [17]. More importantly, only the lesioned pups developed status epilepticus following a brief exposure to hyperthermia. This model therefore reproduces the selective vulnerability of some individuals to a common insult. Furthermore, a brain and ipsilateral hippocampal atrophy was already measurable ten days following HSs at P20 [12]. This suggests that the lesion alone seems to predispose the brain and the hippocampus to prolonged FSs and their consequences.

At P80, the hippocampal atrophy is more severe than at P20; however, it may be prevented by limiting seizure duration with diazepam at P10 [2]. Furthermore, using in vitro electrophysiological recordings, CA1 pyramidal cell hyperexcitability has been shown, yielding greater evoked excitatory postsynaptic potentials (EPSPs) and more frequent spontaneous excitatory postsynaptic currents (sEPSCs) specifically in the double-hit group onto pyramidal cells [87] and onto CA1 interneurons [88]. As the excitatory activity, the inhibitory activity is also altered with greater amplitude GABAA and GABAB inhibitory postsynaptic potentials (IPSPs) and evoked inhibitory postsynaptic currents (eIPSCs) on CA1 pyramidal cells in the double-hit group [87]. This would suggest an excitatory/inhibitory imbalance favoring excitation already at P20, prior to the occurrence of spontaneous recurrent seizures at P80.

In adulthood, we have found that the double hit results in the occurrence of spontaneous seizures occurring in 86–100% of male rats with the seizures arising ipsilateral to the lesion [2, 9, 12], numbers similar to the MAM model and more significant than the 33% observed in naive rats exposed to prolonged FSs [11]. Ipsilateral hippocampal atrophy persists in the double-hit group and is associated in adults with neuronal loss and memory deficits in performance of a hippocampus-dependent task [9].

2.3.2. Putative Mechanisms Implicated in TLE Generation in the Dual Pathology Model

Our data indicate that ionotropic glutamate receptor expression, especially the NMDA subtype, is upregulated in the double-hit animals: NR2B subtype being overexpressed at approximately P20 and NR2A at P80 [87]. This is in accordance with findings from other two-hit models where high levels of NR2B expression are also found: such as in the MAM + pilocarpine model [84] or in the prenatal freeze lesion + electrical kindling [85]. The fact that lesion-only animals show higher NR2B levels and greater NMDA currents at P20 suggests that the lesion itself may underlie the hyperexcitability at P20 and may be a predisposing factor to prolonged HSs susceptibility at P10 [87], which is supported by a study in the freeze-lesion-only model [78]. Furthermore, it is possible that the IL-1β expression during hyperthermia, as earlier stated, further exacerbates the effect of the lesion on NMDAR.

In parallel with the excitatory changes, the inhibitory activity is also altered in the model. In this case, HSs appear to be the key event in modifying inhibitory currents and potentials [87]. The findings of this study are similar to those in naive animals [89]. Whether the changes in inhibitory circuits reduce or increase the risk of recurrent seizures remains to be determined. In summary, the lesion alone and the hyperthermia alone appear to each leave the developing brain more vulnerable, but the presence of two hits strongly promotes epileptogenesis.

3. Clinical Relevance of the Two-Hit Models

In humans, development of mTLE is more and more thought to be a multistage process taking place in early life and including a history of childhood prolonged febrile seizures. A retrospective study from our group demonstrated that 66% of children affected with mTLE and a history of FSs had dual pathology with the coexistence of hippocampal sclerosis and of a cortical malformation on pathology [59]. More recently, the FEBSTAT study group was able to distinguish two subpopulations of FSs with those experiencing prolonged FSs being younger and with developmental delay [90]. In an earlier publication, they had demonstrated that these same children were more likely (OR = 4.3) to have imaging abnormalities on MRI including cortical malformations [91]. Although the models described here involve disorders of neuronal migration, other predisposing factors such as genetic susceptibility can represent the first hit. Indeed, it has been shown that, in familial mTLE, mesial temporal sclerosis develops in those who have experienced prolonged FSs in early life [92]. More so, prospective studies suggest that FS duration is a key factor in leading to hippocampal injury and that developmental abnormalities are indeed also present in children with febrile status and mTLE [93]. Therefore, we believe that any child who presents with a febrile status epilepticus could benefit from a thorough imaging evaluation, including high-resolution MRI. Up to now, a true antiepileptogenic treatment is not available. However, experimental evidence suggests a potential role for NR2B antagonists as not only a good seizure medication but also a potential antiepileptogenic treatment in the developing brain.

