Summary: Epileptogenesis refers to a phenomenon in which the brain undergoes molecular and cellular alterations after a brain-damaging insult, which increase its excitability and eventually lead to the occurrence of recurrent spontaneous seizures. Common epileptogenic factors include traumatic brain injury (TBI), stroke, and cerebral infections. Only a subpopulation of patients with any of these brain insults, however, will develop epilepsy. Thus, there are two great challenges: (1) identifying patients at risk, and (2) preventing and/or modifying the epileptogenic process. Target identification for antiepileptogenic treatments is difficult in humans because patients undergoing epileptogenesis cannot currently be identified. Animal models of epileptogenesis are therefore necessary for scientific progress. Recent advances in the development of experimental models of epileptogenesis have provided tools to investigate the molecular and cellular alterations and their temporal appearance, as well as the epilepsy phenotype after various clinically relevant epileptogenic etiologies, including TBI and stroke. Studying these models will lead to answers to critical questions such as: Do the molecular mechanisms of epileptogenesis depend on the etiology? Is the spectrum of network alterations during epileptogenesis the same after various clinically relevant etiologies? Is the temporal progression of epileptogenesis similar? Work is ongoing, and answers to these questions will facilitate the identification of molecular targets for antiepileptogenic treatments, the design of treatment paradigms, and the determination of whether data from one etiology can be extrapolated to another. Key Words: Endothelin-1-Gene arrayLateral fluid-percussion injury-Magnetic resonance imagingPhotothrombotic stroke-Traumatic brain injury-Video-EEG monitoring.According to the World Health Organization, approximately 0.8% (50 million) of the world population has epilepsy (available from http://www.who.int/ mediacentre/factsheets/fs165/en/). Epilepsies can be divided into three major categories based on etiology: idiopathic, symptomatic, and presumed symptomatic (previously called "cryptogenic") (Engel, 2001). In idiopathic epilepsies, genetic factors causing, for example, channelopathies, are presumed to have a major causative role in the development of seizures. In symptomatic epilepsies, there is an identifiable lesion in the brain that triggers seizures. The lesion can be a genetically programmed cellular alteration like neuronal migration disorder in cortex or an acquired lesion like traumatic brain injury (TBI) or stroke. Presumed symptomatic epilepsies are those most likely to be symptomatic, but the lesions cannot be identified using currently available methods (Engel, 2001).

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Summary:Purpose: This study examined the hypothesis that neurodegeneration continues after status epilepticus (SE) ends and that the severity of damage at the early phase of the epileptogenic process predicts the outcome of epilepsy in a long-term follow-up.Methods: SE was induced in rats by electrical stimulation of the amygdala, and the progression of structural alterations was monitored with multiparametric magnetic resonance imaging (MRI). Absolute T 2 , T 1ρ , and diffusion (D av ) images were acquired from amygdala, piriform cortex, thalamus, and hippocampus for ≤4.5 months after SE. Frequency and type of spontaneous seizures were monitored with video-electroencephalography recordings. Histologic damage was assessed from Nissl, Timm, and Fluoro-Jade B preparations at 8 months.Results: At the acute phase (2 days after SE induction), quantitative MRI revealed increased T 2 , T 1ρ , and D av values in the primary focal area (amygdala), reflecting disturbed water homeostasis and possible early structural damage. Pathologic T 2 and T 1ρ were observed in mono-or polysynaptically connected regions, including the piriform cortex, midline thalamus, and hippocampus. The majority of acute MRI abnormalities were reversed by 9 days after SE. In later time points (>20 days after induction), both the T 1ρ and diffusion MRI revealed secondarily affected areas, most predominantly in the amygdala and hippocampus. At this time, animals began to have spontaneous seizures. The initial pathology revealed by MRI had a low predictive value for the subsequent severity of epilepsy and tissue damage.Conclusions: The results demonstrate progressive neurodegeneration after SE in the amygdala and the hippocampus and stress the need for continued administration of neuroprotectants in the treatment of SE even after electrographic seizure activity has ceased. Key Words: Diffusion-EpilepsyEpileptogenesis-MRI-Relaxation.Status epilepticus (SE) is a clinical emergency with an incidence of ∼0.1%, resulting in estimated 180,000 episodes in the United States and 365,000 in Europe annually (1). SE is associated with a high risk of mortality (20-60%) as well as morbidity, including epileptogenesis (2) and cognitive decline (1). Data from humans and experimental models of SE suggest that both the risks of epilepsy and the severity of cognitive impairment are associated with brain damage caused by prolonged seizure activity (1).Histologic studies in experimental models indicate that SE lasting for 30 to 40 min in rats (3,4) or 80 min in nonhuman primates (5) is long enough to initiate neurodegeneration. It is not, however, known for how long the neurodegenerative process advances after SE in different Accepted April 27, 2004. Address correspondence and reprint requests to Dr. A. Pitkänen at AI Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, FIN-70 211 Kuopio, Finland. E-mail: asla.pitkanen@uku.fi brain regions, and what is its temporal relation to epileptogenesis. Several studies in rats indicate widespread damage in c...

