Oxygen and epilepsy
About 1% of people are affected by epilepsy, in which a cluster of nerve cells in the brain spontaneously develop an abnormal pattern of firing. This spreads to adjacent brain areas, affecting their activity too, and the patient often becomes unconscious. Once the underlying abnormal nerve activity settles down, which can take a minute or two, the person begins to recover, but they’re often confused and drowsy for a long time afterwards, which can have profound effects on an individual’s quality of life. Cam Teskey, at the University of Calgary, explained to Chris Smith how, thanks to some careful observations in rats, he's worked out why this happens and highlighted a potential way to stop it…
Cam - People with epilepsy, after they’ve had a seizure, about 80% of them will experience what we call postictal or post seizure behavioural dysfunction. And it might be a sensory disturbance, it might be a cognitive disturbance or it might be a motor disturbance. In fact, a guy named Robert Bentley Todd described these motor disturbances over 150 years ago. But we never understood the brain mechanisms that are responsible. We reasoned that these postictal dysfunctions were very much like a transient ischemic attack, like a stroke. And so what we did is we took a very fine oxygen recording device and we put it into the brain of rats and we elicited seizures, and we just wanted to see if oxygen levels changed.
Chris - And do they?
Cam - They dramatically do. Interestingly, oxygen levels will drop somewhat during the seizure and then they will recover right back to baseline levels. But about a minute or two after, the oxygen levels drop dramatically, down below what we call the severe hypoxic threshold and this would go on for an hour before eventually coming back to baseline. And what we noticed is that there was a relationship between this hypoxic period and behavioural dysfunction in these rats. They were unable to form new memories and they were unable to show muscle strength if the seizures were in motor cortex.
Chris - Do you think or do you know whether the dip in oxygen tension is because there's a problem with supply or is it that that patch of the brain was so over exerted when the seizure was happening, there's an effective oxygen debt so the cells were just pulling the oxygen in like there's no tomorrow and this accounts for the locally recorded low level of oxygen?
Cam - Yeah. We learned two things. We learned that the blood vessels themselves that feed those local areas involved in the seizure, they constrict and they constrict to the point where you have less than 50% of the normal blood supply supplying those areas. It’s a reduction in blood supply that’s responsible for the low oxygen levels. But it’s not the seizure per se and what I mean by that is that we found two mechanisms that cause this vaso-constriction. And one of them is an enzyme called cyclooxygenase 2 or COX-2 for short. And what happens is COX-2 becomes very active during the seizure and what we did is we used a drug that blocks that enzyme. So when a seizure happens but you don’t get the vaso- constriction and you don’t get the low oxygen levels, then the animals did not show the behavioural disruption. So it’s not simply the seizure. What the seizure does is it starts a cascade of events mediated by COX-2 that result in this vaso-constriction, a reduction in blood flow and then a debt in oxygen. And it’s that that is responsible for these behavioural impairments.
Chris - Now aspirin is quite a good way to inhibit cyclooxygenase. So, do epilepsy sufferers who are on aspirin have a lower rate of postictal drowsiness?
Cam - That’s a terrific question, Chris, and we’ve been trying to scour the literature and some databases to answer that. I can't give you definitive answer right now. We have found other drugs that are far more effective. In fact, the most effective drug we have found in our animal models is ibuprofen and ibuprofen works on the COX-2 enzyme. And that is some work that we are hot after in the lab right now.
Chris - And have you looked in, in human patients to see if what is manifest in these experimental animals is there in people with genuine idiopathic human epilepsy?
Cam - Yes. I have a close friend and colleague by the name Paolo Federico. He’s a neurologist at the University of Calgary. We have something called a video EEG laboratory and people with epilepsy come in and they are weaned off of their anticonvulsant drugs or anti-seizure drugs. They will very often have spontaneous seizures. Now, the reason they're on this ward is to determine what areas of their brain are involved in the seizures as a run-up to potential brain surgery. But Paolo, using arterial spin labelling fMRI, looked one hour after seizures in 10 of these patients and 8 of them showed those areas of their brain that participated in the seizures had much reduced blood flow, analogous to what we were seeing in the rats.