The role of other potential first hits such as early-life stress in the development of mTLE remains to be properly studied. Only few animal models of mTLE models implying early-life stress paradigms exist in the present literature [9498]. Both corticotropin releasing factor (CRF) and the glucocorticoid cortisol (or corticosterone in rodents) appear to exert potent proconvulsive or hyperexcitable effects on limbic structures in the developing brain [96, 99107]. Although there is no clear evidence that isolated early-life stressors can induce epileptogenesis, the anatomical and physiological changes produced by these hormones could predispose the developing brain to a second hit.

In conclusion, a better understanding of the pathophysiology of mTLE in the developing brain will help us develop age-specific treatments not only to control the seizures but also to prevent their occurrence altogether, an important step toward our ultimate goal of no seizure, no side effect.


Dr. Nathalie T. Sanon and Dr. Sébastien Desgent shared the cofirst authorship.


  1. J. Engel, “Mesial temporal lobe epilepsy: what have we learned?” Neuroscientist, vol. 7, no. 4, pp. 340–352, 2001. View at Scopus
  2. S. Gibbs, B. Chattopadhyaya, S. Desgent et al., “Long-term consequences of a prolonged febrile seizure in a dual pathology model,” Neurobiology of Disease, vol. 43, no. 2, pp. 312–321, 2011. View at Publisher · View at Google Scholar
  3. M. H. Scantlebury and J. G. Heida, “Febrile seizures and temporal lobe epileptogenesis,” Epilepsy Research, vol. 89, no. 1, pp. 27–33, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. K. E. VanLandingham, E. R. Heinz, J. E. Cavazos, and D. V. Lewis, “Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions,” Annals of Neurology, vol. 43, no. 4, pp. 413–426, 1998. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Ahmad and E. D. Marsh, “Febrile status epilepticus: current state of clinical and basic research,” Seminars in Pediatric Neurology, vol. 17, no. 3, pp. 150–154, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. A. T. Berg, S. Shinnar, S. R. Levy, and F. M. Testa, “Childhood-onset epilepsy with and without preceding febrile seizures,” Neurology, vol. 53, no. 8, pp. 1742–1748, 1999. View at Scopus
  7. L. Carmant, “Developing a new animal model of temporal lobe epilepsy,” Medecine/Sciences, vol. 23, no. 11, pp. 929–933, 2007. View at Scopus
  8. S. McClelland, C. M. Dubé, J. Yang, and T. Z. Baram, “Epileptogenesis after prolonged febrile seizures: mechanisms, biomarkers and therapeutic opportunities,” Neuroscience Letters, vol. 497, no. 3, pp. 155–162, 2011. View at Publisher · View at Google Scholar
  9. M. H. Scantlebury, S. A. Gibbs, B. Foadjo, P. Lema, C. Psarropoulou, and L. Carmant, “Febrile seizures in the predisposed brain: a new model of temporal lobe epilepsy,” Annals of Neurology, vol. 58, no. 1, pp. 41–49, 2005. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Shinnar and T. A. Glauser, “Febrile seizures,” Journal of Child Neurology, vol. 17, no. 1, pp. S44–S52, 2002. View at Scopus
  11. C. Dubé, C. Richichi, R. A. Bender, G. Chung, B. Litt, and T. Z. Baram, “Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis,” Brain, vol. 129, no. 4, pp. 911–922, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. S. A. Gibbs, M. H. Scantlebury, P. Awad et al., “Hippocampal atrophy and abnormal brain development following a prolonged hyperthermic seizure in the immature rat with a focal neocortical lesion,” Neurobiology of Disease, vol. 32, no. 1, pp. 176–182, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. W. H. Theodore, S. Bhatia, J. Hatta et al., “Hippocampal atrophy, epilepsy duration, and febrile seizures in patients with partial seizures,” Neurology, vol. 52, no. 1, pp. 132–136, 1999. View at Scopus
  14. K. B. Nelson and J. H. Ellenberg, “Predictors of epilepsy in children who have experienced febrile seizures,” New England Journal of Medicine, vol. 295, no. 19, pp. 1029–1033, 1976. View at Scopus
