Rationale:
Post-traumatic epilepsy (PTE) is a significant long-term complication of moderate-to-severe traumatic brain injuries (TBI) and comprises as much as 20% of all structural epilepsies. However, there are currently no effective early biomarkers or therapies to prevent epilepsy after TBI, in part because the factors precipitating epileptogenesis after TBI are not fully known.
Most non-TBI rodent models of epilepsy are induced by status epilepticus, which is followed by a latent epileptogenic period of weeks or months before spontaneous seizures arise. The lateral Fluid Percussion Injury (FPI) model of PTE similarly involves a latent epileptogenic period and, as is the case in human TBI, non-convulsive status epilepticus (NCSE) is known to occur beginning hours to days after the injury. However, treatment with antiepileptic drugs (AEDs) during this window does not prevent epileptogenesis in humans.
In this study, we investigated whether epileptiform activity or NCSE occurs during, or within minutes after, FPI prior to regaining consciousness – much earlier than prior studies have investigated, or administered AEDs in attempts to reduce PTE risk in TBI patients.
Methods:
Continuous, noninvasive high-resolution cortical EEG was recorded before, during, and after severe TBI by placing an ultra-flexible EEG array (NeuroNexus) on the skull surface of adult male Sprague Dawley rats during the normal FPI surgical procedures for craniectomy and placement of a Luer Lock and dental cement. The EEG recordings were acquired bilaterally using an Open Ephys Acquisition Board at a sampling rate of 15-kHz from 24 contacts distributed over the ipsilateral and contralateral hemispheres. Following injury, EEG, apnea time, and time to righting reflex were monitored. EEG was then recorded for an additional 12 hours or more following FPI.Results:
Seizure activity marking the cortical electrographic onset of NCSE was observed on average 4.5 minutes (range 3.3-7.2 minutes) after inducing severe TBI (N=5 rats), and cortical electrographic seizure offset coincided with the time of righting reflex return. As has been previously reported, hours later after FPI, additional non-convulsive epileptiform activity was observed on EEG.Conclusions:
These results support a pivotal rethinking of the immediate aftermath of TBI, correlating the transient unconsciousness following injury, colloquially known as being “knocked out”, with a prolonged state of non-convulsive status epilepticus. This previously unrecognized window of epileptiform activity may support a new temporal urgency for early intervention within minutes after TBI, and could help to explain the lack of success of previous attempts to prevent chronic PTE with treatment on the scale of hours after injury. Status epilepticus is known to promote epileptogenesis across many etiologies, and our results demonstrate that just minutes after TBI, a critical therapeutic window may already be closing.Funding:
Virginia Commonwealth University
Department of Defense
Department of Veterans Affairs