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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 T2, T1ρ, and diffusion (Dav) 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 T2, T1ρ, and Dav values in the primary focal area (amygdala), reflecting disturbed water homeostasis and possible early structural damage. Pathologic T2 and T1ρ 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 T1ρ 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.
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 brain regions, and what is its temporal relation to epileptogenesis. Several studies in rats indicate widespread damage in cortical and subcortical regions a few days after either chemically or electrically induced SE (6,7). Recent histologic data from animal models suggest that SE-induced damage continues for several weeks (8). A growing number of follow-up studies in humans with magnetic resonance imaging (MRI) indicate that hippocampal atrophy progresses over weeks, months, or years after the first SE (for review, see Pitkänen et al., 1999). However, several caveats exists in the interpretation of the previous studies. Data from animal models are cross-sectional, and human studies are based on the follow-up of single patients; therefore it is difficult to assess the time-course of damage and its association with morbidity. These data, using surrogate markers to predict the phase of epileptogenesis after SE, are critically important for determining the window for optimal neuroprotective treatment.
Recent advances in quantitative MRI methods provide noninvasive tools for assessing the functional integrity (9), disturbed water homeostasis, and progressing structural damage over a period of time in experimental animals (10). Much of our understanding of the behavior of quantitative MRI parameters, such as relaxation times and diffusion, during evolving tissue damage comes from both experimental and clinical studies of stroke (11). These studies show a decrease in the diffusion coefficient of water in the hyperacute phase of cerebral ischemia, generally associated with depolarization of the cells due to energy failure, with subsequent changes in the intracellular-to-extracellular water ratio, as well as with decreased diffusivity in the cell interior and increased extracellular tortuosity (12). These initial changes might be reversible and, in many cases, might not correlate with the outcome of the tissue. During the evolution of damage, diffusion MRI normalizes, and in the chronic phase, it increases above normal levels. This MRI characteristic of the chronic stroke phase most likely reflects increased water content in the tissue and disruption of cellular structures. Changes in relaxation times are detected several hours after the induction of cerebral ischemia and thus are often associated with irreversible damage. Edema, magnetic susceptibility, and microenvironmental changes determine relaxation time–based contrast in damaging tissue. Recently, T1ρ MRI was reported to be sensitive to ischemia-induced changes in brain tissue, showing a high predictive value for the degree of developing neuronal damage (13). Because the disease processes leading to cell death after ischemia and other epileptogenic insults share some common features (14), multiparametric MRI might be useful to assess tissue status during evolving epileptogenesis.
We hypothesized that structural degeneration would progress for much longer than SE-associated seizure activity, and that the severity of damage at the early phase of the epileptogenic process predicts the severity of epilepsy in a long-term follow-up. We used a model of temporal lobe epilepsy (TLE) recently developed in our laboratory, in which SE triggered by electrical stimulation of the amygdala induces epileptogenesis, resulting in spontaneous seizures (15). Animals were examined by using quantitative MRI focusing on the brain areas associated with epileptogenesis (amygdala, hippocampus, piriform cortex, thalamus) sequentially until ≤4.5 months after inducing SE. Animals also were monitored with video-EEG for ∼8 months to determine the nature and frequency of spontaneous seizures. Histologic assessment was performed at the end of the study. Some of the MRI data were previously published as a preliminary report (8).