  15. T. Z. Baram, A. Gerth, and L. Schultz, “Febrile seizures: an appropriate-aged model suitable for long-term studies,” Developmental Brain Research, vol. 98, no. 2, pp. 265–270, 1997. View at Publisher · View at Google Scholar · View at Scopus
  16. T. Morimoto, H. Nagao, N. Sano, M. Takahashi, and H. Matsuda, “Electroencephalographic study of rat hyperthermic seizures,” Epilepsia, vol. 32, no. 3, pp. 289–293, 1991. View at Scopus
  17. M. H. Scantlebury, P. L. Ouellet, C. Psarropoulou, and L. Carmant, “Freeze lesion-induced focal cortical dysplasia predisposes to atypical hyperthermic seizures in the immature rat,” Epilepsia, vol. 45, no. 6, pp. 592–600, 2004. View at Publisher · View at Google Scholar · View at Scopus
  18. D. Holtzman, K. Obana, and J. Olson, “Hyperthermia-induced seizures in the rat pup: a model for febrile convulsions in children,” Science, vol. 213, no. 4511, pp. 1034–1036, 1981. View at Scopus
  19. T. Morimoto, M. Fukuda, Y. Aibara, H. Nagao, and K. Kida, “The influence of blood gas changes on hyperthermia-induced seizures in developing rats,” Developmental Brain Research, vol. 92, no. 1, pp. 77–80, 1996. View at Publisher · View at Google Scholar · View at Scopus
  20. D. L. Hjeresen, A. W. Guy, F. M. Petracca, and J. Diaz, “A microwave-hyperthermia model of febrile convulsions,” Bioelectromagnetics, vol. 4, no. 4, pp. 341–355, 1983. View at Scopus
  21. T. Morimoto, H. Nagao, N. Sano, M. Takahashi, and H. Matsuda, “Hyperthermia-induced seizures with a servo system: neurophysiological roles of age, temperature elevation rate and regional GABA content in the rat,” Brain and Development, vol. 12, no. 3, pp. 279–283, 1990. View at Scopus
  22. M. R. Sarkisian, G. L. Holmes, L. Carmant, Z. Liu, Y. Yang, and C. E. Stafstrom, “Effects of hyperthermia and continuous hippocampal stimulation on the immature and adult brain,” Brain and Development, vol. 21, no. 5, pp. 318–325, 1999. View at Publisher · View at Google Scholar · View at Scopus
  23. W. Jiang, T. M. Duong, and N. C. De Lanerolle, “The neuropathology of hyperthermic seizures in the rat,” Epilepsia, vol. 40, no. 1, pp. 5–19, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Dube, K. Chen, M. Eghbal-Ahmadi, K. Brunson, I. Soltesz, and T. Z. Baram, “Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term,” Annals of Neurology, vol. 47, no. 3, pp. 336–344, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. R. A. Bender, C. Dubé, R. Gonzalez-Vega, E. W. Mina, and T. Z. Baram, “Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures,” Hippocampus, vol. 13, no. 3, pp. 399–412, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. H. X. Chen and S. N. Roper, “Reduction of spontaneous inhibitory synaptic activity in experimental heterotopic gray matter,” Journal of Neurophysiology, vol. 89, no. 1, pp. 150–158, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. C. M. Dubé, A. L. Brewster, and T. Z. Baram, “Febrile seizures: mechanisms and relationship to epilepsy,” Brain and Development, vol. 31, no. 5, pp. 366–371, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. J. G. Heida, L. Boissé, and Q. J. Pittman, “Lipopolysaccharide-induced Febrile Convulsions in the rat: short-term sequelae,” Epilepsia, vol. 45, no. 11, pp. 1317–1329, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. M. T. Liebregts, R. S. McLachlan, and L. S. Leung, “Hyperthermia induces age-dependent changes in rat hippocampal excitability,” Annals of Neurology, vol. 52, no. 3, pp. 318–326, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. J. G. Heida and Q. J. Pittman, “Causal links between brain cytokines and experimental febrile convulsions in the rat,” Epilepsia, vol. 46, no. 12, pp. 1906–1913, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Toshihiro, D. E. Tracey, W. M. Mitchell, and E. B. De Souza, “Interleukin-1 receptors in mouse brain: characterization and neuronal localization,” Endocrinology, vol. 127, no. 6, pp. 3070–3078, 1990. View at Scopus
