Authors :
Andrew Zayachkivsky, PhD – University of Utah
Hannah Culbertson, BS – University of Utah
Mitchell Couldwell, MD – University of Utah
Jordan Pollard, BS – University of Utah
Kevin Staley, MD – Massachusetts General Hospital
Daniel Barth, PhD – University of Colorado, Boulder
Presenting Author: F. Edward Dudek, PhD – University of Utah
Rationale:
Several publications have described evidence for post-traumatic epilepsy (PTE) after controlled-cortical impact (CCI), a model of traumatic brain injury (TBI). Although previous researchers have reported “late” spontaneous recurrent seizures (SRSs) after CCI, compared to models based on status epilepticus, the percent of animals with SRSs has generally been small and variable, with low SRS frequencies and possible species/strain dependence. Here, we share data suggesting that PTE after CCI in Sprague-Dawley (SD) rats is rare, with low SRS frequencies and probably long latent periods.
Methods:
Male SD rats were brain-injured with a CCI impactor (6-mm at 5 m/s 2.8 mm deep with a dwell time of 1-3 msec) over caudal neocortex. CCI caused severe damage to neocortex, hippocampus and thalamus. Sham controls (n=19) were treated identically, but without CCI. Rats (n=44) were implanted with electrodes in neocortex ipsilateral and contralateral to CCI-induced injury using wireless DSI or EPOCH telemetry systems and monitored for 1-6 months. A second group (n=17) was implanted with a wired Pinnacle system and monitored after 6-13 months. Many rats (n=34) received a Neurological Severity Score based on their behavior. SRSs were analyzed with various seizure/spike-detection algorithms and manually with direct observation.
Results:
Based on gross anatomic observations and Neurological Severity Scores, CCI caused severe cortical and subcortical damage. For weeks after injury, the EEG of the CCI-treated rats (n=8) showed “slowing”, which was not present in sham controls (n=8). “Early” seizures (i.e., within 1 week) were observed in many CCI and sham rats (n= 3 CCI, n=2 shams). SWDs were observed in virtually all sham and CCI-treated rats, had different waveforms compared to SRSs, could have a prolonged duration of >10 sec (often showed a “waxing and waning” pattern), and generally increased with age in both groups. “Late” or epileptic SRSs were only detected in n=4 rats monitored 6-13 months after injury (i.e., implanted with wired system), suggesting an incidence of 9% between the two studies.
Conclusions:
Similar to our previous work, PTE in CCI-treated SD rats was rare, and when present, seizure frequency was low. SRSs were infrequent even though both structural and behavioral data indicated the CCI-induced brain injury was quite severe. “Early” seizures in both CCI- and sham-treated rats suggests that early seizures were due in part to the craniotomy and may not be a good predictor of PTE, at least under these conditions. Long-duration SWDs - with “waxing and waning” of the oscillations - suggests that these long-duration SWDs could have been misidentified as seizures in previous studies of PTE. Although additional experiments and analyses are necessary to ensure that these data do not represent a “false negative”, our results suggest that PTE is relatively rare in SD rats after CCI. Previous papers with rat models of PTE may have over-estimated the amount of PTE.
Funding:
Funded by grants from NINDS (NS NS086364) and CDMRP EP150033 and
EP210067).