Decades of research culminated in a case for a new strategy in which a drug regularly used for amnesia and Parkinson's disease would become the first to prevent the development of epilepsy in patients with traumatic brain injury.

An article published March 3 in Seizure - European Journal of Epilepsy presents evidence developed by a University of Sao Paulo research team, spanning from animal models to an ongoing trial on the drug's efficacy. Detailing two decades of research, the team asserts that the drug biperiden may have the potential to help prevent epilepsy by affecting the brain's ability to develop.

Project lead and Sao Paolo Research Foundation Scientific Director Luiz Mel explained to The Academic Times how a type of immunoglobulin at the heart of six experimental animal studies detailed in the paper, Immunotoxin IgG 192-saporin, selectively kills a subgroup of neurons, cholinergic neurons, that are critically involved in learning and memory. 

"What we found is that when you completely destroy that specific subgroup of cholinergic neurons, you're unable to develop epilepsy in that brain, regardless of what you try," Mello said. "Something has happened to that brain in which, despite you being able to subject it to injury and that injury being able to generate critical events that should lead to epilepsy, [epilepsy] doesn't happen."  

Mello, who has been at the forefront of the project for about 30 years, added, "That, to me, was quite, quite amazing because I had never seen anything like that before — and I had tried a number of different lesions to the brain."

He is now paying for the efficacy trial out-of-pocket. 

"Where there is a will, there is a way," he said, "and I have a firm conviction, a firm belief on what we demonstrated in animal models."

There are no clinically available treatments proven to alter disease progression after traumatic brain injury, a leading cause of symptomatic epilepsy.

Previous efforts to address epilepsy have concentrated on anti-seizure drugs, formerly known as anti-epileptic drugs. But these often fail to prevent or suppress epileptic seizures after traumatic brain injury. 

Patients with post-traumatic epilepsy, in which someone develops epilepsy after a traumatic brain injury, are at risk for recurrent seizures because of brain injuries. About one in 50 patients with traumatic brain injuries will develop post-traumatic epilepsy, according to the Epilepsy Foundation. The spectrum of severity ranges from well-controlled seizures to disabling seizures resistant to medical treatments.

Traumatic brain injury-related emergency department visits, hospitalizations and deaths, meanwhile, have increased by 45% since 2007, according to the U.S. Centers for Disease Control and Prevention.

The Sao Paolo research team ended up looking at brain plasticity, or the ability of a "normal" brain to modify its connections or rewire itself. This allows any brain — human or animal — to develop from infancy to adulthood or recover from injuries. 

Experiments showed that anticholinergic agents such as biperiden could change the natural course of post-traumatic epilepsy if administered soon after the injury for between 10 and 20 days.

In the double-blind, randomized placebo-controlled trial, researchers are evaluating the effectiveness of biperiden in preventing the development of epilepsy in patients who suffered traumatic brain injury. The efficacy study began about three years ago and recruited 123 patients with traumatic brain injury of varying severity before patient recruitment and two-year follow-ups were suspended because of COVID-19 in March 2020.

Twenty-four, or 19% of these patients have since died — eight during the first 10 days after being discharged from the hospital, and 16 after more than 10 days. The 19% mortality rate is higher in patients with more serious injuries but below the 55% mortality rate estimated for severe brain trauma patients in previous literature. 

Of the study recruits, 11 did not follow up with researchers. These cases have been classified as "tentative," rather than being excluded from the protocol. 

The pandemic's onset also meant the team could not monitor patients after hospital discharge. But reorganizing the approach allowed for some follow-up clinical and quality of life evaluations to maintain a connection with patients and monitor the emergence of post-traumatic epilepsy. 

Seven of the recruits have developed epilepsy. The team does not know who received biperiden in the study because of protocol.

"If we opened the study today, given the low sample that we still have, we wouldn't have enough statistical power to demonstrate our hypothesis," Mello said. "However, we can safely say that we do not have any evidence that biperiden is harming the patients in any way." 

Mello pointed to the literature on biperiden safety. 

"At least from the safety side, we are very confident that we will have good results that may encourage other researchers and other groups to further develop similar projects or ideas," he said.

Now, the team has a grant from Brazil's Ministry of Health to study biperiden as a new sequence in a double-blind, randomized placebo-controlled study with two years of follow-up, but with more than 300 patients across multiple centers. 

"We're paving the way towards demonstrating in a sequence of papers, I hope, that this is a potential way to modify disease progression in traumatic brain injury," Mello said. 

The article, "Two decades of research towards a potential first anti-epileptic drug," published March 3 in Seizure - European Journal of Epilepsy, was authored by Simone Kastropil Benassi, Julieta Goncalves Silva Macedo Alves, Cristiane Gorgatti Guidoreni, Cristina Gonçalves Massant, Claudio M Queiroz, Emilio Garrido-Sanabria, Rafael Duarte de Souza Loduca, Maria Alice Susemihl, Wellingson Silva Paiva, Almir Ferreira de Andrade, Manoel Jacobsen Teixeira, Joaquina Queiroz Andrade, Eliana Garzon, Maira Licia Foresti and Luiz E Mello, University of Sao Paolo.