  32. G. Li, S. Bauer, M. Nowak et al., “Cytokines and epilepsy,” Seizure, vol. 20, no. 3, pp. 249–256, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. C. A. Dinarello, “Infection,fever, and exogenous and endogenous pyrogens: some concepts have changed,” Journal of Endotoxin Research, vol. 10, no. 4, pp. 201–222, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. C. B. Saper and C. D. Breder, “Seminars in medicine of the Beth Israel Hospital, Boston: the neurologic basis of fever,” New England Journal of Medicine, vol. 330, no. 26, pp. 1880–1886, 1994. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Helminen and T. Vesikari, “Increased interleukin-1 (IL-1) production from LPS-stimulated peripheral blood monocytes in children with febrile convulsions,” Acta Paediatrica Scandinavica, vol. 79, no. 8-9, pp. 810–816, 1990. View at Scopus
  36. K. Kanemoto, J. Kawasaki, S. Yuasa et al., “Increased frequency of interleukin-1β-511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion,” Epilepsia, vol. 44, no. 6, pp. 796–799, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. R. Kira, H. Torisu, M. Takemoto et al., “Genetic susceptibility to simple febrile seizures: interleukin-1β promoter polymorphisms are associated with sporadic cases,” Neuroscience Letters, vol. 384, no. 3, pp. 239–244, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Matsuo, K. Sasaki, T. Ichimaru, S. Nakazato, and Y. Hamasaki, “Increased IL-1β Production From dsRNA-stimulated Leukocytes in Febrile Seizures,” Pediatric Neurology, vol. 35, no. 2, pp. 102–106, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Wang, Q. Cheng, S. Malik, and J. Yang, “Interleukin-1β inhibits γ-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons,” Journal of Pharmacology and Experimental Therapeutics, vol. 292, no. 2, pp. 497–504, 2000. View at Scopus
  40. B. Viviani, S. Bartesaghi, F. Gardoni et al., “Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases,” Journal of Neuroscience, vol. 23, no. 25, pp. 8692–8700, 2003. View at Scopus
  41. J. Fotheringham, D. Donati, N. Akhyani et al., “Association of human herpesvirus-6B with mesial temporal lobe epilepsy,” PLoS Medicine, vol. 4, no. 5, pp. 0848–0857, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. H. Karatas, G. Gurer, A. Pinar et al., “Investigation of HSV-1, HSV-2, CMV, HHV-6 and HHV-8 DNA by real-time PCR in surgical resection materials of epilepsy patients with mesial temporal lobe sclerosis,” Journal of the Neurological Sciences, vol. 264, no. 1-2, pp. 151–156, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. W. H. Theodore, L. Epstein, W. D. Gaillard, S. Shinnar, M. S. Wainwright, and S. Jacobson, “Human herpes virus 6B: a possible role in epilepsy?” Epilepsia, vol. 49, no. 11, pp. 1828–1837, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. D. M. Zerr, A. S. Meier, S. S. Selke et al., “A population-based study of primary human herpesvirus 6 infection,” New England Journal of Medicine, vol. 352, no. 8, pp. 768–776, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. M. V. Solbrig, R. Adrian, D. Y. Chang, and G. C. Perng, “Viral risk factor for seizures: pathobiology of dynorphin in herpes simplex viral (HSV-1) seizures in an animal model,” Neurobiology of Disease, vol. 23, no. 3, pp. 612–620, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. H. M. Wu, C. C. Huang, S. H. Chen et al., “Herpes simplex virus type 1 inoculation enhances hippocampal excitability and seizure susceptibility in mice,” European Journal of Neuroscience, vol. 18, no. 12, pp. 3294–3304, 2003. View at Publisher · View at Google Scholar · View at Scopus
  47. G. Battaglia and S. Bassanini, “MAM and other “lesion“ models of developmental epilepsy,” in Models of Seizure and Epilepsy, A. Pitkanen, P. A. Schwartzkroin, and S. Moshé, Eds., pp. 265–270, Elsevier Academic Press, San Diego, Calif, USA, 2006.
