Mild passive focal cooling prevents epileptic seizures after head injury in rats

Abstract

Objective Posttraumatic epilepsy is prevalent, often difficult to manage, and currently cannot be prevented. While cooling is broadly neuroprotective, cooling-induced prevention of chronic spontaneous recurrent seizures has never been demonstrated. We examined the effect of mild passive focal cooling of the perilesional neocortex on the development of neocortical epileptic seizures after head injury in the rat. Methods Rostral parasagittal fluid percussion injury in rats reliably induces a perilesional, neocortical epileptic focus within weeks after injury. Epileptic seizures were assessed by 5-electrode video-electrocorticography (ECoG) 2–16 weeks post-injury. Focal cooling was induced with ECoG headsets engineered for calibrated passive heat dissipation. Pathophysiology was assessed by GFAP immunostaining, cortical sclerosis, gene expression of inflammatory cytokines IL-1α and IL-1β, and ECoG spectral analysis. All animals were formally randomized to treatment groups and data were analyzed blind. Results Cooling by 0.5–2°C inhibited the onset of epileptic seizures in a dose dependent fashion. The treatment induced no additional pathology or inflammation, and normalized the power spectrum of stage N2 sleep. Cooling by 2°C for 5.5 weeks beginning 3 days after injury virtually abolished ictal activity. This effect persisted through the end of the study, over ten weeks after cessation of cooling. Rare remaining seizures were shorter than in controls. Interpretation These findings demonstrate potent and persistent prevention and modification of epileptic seizures after head injury with a cooling protocol that is neuroprotective, compatible with the care of head-injury patients, and conveniently implemented. The required cooling can be delivered passively without Peltier cells or electrical power.

Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat

“…Our previous work has shown that, while rpFPI is progressive in seizure frequency and duration, behavioral correlates, and underlying pathology, the frequency of focal neocortical seizures originating from the perilesional epileptic focus appears relatively stable for a period of several weeks around 1 month post-injury (Curia et al, 2011; D’Ambrosio et al, 2005, 2013). This is, thus, a convenient time for the assessment of investigational treatments, and we have successfully used periodic recordings to evaluate both AS and AEG/DM effects on frontal neocortical PTE at 1 month postinjury (D’Ambrosio et al, 2013; Eastman et al, 2010, 2011).…”

“…This is, thus, a convenient time for the assessment of investigational treatments, and we have successfully used periodic recordings to evaluate both AS and AEG/DM effects on frontal neocortical PTE at 1 month postinjury (D’Ambrosio et al, 2013; Eastman et al, 2010, 2011). In the present study, continuous ECoG recordings conducted 1 month postinjury detected numerous CSRSs with focal perilesional onset that did (Figs.…”

“…rpFPI and epidural electrode implantation were performed as detailed previously (D’Ambrosio et al, 2013; Eastman et al, 2010). For rpFPI, 17 animals were anesthetized (4% halothane), intubated and mechanically ventilated (1–1.5% halothane, 30% O 2 and air).…”

“…We have previously optimized this model with respect to the location and severity of injury to produce rapid and reliable epileptogenesis with low acute mortality (Curia et al, 2011, in press; D’Ambrosio et al, 2009), and have identified the location of the early epileptic focus that develops after injury. This has been mapped with grid and depth electrode recordings (D’Ambrosio et al, 2005, 2009), as well as by focal cooling of the perilesional neocortex (D’Ambrosio et al, 2013). The localization of the neocortical epileptic focus permits use of a recording montage that closely monitors its activity.…”

How Clinical Development Can, and Should, Inform Translational Science

“…This resulted in the FDA never approving carisbamate for partial-onset seizures, despite the preclinical efficacy in relevant animal models (Bialer et al, 2009). There is now a concerted effort to develop and implement new preclinical models of epilepsy (Barton et al, 2001;Bouilleret et al, 1999;D'Ambrosio et al, 2013;Stewart et al, 2010) in an attempt to overcome the perceived similarity in efficacy of many antiseizure drugs. These new models may be useful in the identification, differentiation, and development of compounds with novel mechanisms of action, attempting not only to confer an improved antiseizure effect (particularly in the patients who have been resistant to all available therapies), but ideally to modify the course of the underlying disease (disease modification and perhaps even antiepileptogenesis; Kelley et al, 2009;Lowenstein, 2011).…”