The Use of Biperiden as an Antiepileptogenic Drug in Patients with Moderate or Severe Traumatic Brain Injury

Abstract: Traumatic brain injury (TBI) is a public health problem, with considerable social and economic burden. TBI is one of the most important causes of secondary epilepsy, with a cumulative probability of 10% over a 5 years period. TBI leads to post-traumatic epilepsy (PTE) most likely by means of direct damage to the brain parenchyma, which in turn leads to neurodegeneration and inflammatory responses, as well as molecular, structural and electrophysiological changes. There is currently no treatment that prevents the development of PTE. In the course of 2 decades of experiments, our group chose biperiden in order to move forward with a deeper investigation. Biperiden was able to reduce the frequency of spontaneous seizures, increased the time for the first spontaneous seizure observed and reduced the severity of these spontaneous seizures in the pilocarpine model of epilepsy (Bittencourt et al., 2017). In this study we aim to investigate the safety and efficacy of biperiden in adult patients, who suffered moderate and severe TBI.

Methods: This is a double-blinded, randomized, controlled trial of patients with moderate or severe TBI resulting in cerebral contusion and intraparenchymal haemorrhage documented in the imaging exams. The patients will be treated in the acute phase of the trauma, in order to avoid the outset of an epileptogenic focus. A total of 264 patients will be evaluated, randomized into two groups: those who will receive placebo and those who will receive biperiden. Patients included will receive the study drug (biperiden or placebo) intravenously every 6 hours for 10 days. An interim analysis will be performed after the first 132 patients have completed 12 months of study. The study hypotheses are as follows: (1) whether biperiden can reduce the frequency of PTE; (2) whether biperiden-treated patients that develop PTE have epilepsies that are less severe and more amenable to treatment.

Discussion: The prevention of PTE is the subject of a great research effort that so far has eluded the medical community. The use of classical antiepileptic drugs such as sodium valproate and carbamazepine, as well as the deployment of neuroprotective and anti-inflammatory strategies all have failed in providing an effective treatment for PTE. In the event our study successfully manages to achieve some level of prevention we would be not only providing a potential treatment but also indicating a much-needed lead for further discoveries in this area.