Impact of Injury Location and Severity on Posttraumatic Epilepsy in the Rat: Role of Frontal Neocortex

Abstract

Human posttraumatic epilepsy (PTE) is highly heterogeneous, ranging from mild remitting to progressive disabling forms. PTE results in simple partial, complex partial, and secondarily generalized seizures with a wide spectrum of durations and semiologies. PTE variability is thought to depend on the heterogeneity of head injury and patient's age, gender, and genetic background. To better understand the role of these factors, we investigated the seizures resulting from calibrated fluid percussion injury (FPI) to adolescent male Sprague-Dawley rats with video electrocorticography. We show that PTE incidence and the frequency and severity of chronic seizures depend on the location and severity of FPI. The frontal neocortex was more prone to epileptogenesis than the parietal and occipital, generating earlier, longer, and more frequent partial seizures. A prominent limbic focus developed in most animals, regardless of parameters of injury. Remarkably, even with carefully controlled injury parameters, including type, severity, and location, the duration of posttraumatic apnea and the age and gender of outbred rats, there was great subject-to-subject variability in frequency, duration, and rate of progression of seizures, indicating that other factors, likely the subjects' genetic background and physiological states, have critical roles in determining the characteristics of PTE.

Targeting Microglia to Prevent Post-Traumatic Epilepsy

“…While this resulted in a 10% mortality rate with severe impact pressures, post-trauma apnea >15 sec that required resuscitation, and substantial brain damage evident in histology, these initial outcome measures alone may not indicate sufficient cortical and subcortical damage for epileptogenesis. In contrast to earlier reports (Curia et al, 2011), recent studies suggest that more caudal and lateral impact locations with a wider (5 mm) craniotomy access may be more effective in yielding convulsive seizures and that the impact pressure wave must be sufficient to produce essential damage to entorhinal cortex and hippocampus (Kharatishvili and Pitkanen, 2010). If morphological and/or spatiotemporal changes in SWD sufficient to be conclusively defined as seizures are to be discovered, perhaps these limbic structures would also be the most productive target for recording and analysis.…”

“…We relied on more rostral parasagittal impact locations and performed FPI through a 3 mm diameter craniotomy, parameters reported by others to be highly successful (Curia et al, 2011;. While this resulted in a 10% mortality rate with severe impact pressures, post-trauma apnea >15 sec that required resuscitation, and substantial brain damage evident in histology, these initial outcome measures alone may not indicate sufficient cortical and subcortical damage for epileptogenesis.…”

Traumatic brain injury causes a Tacrolimus-sensitive increase in non-convulsive seizures in a rat model of post-traumatic epilepsy

“…The corresponding video showed subtle but stereotyped changes in behavior, ranging from behavioral arrest (or immobility) to head bobbing (Racine stage 0 to 2; see representative example in Supplementary Video 2) -we termed these events "non-convulsive seizures." Similar seizures have been described in studies of adult rats following lateral [13] or parasagittal fluid percussion TBI [13,28,29] or neonatal hypoxic injury [30].…”

“…Recent research by our lab suggests that calcineurin may also be involved in the epileptogenesis after TBI. In a study of lateral fluid percussion TBI in rats, a well-characterized model of post-traumatic epilepsy [13,14], we identified an acute post-injury increase in calcineurin activity [15]. This increase could facilitate epileptogenesis through the dysregulation of hyperpolarizing cyclic nucleotide-gated (HCN) channels [10] or voltage-gated potassium channels (K V 2.1) [16].…”

Ceftriaxone Treatment after Traumatic Brain Injury Restores Expression of the Glutamate Transporter, GLT-1, Reduces Regional Gliosis, and Reduces Post-Traumatic Seizures in the Rat

“…These data support ceftriaxone as a safe prophylactic treatment after TBI, which may mitigate posttraumatic seizures. 30 Although this does not affect our main finding of seizure reduction with ceftriaxone treatment, this underscores the variability in seizure expression among rodent TBI models, which complicates translational post-traumatic epilepsy research in general. Relevant to our experiment, strain differences (Long-Evans rats may be more seizure prone than other strains 31 ), craniotomy size, and other factors, such as choice of anesthetic, postoperative analgesia, differences in EEG recording techniques, and sensitivities of seizure detection algorithms, distinguish our model from those in past published reports.…”