Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?

Abstract

Summary Purpose Post-traumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, risk of injury, and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham-injury. Serial MR and PET imaging, and behavioral analyses were performed over six months post-injury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-EEG to assess for PTE. Of the LFPI rats, 52% (n=12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F-FDG PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at one week, one month, three months, and six months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and non-epileptic groups. However, hippocampal surface shape analysis using high dimensional mapping-large deformation identified significant changes in the ipsilateral hippocampus at one week post-injury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the one week, one month, and three month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and non-epileptic animals into the correct group.

Neuroimaging the Epileptogenic Process

“…As shown in Fig. 1, volumetric and morphological changes in the hippocampus and other limbic structures have been reported in both SE [26][27][28][29] and FPI models [11,23,30,31]. However, these changes are typically preceded by abnormalities identified by other more sensitive neuroimaging methods [11,23,[28][29][30][31].…”

“…As seen in Fig. 1, [18F]FDG-PET following FPI in rats has also identified acute and persistent hypometabolism that preceded significant structural atrophy [11,30], and may predict the later onset of PTE [11]. While further research is clearly required, and other limitations must be considered [62], these findings, together with the ability to assess other relevant pathophysiological processes in vivo, make PET a valuable experimental tool in the investigation of epileptogenesis.…”

“…Animal models of epilepsy, both acquired and genetic, provide the opportunity to rigorously investigate experimental subjects known to be experiencing epileptogenic processes, and thereby hold the potential to increase our understanding and identify early biomarkers of this disease. Briefly, some of the most commonly used and well-validated animal models of epilepsy that will be discussed in this section include exposure to proconvulsant chemicals, such as pilocarpine or kainic acid, to induce status epilepticus (SE) and consequent spontaneous seizures modeling temporal lobe epilepsy (TLE) [8]; electrical stimulation, or kindling, of temporal brain regions (e.g., amygdala) to model TLE [8]; and the fluid percussion brain injury (FPI) model of traumatic brain injury (TBI) and posttraumatic epilepsy (PTE) [9][10][11]. This section will provide a summary of the epileptogenic-related changes and neuroimaging biomarkers that have been identified to date within these models.…”

“…However, these changes are typically preceded by abnormalities identified by other more sensitive neuroimaging methods [11,23,[28][29][30][31]. As such, volumetric and morphological changes may not be ideal neuroimaging biomarkers to identify early pathophysiological processes involved in epileptogenesis, but may have more of a role to assess subsequent progressive neurodegenerative changes, in particular atrophy of key structures such as the hippocampus, that may follow an epileptogenic brain insult [11,29,30,32].…”

Epilepsy Related to Traumatic Brain Injury

“…Recently, Schultz et al [67] reported that abnormalities in the surface morphology of the ipsilateral hippocampus present at 1 week after lateral FPI predicted the occurrence of epilepsy 6 months after TBI [67]. We recently investigated whether quantitative T2, T1ρ, and diffusion (Dav) assessed with MRI at 9 days, 23 days, or 2 months after TBI in the peri-lesional cortex, thalamus, and hippocampus would predict seizure susceptibility in the PTZ test at 12 months after TBI [68].…”