  48. M. R. De Feo, O. Mecarelli, and G. F. Ricci, “Seizure susceptibility in immature rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate,” Pharmacological Research, vol. 31, no. 2, pp. 109–114, 1995. View at Publisher · View at Google Scholar · View at Scopus
  49. S. C. Baraban, H. J. Wenzel, D. W. Hochman, and P. A. Schwartzkroin, “Characterization of heterotopic cell clusters in the hippocampus of rats exposed to methylazoxymethanol in utero,” Epilepsy Research, vol. 39, no. 2, pp. 87–102, 2000. View at Publisher · View at Google Scholar · View at Scopus
  50. C. Colacitti, G. Sancini, S. DeBiasi et al., “Prenatal methylazoxymethanol treatment in rats produces brain abnormalities with morphological similarities to human developmental brain dysgeneses,” Journal of Neuropathology and Experimental Neurology, vol. 58, no. 1, pp. 92–106, 1999. View at Scopus
  51. I. M. Germano and E. F. Sperber, “Increased seizure susceptibility in adult rats with neuronal migration disorders,” Brain Research, vol. 777, no. 1-2, pp. 219–222, 1997. View at Publisher · View at Google Scholar · View at Scopus
  52. I. M. Germano, E. F. Sperber, S. Ahuja, and S. L. Moshe, “Evidence of enhanced kindling and hippocampal neuronal injury in immature rats with neuronal migration disorders,” Epilepsia, vol. 39, no. 12, pp. 1253–1260, 1998. View at Publisher · View at Google Scholar · View at Scopus
  53. G. Sancini, S. Franceschetti, G. Battaglia et al., “Dysplastic neocortex and subcortical heterotopias in methylazoxymethanol-treated rats: an intracellular study of identified pyramidal neurones,” Neuroscience Letters, vol. 246, no. 3, pp. 181–185, 1998. View at Publisher · View at Google Scholar · View at Scopus
  54. E. P. Harrington, G. Möddel, I. M. Najm, and S. C. Baraban, “Altered glutamate receptor—transporter expression and spontaneous seizures in rats exposed to methylazoxymethanol in utero,” Epilepsia, vol. 48, no. 1, pp. 158–168, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. P. A. Castro, E. C. Cooper, D. H. Lowenstein, and S. C. Baraban, “Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy,” Journal of Neuroscience, vol. 21, no. 17, pp. 6626–6634, 2001. View at Scopus
  56. F. Gardoni, S. Pagliardini, V. Setola et al., “The NMDA receptor complex is altered in an animal model of human cerebral heterotopia,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 6, pp. 662–675, 2003. View at Scopus
  57. A. Karlsson, C. Lindquist, K. Malmgren, and F. Asztely, “Altered spontaneous synaptic inhibition in an animal model of cerebral heterotopias,” Brain Research, vol. 1383, pp. 54–61, 2011. View at Publisher · View at Google Scholar
