Post-traumatic epilepsy (PTE) is the most common form of acquired epilepsy, which is often refractory to treatment. PTE is usually defined as two seizures occurring at least 2 weeks after the traumatic brain injury (TBI) event . The mechanism by which these seizures develop is still unclear. Many mechanisms have been identified through studies of status epilepticus and temporal lobe epilepsy With few models and limited understanding of the underlying progression of epileptogenesis, progress is extremely slow to find a preventative treatment for PTE. The antiepileptogenic effectiveness of current antiseizure medications (ASMs) has been found to be unsuccessful in preventing PTE in clinical studies. Previous TBI study using in-vitro injured cortical slice and the controlled cortical impact (CCI) experimental models; showed the administration of the ASM levetiracetam (LEV) within 1 hour after a head injury successfully stopped the growth of posttraumatic evoked and spontaneous epileptiform activity.
Brivaracetam (BRV) is a novel molecule that was discovered and developed by UCB Pharmaceuticals. In a new study published in Epilepsia scientists from the SUNY Downstate Health Sciences University: Drs. Douglas Ling, Lie Yang, and Jeffrey Goodman used ex-vivo electrophysiological assessments of cortical epileptogenicity in brain slices prepared 3–4 weeks after injury to analyze the antiepileptogenic effectiveness of BRV given early after damage in CCI-injured rats. By suppressing and preventing the development of cortical hyperexcitability and spontaneous epileptiform (interictal and ictal-like) activity in cortical circuits, early administration of a single dose of BRV after cortical TBI demonstrated a high degree of antiepileptogenic protection. When given to rats 30 minutes after cortical TBI, the lower dosage of BRV prevented the emergence of evoked epileptiform activity.
One of the main research activities of the group is to identify the most promising strategies for preclinical and clinical development of treatments to prevent PTE and its comorbidities. Earlier findings from the group showed that applying valproate to an in-vitro traumatized cortical slice within 30 minutes of injury prevented the emergence of stimulus-evoked epileptiform activity and further experimental data on humans showed an increase in extracellular glutamate soon after the initial injury. This trauma-induced rise in glutamate probably serves as a trigger, setting off a series of subsequent processes that resulted in more cell death and amplifying many of the systems involved in the epileptogenic process following TBI. This time the research team showed that BRV, which inhibits the release of synaptic glutamate and may also block voltage-gated sodium currents and allosterically modulate g-aminobutyric acid receptor A currents, may reduce cortical hyperexcitation and, thus, prevent the development of posttraumatic epileptogenesis. When given up to 60 minutes after TBI, the greater dosage of BRV was still efficacious in preventing the emergence of both evoked and spontaneous epileptiform activity.
In addition to reducing the proportion of neocortical slices per rat that displayed both evoked and spontaneous epileptiform discharges, BRV treatment significantly decreased the number of CCI-injured rats that developed epileptiform activity, suggesting that BRV may inhibit or slow the onset of trauma-induced epileptogenesis in the neocortex. Many of the systems that contribute to the epileptogenic process after TBI are altered and amplified by glutamate increase brought on by trauma. These secondary processes cause further cell death. As the trauma-induced glutamate surge remained unchecked, the likelihood of averting epileptogenesis decreased. Therefore, the likelihood that early intervention can prevent epileptogenesis will be higher if it reduces the severity of the trauma-induced increase in extracellular glutamate.
According to a study, both LEV and BRV prevent seizures by attaching to the SV2A synaptic vesicle protein and preventing transmitter release. The enhanced effectiveness of BRV in animal seizure models may be due to its 10 to 20-fold higher binding affinity to SV2A than LEV. Research has revealed that early post-injury treatment with pentobarbital, valproate, or the glutamate receptor antagonists CNQX and CPP prevented the emergence of posttraumatic hyperexcitability in an in-vitro model of cortical neurotrauma. Future research efforts should be directed toward filling these gaps to open new frontiers in the field of PTE therapeutics and the authors’ findings on BRV and a prior study with LEV, suggest the prospect that other drugs, including first-generation ASMs, may have antiepileptogenic if administered early after cortical damage.
In a nutshell, the study of the Ling research group indicates that early BRV treatment, up to 60 minutes after severe cortical damage may stop or slow the epileptogenic process when observed 3–4 weeks after the injury. It is yet unknown if delaying spontaneous epileptiform burst activity is a permanent solution or only a temporary one, whether the hippocampus exhibits a similar reaction, and whether this method effectively prevents or lowers the frequency of spontaneous recurring seizures in-vivo. The authors also propose testing BRV in a clinical trial to assess if early intervention with pyrrolidine, SV2A-ligand ASMs during the “golden hour” of neurotrauma care can prevent PTE.
In a joint statement to Medicine Innovates, the authors said “The prevention of posttraumatic epilepsy continues to be a significant clinical challenge. Our results have identified a new approach that could be effective and suggest that early intervention could be the key.”
Ling DS, Yang L, Goodman JH. Brivaracetam prevents the development of epileptiform activity when administered early after cortical neurotrauma in rats. Epilepsia. 2022 Apr;63(4):992-1002.