The initial four patients have been enrolled in a first-of-its-kind trial to test a treatment for so-called ‘brain tsunamis’ often suffered by heart attack and stroke victims.
The phenomenon – officially called spreading depolarisations (SD) – can see brain cells die for weeks following head trauma.
This is because damaging seizure-like electrical waves can spread through the brain after a traumatic health event such as a stroke or heart attack, preventing it from communicating and gradually poisoning the nerve cells.
Now researchers in the United States believe they may have a way of intervening and treating SDs.
A team from the University of Cincinnati plans to enrol around 70 patients in total across trial sites at UC, the University of Pennsylvania, and the University of California San Francisco, to see if SDs can be treated when they are first spotted – and to discover if doing so will result in better outcomes for patients.
Jed Hartings, professor and vice chair of research in the Department of Neurosurgery in UC’s College of Medicine and principal investigator of the trial, explained that just like a battery, brain cells have a stored, or polarised, charge that enables them to send electrical signals to each other.
During SD, the brain cells lose their charge, becoming depolarised and unable to send electrical signals to each other.
“This happens en-masse in a local area of tissue and then spreads out like a wave, like ripples in a pond, and it interrupts every aspect of cell function. I sometimes explain that the brain cells become a swollen sack of saline, just a big bag of saltwater, that’s not functional anymore.”
SD can occur continuously in patients for up to a couple of days, but they can also endure on and off for up to two weeks after a severe brain injury.
Dr Jed Hartings Image: University of Cincinnati
Dr Hartings said: “It’s a big open question whether or not these might continue for many weeks or a month, and it’s also a big question to what extent do they occur in less severe injuries that don’t require surgery. There’s strong emerging evidence that they would occur even in something as mild as a concussion.”
Because SDs cause a complete shutdown in affected brain regions, they generate an electrical discharge measured at about 10 times the size of a typical seizure.
SDs were first discovered in animals in 1944, but research into how they affect human brains only began around 2002.
Dr Hartings said: “I think in the past maybe five to 10 years we’ve turned the corner and our results have shown that these are very common and that they are detrimental. They’re consistently associated with worse patient outcomes.”
Research has focused on patients that have required surgery because an electrode strip needs to be placed in the brain to monitor for SDs. However, it is estimated that SDs affect patients with virtually every type of acute brain injury, including different kinds of strokes and traumatic brain injuries (TBI).
Dr Hartings commented: “It’s across the spectrum and we have been monitoring all those different types of patients as an international research community.
“It’s in the range of 60% to 100% of all patients in these different disease categories. It’s just mind-boggling. This is the iceberg that’s been submerged under the water that we never knew about.”
There is currently no standard of care or treatment for SDs. This trial is the first Phase 2 testing the feasibility of treating patients with SDs.
“This is a pretty exciting moment for us here and globally in this community. We really rebooted and created a field of science globally, both basic scientists in the laboratory as well as clinical scientists who monitor the brain,” Dr Hartings said.
“There’s a large basic science community that’s been trying to understand these events better now that we know that they have clinical significance. Now this is for the first time in this global community that we actually have a trial that’s trying to intervene and treat them.”
Due to the need for surgery to place the electrode strip for monitoring, the trial is focused on patients with TBIs that need to be operated on. It is standard practice to place these electrode strips to monitor for seizures, but they will now be additionally used to look for SDs.
The patients will then be monitored while they are in the intensive care unit for signs of SDs. The trial will test three different tiers of treatments.
Certain ranges of blood pressure, blood sugar and body temperature measurements are associated with a higher likelihood of having SDs, so the first tier of treatment will focus on managing those levels.
The second tier will continue managing the physiologic measurements into a slightly higher range in combination with a low dose of the drug ketamine, which has been shown to be able to stop SDs. Tier three will involve a higher dose of ketamine.
As a feasibility study, Dr Hartings said the first goal of the trial is to test the practicality of the process of monitoring for SDs and then responding with treatments in a real-world clinical setting.
Dr Hartings said. “The concept that we can treat these in real time hasn’t been proven yet, so that’s the first step of feasibility.”
The study’s second goal is to determine if the treatments have an effect to positively impact brain health and prevent SDs. The study also marks the first step of providing personalized treatments for every patient with a TBI.
Dr Hartings began to study SDs in animal models shortly after he earned his doctorate and said it is rewarding to see the progress that has been and continues to be made in moving research in this area forward.
“It’s really a great success story of bench to bedside medicine, and of collaboration between physicians and academics from different disciplines.
“Since the initial animal studies, we’ve formed an international coalition of researchers and clinicians who have advanced and developed the science, from neurosurgeons all the way to computer scientists. Now we are testing a clinical methodology to see how these advances could positively impact patients.”
