June 27, 2024

CURE Epilepsy Discovery: Post-Traumatic Epilepsy (PTE): Stealth Mode No More

CURE Epilepsy continues its commitment to uncovering the biology of PTE

As a Marine deployed in Afghanistan, Captain Jack Somers was familiar with operating in stealth mode, hidden from enemies. But unbeknownst to him, similarly covert changes were taking root in his brain after a particularly close grenade blast experienced in 2010 while serving overseas. This likely set in motion a cascade of brain changes that announced themselves one month later, in the form of Jack’s first-ever seizure.

But neither Somers — nor his doctors — were aware of his risk at the time. Instead, it seemed as though his first seizure came out of nowhere, at a local Thanksgiving Day Turkey Trot, soon after completing his Afghanistan tour.

After this first absence seizure, others followed, including more absence seizures, drop seizures, and eventually grand mal seizures, which resulted in his medical retirement after almost six years of service.  The seizures continued, while Somers cycled through about 50 treatment plans with different anti-seizure medications. In 2022, 12 years after that first seizure, Somers finally received a diagnosis of post-traumatic epilepsy (PTE).

With that diagnosis, Somers felt like he understood for the first time what was happening to him. “It’s like you can take the blindfold off and start to see what you are fighting,” he says.

Somers’ story highlights key unknowns in the science of PTE. How can we recognize someone who is at risk for PTE after a head injury? Is it possible to prevent seizure development before it starts? Can we treat PTE to keep it from progressing to other parts of the brain?

Since 2017, CURE Epilepsy has been committed to answering these questions. This has meant supporting research to uncover the fundamental changes that lay the groundwork for epilepsy to take hold in the brain in the first place — a process referred to as “epileptogenesis.” Beginning with the PTE Initiative, funded with $10 million from the US Department of Defense, CURE Epilepsy charged six multidisciplinary teams of scientists to study the changes that unfold in the brain after injury, and to find telltale signs of risk for PTE. As the original PTE Initiative nears completion, its momentum continues in the form of CURE Epilepsy’s new project called the PTE Astrocyte Biomarkers Initiative (PABI) that focuses on astrocytes, the support cells in the brain responsible for maintaining neuron health. After brain injury, astrocytes are activated, and they may drive some of the brain changes that promote PTE. In addition, CURE Epilepsy convened the International Conference for Post-Traumatic Epilepsy (IC-PTE) in Milan, Italy in May. This conference gathered researchers from around the world to share progress and pitfalls in PTE research, which should hasten important therapeutic discoveries.

Ideally, this kind of commitment will ultimately lead to therapeutics that can help a person like Somers, who for too long tried to keep his seizures apart from life-as-usual. “I think it is all too common in this community to think, ‘I can get past this on my own, I can do it,’” he says. “But [PTE] keeps punching back.”

The Path to PTE

PTE is an acquired form of epilepsy, with seizures beginning weeks, months, or years after a traumatic brain injury (TBI). PTE accounts for 5% of all epilepsies and develops in up to 50% of those who have a severe TBI. The ensuing seizures not only slow recovery from a TBI, but can worsen in type and frequency, as they did for Somers, eventually resulting in difficulties in thinking, mood, and memory.

Despite these challenges, Somers initially muscled through his life while hiding his epilepsy. But seizures impacted his abilities to manage work, communicate, and lead as he had before, which brought on panic attacks. He was eventually fired, for the first time in his life. “That was a knock on my confidence, a real humbling experience,” he says. “It was so unlike me, I needed to figure out what was going on.”

In his brain, a lot had been going on.

During the time between a TBI and the first seizure, the brain is in flux. A TBI can initiate changes that rework the brain to make it hyperexcitable and prone to seizures. After seizure onset, PTE can continue to progress, with seizures priming the brain for more and different kinds of seizures, as hyperexcitability spreads to other parts of the brain.

Researchers are now working to reveal the specific TBI-induced changes that lay the groundwork for PTE. Neurons remake their connections to other neurons and alter their electrical activity due to shifts in gene expression; astrocytes are activated and orchestrate changes in the environment around neurons; long-lasting inflammation sets in, and in some cases, blood from the injury enters neural tissue, which may affect neuron health.

The quiet interval between a TBI and the first seizure (also called the “latent period”) can also make it difficult to recognize PTE. In Somers’ case, there was additional difficulty because his TBI from a grenade blast went unrecognized. This points to the urgent need to identify risk factors for PTE, not only among those with a diagnosed TBI, but among those like Somers with no immediately obvious brain injury. Ideally, an easily measured “biomarker” found in a blood test or in brain waves from an electroencephalogram (EEG) could detect whether someone is on a path to PTE.