  58. F. Cattabeni and M. Di Luca, “Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol,” Physiological Reviews, vol. 77, no. 1, pp. 199–215, 1997. View at Scopus
  59. C. Bocti, Y. Robitaille, P. Diadori et al., “The pathological basis of temporal lobe epilepsy in childhood,” Neurology, vol. 60, no. 2, pp. 191–195, 2003. View at Scopus
  60. K. I. Park, K. Chu, K. H. Jung et al., “Role of cortical dysplasia in epileptogenesis following prolonged febrile seizure,” Epilepsia, vol. 51, no. 9, pp. 1809–1819, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Kondo, I. Najm, T. Kunieda, S. Perryman, K. Yacubova, and H. O. Lüders, “Electroencephalographic characterization of an adult rat model of radiation-induced cortical dysplasia,” Epilepsia, vol. 42, no. 10, pp. 1221–1227, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. S. N. Roper, L. A. Abraham, and W. J. Streit, “Exposure to in utero irradiation produces disruption of radial glia in rats,” Developmental Neuroscience, vol. 19, no. 6, pp. 521–528, 1997. View at Scopus
  63. M. Marín-Padilla, R. J. Tsai, M. A. King, and S. N. Roper, “Altered corticogenesis and neuronal morphology in irradiation-induced cortical dysplasia: a Golgi-Cox study,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 11, pp. 1129–1143, 2003.
  64. D. D. Lin and S. N. Roper, “In utero irradiation as a model of cortical dysplasia,” in Models of Seizure and Epilepsy, A. Pitkanen, P. A. Schwartzkroin, and S. Moshé, Eds., pp. 271–290, Elsevier Academic Press, San Diego, Calif, USA, 2006.
  65. J. Altman, W. J. Anderson, and K. A. Wright, “Differential radiosensitivity of stationary and migratory primitive cells in the brains of infant rats,” Experimental Neurology, vol. 22, no. 1, pp. 52–74, 1968. View at Scopus
  66. C. Kellinghaus, T. Kunieda, Z. Ying, A. Pan, H. O. Lüders, and I. M. Najm, “Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent,” Epilepsia, vol. 45, no. 6, pp. 583–591, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. F.-W. Zhou and S. N. Roper, “Altered firing rates and patterns in interneurons in experimental cortical Dysplasia,” Cerebral Cortex, vol. 21, no. 7, pp. 1645–1658, 2011. View at Publisher · View at Google Scholar
  68. K. Dvorak and J. Feit, “Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats: contribution to the problems of morphological development and developmental period of cerebral microgyria. Histological and autoradiographical study,” Acta Neuropathologica, vol. 38, no. 3, pp. 203–212, 1977. View at Scopus
  69. H. J. Luhmann, “The cortical freeze lesion model,” in Models of Seizure and Epilepsy, A. Pitkanen, P. A. Schwartzkroin, and S. Moshé, Eds., pp. 243–265, Elsevier Academic Press, San Diego, Calif, USA, 2006.
