Abstracts

Rationale: Approximately 5-30% of patients with traumatic brain injury (TBI) will develop posttraumatic epilepsy (PTE), depending on injury severity. Studies to date have shown that a variety of drugs, including antiepileptic drugs, administered after injury, do not prevent the development of PTE. Establishing non-invasive MRI end-points as biomarkers of posttraumatic epileptogenesis may be of particular benefit as we continue to search for possible agents to prevent PTE. The presence of blood-brain barrier disruption (BBBD) has been increasingly indentified as a prominent contributor to epileptogenesis in multiple models of experimental epilepsy. Methods: A total of 12 animals underwent functional neurological and MRI evaluations after either moderate-to-severe fluid percussion or sham brain injury. At three months after injury, animals were challenged with a chemoconvulsant, kainic acid, in doses lower than those used to induce status epilepticus to assess post-injury provoked seizure susceptibility. Results: Gadolinium-enhanced T1-weighted MRI evaluations of injury-related BBBD reliably distinguished between injured and sham-injured animals at 72 hours after injury. BBBD at 72 hours after injury was also significantly correlated with total number of seizures in the first 60 minutes after kainate administration and with latency to seizure onset (r= 0.738, p= 0.010 and r= - 0.758, p= 0.007, respectively). Conclusions: Our MRI-based protocol (including pre- and post-gadolinium T1 scans) for assessing TBI-related BBBD is reliable and has a unique advantage over commonly used methods due to its non-invasive nature. The strong correlation between the MRI-based BBBD end-points and post-injury seizure susceptibility supports its use as a biomarker for posttraumatic epileptogenesis. The potential of this information for improving our clinical standard-of-care protocols to predict long-term risk of developing PTE may be significant. Preclinical MRI biomarkers could be used to guide future study designs by increasing the similarity of preclinical to radiographically-based, clinical patient selection protocols and may enhance translation of potential therapies directly into the clinics.