Functional definition of seizure provides new insight into post-traumatic epileptogenesis

Abstract

Experimental animals’ seizures are often defined arbitrarily based on duration, which may lead to misjudgement of the syndrome and failure to develop a cure. We employed a functional definition of seizures based on the clinical practice of observing epileptiform electrocorticography and simultaneous ictal behaviour, and examined post-traumatic epilepsy induced in rats by rostral parasagittal fluid percussion injury and epilepsy patients evaluated with invasive monitoring. We showed previously that rostral parasagittal fluid percussion injury induces different types of chronic recurrent spontaneous partial seizures that worsen in frequency and duration over the months post injury. However, a remarkable feature of rostral parasagittal fluid percussion injury is the occurrence, in the early months post injury, of brief (<2 s) focal, recurrent and spontaneous epileptiform electrocorticography events (EEEs) that are never observed in sham-injured animals and have electrographic appearance similar to the onset of obvious chronic recurrent spontaneous partial seizures. Simultaneous epidural-electrocorticography and scalp-electroencephalography recordings in the rat demonstrated that these short EEEs are undetectable by scalp electrocorticography. Behavioural analysis performed blinded to the electrocorticography revealed that (i) brief EEEs lasting 0.8–2 s occur simultaneously with behavioural arrest; and (ii) while behavioural arrest is part of the rat's behavioural repertoire, the probability of behavioural arrest is greatly elevated during EEEs. Moreover, spectral analysis showed that EEEs lasting 0.8–2 s occurring during periods of active behaviour with dominant theta activity are immediately followed by loss of such theta activity. We thus conclude that EEEs lasting 0.8–2 s are ictal in the rat. We demonstrate that the assessment of the time course of fluid percussion injury-induced epileptogenesis is dramatically biased by the definition of seizure employed, with common duration-based arbitrary definitions resulting in artificially prolonged latencies for epileptogenesis. Finally, we present four human examples of electrocorticography capturing short (<2 s), stereotyped, neocortically generated EEEs that occurred in the same ictal sites as obvious complex partial seizures, were electrographically similar to rat EEEs and were not noted during scalp electroencephalography. When occurring in the motor cortex, these short EEEs were accompanied by ictal behaviour detectable with simultaneous surface electromyography. These data demonstrate that short (<2 s) focal recurrent spontaneous EEEs are seizures in both rats and humans, that they are undetectable by scalp electroencephalography, and that they are typically associated with subtle and easily missed behavioural correlates. These findings define the earliest identifiable markers of progressive post-traumatic epilepsy in the rat, with implications for mechanistic and prophylactic studies, and should prompt a re-evaluation of the concept of post-traumatic silent perio...

Similarities and Differences of Acute Nonconvulsive Seizures and Other Epileptic Activities following Penetrating and Ischemic Brain Injuries in Rats

“…Although the occipital and temporal IRDA are more commonly associated with seizures than the frontal IRDA, 38 they are not etiologically specific and are relatively less common in TBI and stroke patients. Recently, D'Ambrosio et al 39 described an electrocorticography (ECoG) phenomenon in a rat lateral FP injury model, which seemed to be very similar to the IRDA observed in this study in the PBBI and pMCAO models. In their study the brief (*2 sec) bursts of delta or theta spike oscillations were referred to as ''epiletiform electrocorticography events (EEE),'' and were considered as true post-traumatic ictal activities because of the concomitant behavioral components during each event.…”

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

“…However, since we did not perform electrophysiological measurements, we cannot rule out the possibility that sham-operated animals had subclinical epileptic activity that was not detected behaviorally. Previous studies have correlated these clinical measures of seizure activity to abnormal electrophysiological recordings taken from both cortical and subcortical areas (D'Ambrosio et al, 2004;D'Ambrosio et al, 2009;Hunt et al, 2009Hunt et al, , 2010Kharatishvili et al, 2006;Kharatishvili and Pitkanen, 2010). These studies emphasize that in the clinical situation, periods of PTE could have profound effects on the natural history of the injury process and the long-term consequences of the primary insult (Vespa et al, 2010).…”

“…Clinical studies have demonstrated that spontaneous episodes of PTE occur at variable time periods after TBI and are considered an important second injury mechanism after trauma. In experimental studies, researchers have also reported spontaneous episodes of PTE most commonly after severe TBI in rodent models (Coulter et al, 1996;D'Ambrosio et al, 2004;D'Ambrosio et al, 2009;Hunt et al, 2009Hunt et al, , 2010Kharatishvili et al, 2006;Kharatishvili and Pitkanen, 2010;Lowenstein et al, 1992;Nilsson et al, 1994;Santhakumar et al, 2001). In these studies, PTE is commonly recorded in a subpopulation of rats with injury strategies leading to high mortality.…”

“…Within the cerebral cortex and hippocampus, for example, areas of circuit hyperactivity have been identified (Graber and Prince, 2004;Griesemer and Mautes, 2007;Lowenstein et al, 1992). In a model of severe fluid-percussion injury (FPI), seizure activity has been observed using both electrophysiological and behavioral monitoring (D'Ambrosio et al, 2004;D'Ambrosio et al, 2009;Kharatishvili et al, 2006;Lowenstein et al, 1992;Nilsson et al, 1994;Santhakumar et al, 2001).…”

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

“…This is an etiologically realistic syndrome specific PTE model based on an experimental brain insult, FPI, that has long been regarded as a realistic model of contusive closed head injury in man (Thompson et al., 2005). 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).…”