Characteristics of Blood- Brain Barrier Permeability in Neurological Patients

Traumatic brain injury (TBI) is one of the most common traumatic events, occurring in approximately 200 per 100,000, and is a known risk factor for later development of epileptic seizures. This occurs in up to 17% of TBI patients, and accounts for approximately 20% of symptomatic epilepsies (Annegers, JF. et al, 1998). Typically, post-traumatic epilepsy (PTE) develops or several weeks but even years after the event. PTE is often chronic and poorly controlled pharmacologically. Although several factors have been attributed to an increased risk of developing PTE (e.g. severity of trauma, type of brain injury, time to the appearance of first seizure), the mechanisms underlying it remain unknown. Similar to TBI, ischemic injuries, most frequently occurring in the elderly population are the main cause of new onset epilepsy in this age group. It is still not known what are the risk factors and mechanisms underlying post-ischemic epilepsy. Under normal conditions the central nervous system is protected by the operation of the blood- brain barrier (BBB). Following brain injury (either traumatic or ischemic) the BBB is known to disrupt, leading to focal edema and altered extracellular composition. We have recently established methods for quantitative evaluation of the integrity of the BBB using magnetic resonance imaging (MRI) brain scans. Using these methods we are able to identify BBB disruption in patients suffering from various pathologies (Tomkins, O. et al. 2001; Avivi, E. et al. 2004). Such altered permeability may last up to years following the acute event and was found to correlate to areas of abnormal neurological function (Korn, A. et al. 2005) In recent work using an animal model, we have shown that following focal disruption of the BBB a focus of epileptiform activity is generated within several days. Such pathological activity remains for several weeks, long after the BBB has retained its former function (Seiffert, E. et al. 2004; Iven, S. et al. 2006). Furthermore, this condition may later lead to anatomical alterations as seen by brain MRI scans, as well as in histological sections. Such animals further suffer from functional deterioration and neuronal degeneration in the disrupted region (Tomkins, O. et al. 2006). In this work we will test the hypothesis that BBB disruption following brain injury increases the risk for long-term disability, development of brain dysfunction, epileptic seizures and neuroanatomical alterations. For that we will combine a prospective and retrospective study in patients following cerebral cortical injury (traumatic, hemorrhagic or ischemic). Clinical, functional and anatomical measures will be obtained in addition to BBB permeability measures.