Summary:Purpose: Whether status epilepticus (SE) in early infancy, rather than the underlying illness, leads to temporal lobe neurodegeneration and volume reduction remains controversial.Methods: SE was induced with LiCl-pilocarpine in P12 rats. To assess acute neuronal damage, brains (five controls, five with SE) were investigated at 8 h after SE by using silver and FluoroJade B staining. Some brains from the early phase were processed for electron microscopy. To assess chronic changes, brains from nine controls and 13 rats with SE at P12 were analyzed after 3 months by using histology and magnetic resonance imaging (MRI).Results: MRI analysis of the temporal lobe of adult animals with SE at P12 indicated that 23% of the rats had hippocampal, 15% had amygdaloid, and 31% had perirhinal volume reduction. Histologic analysis of sections from the MR-imaged brains correlated with the MRI data. Analysis of neurodegeneration 8 h after SE by using both silver and Fluoro-Jade B staining revealed degenerating neurons located in the same temporal lobe regions as the volume reduction in chronic samples. Electron microscopic analysis revealed irreversible ultrastructural alterations. As with the chronic histologic and MRI findings, interanimal variability was seen in the distribution and severity of acute damage.Conclusions: Our data indicate that SE at P12 can cause acute neurodegeneration in the hippocampus as well as in the adjacent temporal lobe. It is likely that acute neuronal death contributes to volume reduction in temporal lobe regions that is detected with MRI in a subpopulation of animals in adulthood.Key Words: Amygdala-EpileptogenesisHippocampus-Magnetic resonance imaging-Perirhinal cortex.Status epilepticus (SE) is a neurologic emergency with a higher incidence in infancy and childhood than in any other period of life (1). It remains controversial, however, whether SE causes injury to the developing brain. Prospective imaging studies demonstrated volume reduction of the hippocampus between the two consecutive measurements in a subpopulation of infants and children with prolonged febrile seizures (2). Other studies, however, suggest that the association between prolonged seizures and structural abnormalities can result from complex interactions between developmental abnormalities, prenatal or perinatal insults, and genetic factors [for review, see (3)].In clinical studies, the causality between seizure activity and structural damage is difficult to investigate because of associated illnesses and treatments. Experimental studies in which SE was induced in normal immature brain demonstrated that SE can cause hippocampal and amygdaloid neurodegeneration resembling that in human temporal lobe epilepsy (TLE) in rats older than postnatal day (P) 14 (4). We recently extended these observations by showing that convulsive SE for 2 h can cause neuronal death in the mediodorsal nucleus of the thalamus in 100% of animals as early as P12 (5). Further, rats with SE at P12 had impaired memory and emotional behavior when asses...

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