  70. A. Bordey, S. A. Lyons, J. J. Hablitz, and H. Sontheimer, “Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia,” Journal of Neurophysiology, vol. 85, no. 4, pp. 1719–1731, 2001. View at Scopus
  71. S. Bandyopadhyay and J. J. Hablitz, “NR2B antagonists restrict spatiotemporal spread of activity in a rat model of cortical dysplasia,” Epilepsy Research, vol. 72, no. 2-3, pp. 127–139, 2006. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Kellinghaus, G. Möddel, H. Shigeto et al., “Dissociation between in vitro and in vivo epileptogenicity in a rat model of cortical dysplasia,” Epileptic Disorders, vol. 9, no. 1, pp. 11–19, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. K. M. Jacobs, “Experimental microgyri disrupt the barrel field pattern in rat somatosensory cortex,” Cerebral Cortex, vol. 9, no. 7, pp. 733–744, 1999. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Brill and J. R. Huguenard, “Enhanced infragranular and supragranular synaptic input onto layer 5 pyramidal neurons in a rat model of cortical dysplasia,” Cerebral Cortex, vol. 20, no. 12, pp. 2926–2938, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. H. J. Luhmann, N. Karpuk, M. Qü, and K. Zilles, “Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings,” Journal of Neurophysiology, vol. 80, no. 1, pp. 92–102, 1998. View at Scopus
  76. K. Zilles, “Characterization of neuronal migration disorders in neocortical structures: quantitative receptor autoradiography of ionotropic glutamate, GABAA and GABAB receptors,” European Journal of Neuroscience, vol. 10, no. 10, pp. 3095–3106, 1998. View at Scopus
  77. G. Hagemann, M. M. Kluska, C. Redecker, H. J. Luhmann, and O. W. Witte, “Distribution of glutamate receptor subunits in experimentally induced cortical malformations,” Neuroscience, vol. 117, no. 4, pp. 991–1002, 2003. View at Publisher · View at Google Scholar · View at Scopus
  78. R. A. Defazio and J. J. Hablitz, “Alterations in NMDA receptors in a rat model of cortical dysplasia,” Journal of Neurophysiology, vol. 83, no. 1, pp. 315–321, 2000. View at Scopus
  79. H. J. Luhmann, “Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings,” European Journal of Neuroscience, vol. 10, no. 10, pp. 3085–3094, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. V. N. Kharazia, K. M. Jacobs, and D. A. Prince, “Light microscopic study of GluR1 and calbindin expression in interneurons of neocortical microgyral malformations,” Neuroscience, vol. 120, no. 1, pp. 207–218, 2003. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Schwarz, C. C. Stichel, and H. J. Luhmann, “Characterization of neuronal migration disorders in neocortical structures: loss or preservation of inhibitory interneurons?” Epilepsia, vol. 41, no. 7, pp. 781–787, 2000. View at Scopus
  82. C. Redecker, H. J. Luhmann, G. Hagemann, J. M. Fritschy, and O. W. Witte, “Differential downregulation of GABA(A) receptor subunits in widespread brain regions in the freeze-lesion model of focal cortical malformations,” Journal of Neuroscience, vol. 20, no. 13, pp. 5045–5053, 2000. View at Scopus
  83. S. L. Patrick, B. W. Connors, and C. E. Landisman, “Developmental changes in somatostatin-positive interneurons in a freeze-lesion model of epilepsy,” Epilepsy Research, vol. 70, no. 2-3, pp. 161–171, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. F. Colciaghi, A. Finardi, A. Frasca et al., “Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia,” Brain, vol. 134, no. 10, pp. 2828–2843, 2011. View at Publisher · View at Google Scholar
  85. K. I. Takase, H. Shigeto, S. O. Suzuki, H. Kikuchi, Y. Ohyagi, and J. I. Kira, “Prenatal freeze lesioning produces epileptogenic focal cortical dysplasia,” Epilepsia, vol. 49, no. 6, pp. 997–1010, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Schmid, P. Tandon, C. E. Stafstrom, and G. L. Holmes, “Effects of neonatal seizures on subsequent seizure-induced brain injury,” Neurology, vol. 53, no. 8, pp. 1754–1761, 1999. View at Scopus
  87. M. Ouardouz, P. Lema, P. N. Awad, G. Di Cristo, and L. Carmant, “N-methyl-d-aspartate, hyperpolarization-activated cation current (I h) and -aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampus,” European Journal of Neuroscience, vol. 31, no. 7, pp. 1252–1260, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. M. Ouardouz and L. Carmant, “Changes in inhibitory CA1 network in dual pathology model,” Channels, vol. 6, no. 1, 2012.
