Scientists identify mechanism for brain dysfunction following seizures and drugs that prevent this impairment from occurring.
Six years ago, Cam Teskey, PhD, decided to follow a hunch. Armed with an advanced new tool designed to measure oxygen levels in tissues, he wanted to look at the brains of rats to see what was happening during seizures.
What he saw initially, was unremarkable. However, on a whim, he decided to keep the machine running after the seizure had finished and he knew then that he’d made an astonishing discovery. His work was recently published in the journal eLife.
As Teskey explains, “I was amazed to find that after the seizure ended, suddenly the level of oxygen in that area of the brain crashed and it stayed down – just above zero – for over an hour.”
This is a huge amount of time for the brain to be starved of oxygen and it was the first time anyone had observed this phenomenon occurring in the brain following a seizure.
Brain dysfunction following seizure is common, but not understood
Following a seizure, the sufferer will often experience a temporary period of disability. For example, if a seizure occurs in the motor cortex of the brain, the individual may experience weakness in one side of their body. Similarly, a seizure in the visual cortex of the brain, may result in visual disturbances. These effects can last for minutes, hours, or in some cases even days. It’s a phenomenon referred to as Todd’s Paralysis – and it is neither understood, nor treated.
As he looked at the results on the screen in front of him, Teskey was struck by an enormous realization – “I just figured out how seizures cause brain dysfunction, because the brain is now essentially having a stroke.”
Along with his PhD student, Jordan Farrell, they designed a series of experiments to look more closely at what was going on.
“Essentially what is happening is that the seizure itself starts a cascade of events that leads to a period of severely reduced blood flow and reduced oxygen in the brain,” explains Teskey. “And it appears to last for about an hour.”
Stroke-like events following seizures are caused by an enzyme that forces blood vessels to constrict
Once they had observed the phenomenon, Farrell and Teskey set to work understanding what was going on. They found that an enzyme – called COX2 – was the main culprit.
Large blood vessels, such as arteries, are coated in smooth muscles that control their diameter. Farrell and Teskey found that during a seizure, COX2 becomes extremely active and produces by-products that act on the arteries’ muscles to cause them to constrict, which decreases the amount of blood and oxygen that flows through the vessel.
When the researchers introduced a drug to block COX2 from activating, they were able to prevent the stroke-like event from happening altogether.
“This is extremely exciting, says Teskey. Not only have we found an explanation for Todd’s Paralysis, but we have effectively identified a way that it can be prevented.”
Translating research from the lab bench to the clinic
Equipped with his animal data, Teskey then reached out to clinician-scientist Dr. Paolo Federico, to see if they could translate this research to a human population.
Dr. Federico used an MRI scanner to look at blood flow in the brains of epilepsy patients in hospital, within one hour of experiencing a seizure.
He describes his findings as surprising. “In about 80 per cent of these patients, we saw significant reductions in blood flow following seizures,” says Federico. “This result was striking – and also very concerning.”
To Federico, this result not only explains Todd’s Paralysis, but he thinks it could also offer an explanation for why some people with epilepsy experience cognitive impairment following and even in between their seizures.
“It’s possible that this reduction in blood flow could have a cumulative effect on the brain that over time can result in cognitive impairments,” he says. He is quick to caution though that this discovery is in its infancy and that there is still much to learn, “What we need now is to conduct a clinical trial with a large number of patients who demonstrate this blood flow reduction.”
Clinical research is an essential next step
Although they are armed with convincing evidence from their human and animal data, what Teskey and Federico are looking for now is a dedicated clinical trial to see if a reliable drug can be used to prevent these stroke-like events from happening in human patients.
“We don’t yet fully understand the impact of alterations in blood flow,” says Teskey, who is clearly excited about what the future holds for his work. “This new knowledge is showing us that epilepsy isn’t just an electrical disorder, it’s a mashup of chemical, electrical and blood flow components. Our work highlights an important new avenue of research that has never been explored before.”
Epilepsy is the most expensive neurological disorder when calculated over the lifespan. It is most frequently diagnosed in childhood, adolescence and people over 65 years of age and although some people will grow out of it – others continue to experience seizures throughout their entire lifetime. For approximately 30 per cent of patients with the disorder, their seizures are not completely controlled using current medications. Life for these people is full of uncertainty – which is something that researchers like Teskey and Federico hope to change.
“The ultimate goal is to stop seizures from happening altogether, says Federico. “But if we could develop a drug that would improve recovery time following a seizure or reduce the long-term consequences on patients’ cognitive function, that would be extremely valuable.
There is a lot of potential good that could come out of this.”
Cam Teskey, PhD is a professor in the Department of Cell Biology and is the principle investigator in the Sembo Family Lab for Epilepsy Research at the Hotchkiss Brain Institute in the Cumming School of Medicine at the University of Calgary.
Dr. Paolo Federico is an associate professor in the departments of clinical neurosciences and radiology at the University of Calgary’s Cumming School of Medicine and member of the Hotchkiss Brain Institute.
Source of text and image: Hotchkiss Brain Institute
Original research article:
Farrell JS, Gaxiola-Valdez I, Wolff MD, David LS, Dika HI, Geeraert BL, Rachel Wang X, Singh S, Spanswick SC, Dunn JF, Antle MC, Federico P, Teskey GC. Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent. Elife. 2016 Nov 22;5. pii: e19352. doi: 10.7554/eLife.19352.