The latent period also delineates a key window of time to act. CURE Epilepsy is working to see if a future therapeutic could be given during this time to halt, or even prevent, epileptogenesis. This hypothetical intervention would be different from current anti-seizure medications, which keep seizures from occurring but do not prevent PTE onset. In contrast, an anti-epileptogenic medicine would prevent the brain changes that promote seizures from taking root in the first place, and stop the progression of those changes in people who already have PTE.

The PTE Initiative

In 2017, CURE Epilepsy’s PTE Initiative kicked off with six scientific teams funded to investigate PTE with a variety of approaches. Some research explored whether the nature of the initial TBI mattered to the development of PTE; for example, is damage to brain vessels or the introduction of blood directly to brain tissue somehow important? Other research projects asked whether the brain’s reaction to the injury was critical, be it in the form of inflammation, recruitment of glial support cells to the injury site, or changes to the neurons themselves.

These questions were addressed with different methods. Some groups worked to develop animal models of PTE, which mimicked the development of seizures after a brain injury. These models are valuable because they provide a way to understand the mechanisms of epileptogenesis, and flag changes that might signal PTE risk. These studies were complemented by investigations of brain samples collected from people with TBI and PTE after their death. Other teams focused on finding biomarkers that could signal a person’s risk of developing PTE after a head injury. Additionally, clinicians followed people with severe TBI for two years, collecting data to see if anything predicted PTE development.

Five years later, the research dividends are coming in [1]. One recent study highlights a role for astrocytes in PTE: mice that developed seizures after a brain injury displayed changes in their astrocytes not seen in mice that didn’t develop seizures after the same injury [2]. These changes had to do with the transcriptomic “messages” generated by the genes inside the astrocytes, which could have altered their function. Other CURE Epilepsy grant mechanisms have also allowed early career investigators to explore novel but risky ideas that have pushed the overall progress on PTE forward. For example, a 2022 Taking Flight awardee found that a TBI-like injury in rats impaired blood flow in the brain, and damaged the key energy suppliers of a cell, called mitochondria [3].

Beyond the scientific findings of the PTE Initiative, CURE Epilepsy also learned how to facilitate meaningful collaboration by establishing standard procedures and infrastructure for data collecting, formatting, and sharing. Now in place, these should expedite future collaborations, and facilitate comparisons between different studies and researchers across the globe that will lay bare the mechanisms of epileptogenesis.

Called to Collaborate

CURE Epilepsy’s new PABI project builds off the astrocyte findings in the original PTE Initiative. Funded by the US Department of Defense’s Congressionally-Directed Medical Research Program (CDMRP) Epilepsy Research Program, this new initiative aims to track how astrocytes change in the brain after TBI and before PTE onset. A collaborative effort across multiple scientific teams, PABI will look for signs from astrocytes that predict PTE in mouse models. One team will also study archived blood samples collected from people at various time points after a TBI, to track changes in measures of inflammation. This may reveal a distinctive “signature” that discriminates those who develop PTE from those who do not. “We are extremely excited to continue the momentum of our PTE Initiative in this new astrocyte project,” Lubbers says.

As PTE research intensifies, the field is already looking ahead towards therapeutics. The previously mentioned IC-PTE in Milan brought together dozens of researchers worldwide to share recent scientific findings about PTE, and to draw up a roadmap for the first clinical trials. The conference emphasized how finding reliable biomarkers for PTE risk will be essential to the success of future clinical trials, because these biomarkers will identify the trial participants who stand to benefit most from a preventative PTE therapy.

Meanwhile, Somers maintains his soldier’s mentality of service. In Milan, he opened the conference with a talk describing his experiences with PTE. He has also shared his story in podcasts and newsletters for CURE Epilepsy and is an advisor for PABI.

The perspectives of people like Somers can help researchers sharpen their research ideas, and align their studies to the priorities of people affected by PTE. This includes designing quality of life studies that aim to quantify the challenges PTE can bring to families, given the cognitive, mood, and communication difficulties associated with seizures. Documenting these issues with data should spur agencies to provide families with resources and support.

“I refuse to let my experiences get lost in translation, I refuse to let them go to waste. My hope is that they get leveraged, to help others,” Somers says.


Literature Cited:

  1. Iyengar SS, Lubbers LS, Harte-Hargrove L, CURE Epilepsy Post-Traumatic Initiative Advisors and Investigators. A team science approach for the preclinical and clinical characterization and biomarker development for post-traumatic epilepsy Epilepsia Open. 2023 May; 8: 820-833.
  2. Leonard J, Wei X, Browning J, Gudenschwager-Basso EK, Li J, Harris EA, et al. Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy Sci Rep. 2024 April; 14: 8367.
  3. van Hameren G, Muradov J, Minarik A, Aboghazieh R, Orr S, Cort S, et al. Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury Neurobiol Dis. 2023 Oct; 186: 106269.

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