  89. K. Chen, I. Aradi, N. Thon, M. Eghbal-Ahmadi, T. Z. Baram, and I. Soltesz, “Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability,” Nature Medicine, vol. 7, no. 3, pp. 331–337, 2001. View at Publisher · View at Google Scholar · View at Scopus
  90. D. C. Hesdorffer, E. K.T. Benn, E. Bagiella et al., “Distribution of febrile seizure duration and associations with development,” Annals of Neurology, vol. 70, no. 1, pp. 93–100, 2011. View at Publisher · View at Google Scholar
  91. D. C. Hesdorffer, S. Chan, H. Tian et al., “Are MRI-detected brain abnormalities associated with febrile seizure type?” Epilepsia, vol. 49, no. 5, pp. 765–771, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. D. E. Crompton, I. E. Scheffer, I. Taylor et al., “Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance,” Brain, vol. 133, no. 11, pp. 3221–3231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. R. P. Gamss, S. E. Slasky, J. A. Bello, T. S. Miller, and S. Shinnar, “Prevalence of hippocampal malrotation in a population without seizures,” American Journal of Neuroradiology, vol. 30, no. 8, pp. 1571–1573, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. I. Ali, M. R. Salzberg, C. French, and N. C. Jones, “Electrophysiological insights into the enduring effects of early life stress on the brain,” Psychopharmacology, vol. 214, no. 1, pp. 155–173, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. H. E. Edwards, D. Dortok, J. Tam, D. Won, and W. M. Burnham, “Prenatal stress alters seizure thresholds and the development of kindled seizures in infant and adult rats,” Hormones and Behavior, vol. 42, no. 4, pp. 437–447, 2002. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Joëls, “Stress, the hippocampus, and epilepsy,” Epilepsia, vol. 50, no. 4, pp. 586–597, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Salzberg, G. Kumar, L. Supit et al., “Early postnatal stress confers enduring vulnerability to limbic epileptogenesisy,” Epilepsia, vol. 48, no. 11, pp. 2079–2085, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. N. T. Sawyer and A. Escayg, “Stress and epilepsy: multiple models, multiple outcomes,” Journal of Clinical Neurophysiology, vol. 27, no. 6, pp. 445–452, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. T. Z. Baram and L. Schultz, “Corticotropin-releasing hormone is a rapid and potent convulsant in the infant rat,” Developmental Brain Research, vol. 61, no. 1, pp. 97–101, 1991. View at Publisher · View at Google Scholar · View at Scopus
  100. J. B. Rosen, S. K. Pishevar, S. R. B. Weiss et al., “Glucocorticoid treatment increases the ability of CRH to induce seizures,” Neuroscience Letters, vol. 174, no. 1, pp. 113–116, 1994. View at Publisher · View at Google Scholar · View at Scopus
  101. K. L. Brunson, S. Avishai-Eliner, C. G. Hatalski, and T. Z. Baram, “Neurobiology of the stress response early in life: evolution of a concept and the role of corticotropin releasing hormone,” Molecular Psychiatry, vol. 6, no. 6, pp. 647–656, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Joels, “Steroid hormones and excitability in the mammalian brain,” Frontiers in Neuroendocrinology, vol. 18, no. 1, pp. 2–48, 1997.
  103. M. Joels, H. Krugers, and H. Karst, “Stress-induced changes in hippocampal function,” Progress in Brain Research, vol. 167, pp. 3–15, 2008.
  104. A. S. Koe, N. C. Jones, and M. R. Salzberg, “Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?” Frontiers in Behavioral Neuroscience, vol. 3, p. 24, 2009.
  105. M. C. Lai, G. L. Holmes, K. H. Lee et al., “Effect of neonatal isolation on outcome following neonatal seizures in rats—the role of corticosterone,” Epilepsy Research, vol. 68, no. 2, pp. 123–136, 2006. View at Publisher · View at Google Scholar · View at Scopus
  106. M. C. Lai, S. N. Yang, and L. T. Huang, “Neonatal isolation enhances anxiety-like behavior following early-life Seizure in rats,” Pediatrics and Neonatology, vol. 49, no. 2, pp. 19–25, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. T. R. Taher, M. Salzberg, M. J. Morris, S. Rees, and T. J. O'Brien, “Chronic low-dose corticosterone supplementation enhances acquired epileptogenesis in the rat amygdala kindling model of TLE,” Neuropsychopharmacology, vol. 30, no. 9, pp. 1610–1616, 2005. View at Publisher · View at Google Scholar · View at Scopus