Traumatic brain injury during development reduces minimal clonic seizure thresholds at maturity

Abstract

Post-traumatic seizures affect 12 -35% of children after traumatic brain injury (TBI) and are associated with worse cognitive and functional outcome, even after adjustment for severity of injury. Unfortunately, experimental models of pediatric post-traumatic epilepsy are lacking, and pathogenesis remains poorly understood. We have applied a standard model of TBI in immature rats to determine the effect of TBI on electroconvulsive seizure thresholds later in life.Male rats underwent controlled cortical impact to left parietal cortex on post-natal day (PND) 16-18. Hindbrain, forebrain, and limbic seizure thresholds were assessed, respectively, by tonic hindlimb extension (THE), minimal clonic, and partial psychomotor seizure responses during adolescence and at maturity (PND 60 -63). Post-traumatic seizure thresholds were compared to those obtained in age-and litter-matched sham craniotomy and naïve controls.TBI during immaturity had no clear effect on THE seizure thresholds. In contrast, TBI lowered minimal clonic seizure thresholds at maturity (p < 0.05 vs. sham or naïve rats), but not during adolescence. Consequently, minimal clonic seizure thresholds increased with age for sham and naïve rats but remained similar for TBI rats during adolescence and at maturity. TBI also tended to lower partial psychomotor seizure thresholds, which were determined only during adolescence (p < 0.1 vs. naive).Controlled cortical impact causes both focal cortical injury at the site of impact and ipsilateral hippocampal neuronal death. Since minimal clonic seizures are mediated by the forebrain, partial psychomotor seizures by the limbic system, and THE seizures by the brainstem, the observed pattern of changes in post-traumatic seizure thresholds is not surprising. The apparent age-dependent effects of TBI, however, are unexpected and likely due to a combination of attenuated maturational increases

Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

“…First, a closedskull midline TBI leads to a reduction in seizure threshold in the late phase of recovery. This is consistent with the reduction in seizure threshold reported after focal insults with controlled cortical impact (Statler et al, 2008) and weight drop (Golarai et al, 2001) in the rat. Second, the increase in seizure susceptibility is associated with greater glial activation with the second-hit of ECS, and suppression of the early cytokine response to TBI prevents this later increase in susceptibility.…”

“…In the rat fluid percussion model of chronic spontaneous recurrent seizures (D'Ambrosio et al, 2005), the cumulative probability of detecting epileptiform discharges was greater than 80% after 4-week recovery. In contrast, the present study (7-day recovery), and a rat model of altered susceptibility (16-24 days; Statler et al, 2008), required only a short interval between insults.…”

“…Experimental and clinical evidence has identified inflammatory responses as a significant mechanism contributing to neurological dysfunction in head injury (Schmidt et al, 2005) and epilepsy (Vezzani and Granata, 2005). In a rat weight-drop (Golarai et al, 2001) and a controlled cortical impact (CCI) model (Statler et al, 2008), TBI lowered posttraumatic seizure thresholds. However, the contribution of activated glia to the reduction in the seizure threshold is not known.…”

Post-Traumatic Seizures Exacerbate Histopathological Damage after Fluid-Percussion Brain Injury

“…Consistent with the observations of PTE in models of TBI, decreased seizure threshold has been reported in some models of TBI (Golarai et al, 2001;Statler et al, 2008;Zanier et al, 2003). In one study, a non-convulsant dose of pentylenetetrazole (PTZ), a GABA A receptor antagonist, induced generalized tonic-clonic seizures in animals 15 weeks after the weight-drop contusion injury (Golarai et al, 2001).…”

Functional Plasticity in Childhood Brain Disorders: When, What, How, and Whom to Assess

“…In an auto-pedestrian accident, the speed and type of the vehicle, the road circumstances, position of the child when struck are all unique. Even in animal models of TBI where identical equipment and procedures are used along with identical genetic strains of animals, the exact lesion cannot be consistently replicated across animals (Statler et al, 2008). …”