The future of treating head injuries

Doctors are trying to improve their interventions for brain injuries to better serve their patients, and a crucial aspect moving forward will surely be better drug treatments and diagnostic tools. Professor David Menon is head of the division of anaesthesia at the University of Cambridge, and the project lead of a £9.5 million pound research platform, funded by the Medical research council, which is adding vital knowledge to this pursuit...

David - I've been involved in traumatic brain injury research for the last 30 plus years. Over this period there have been multiple trials of pharmacological agents which have consumed probably a couple of billion dollars, thousands of patients, and pharmaceutical companies investment, which have all failed to show any benefit in terms of improving outcome. And the question is why that should happen? Because the preclinical models of disease suggest that these drugs should be working. And trying to investigate it we came to the conclusion that there were three or four problems that needed to be addressed. The first was when pharmaceutical companies and other investigators took the results from preclinical models (mice and rats) and took it to humans. The assumption was that whatever pathophysiology, whatever mechanisms were present in those experimental animals were going to be there in humans and, what's more, they were going have the same time course, the same importance. The second failure that they had was they made the assumption that because the drug got into the brain of these experimental animals, it would happen in humans as well. And finally, the endpoints that they were using were ones that were relevant to humans as well. And it became technically obvious that this was not the case. That this direct translational route was not going to work. And what we needed to do was to have an intermediate step of what's been called over the years now experimental medicine, where we study what's happening to the disease process in humans. So that was the first part of it. Trying to find drugs that did what they said on the tin that they interfered with the processes of traumatic brain injury in a way that we expected.

James - What is your new initiative, TBI reporter, bringing to the fold here?

David - Because brain injury is very variable, if you want to look at the effect of a drug, typically you have to study many hundreds, often a thousand patients because of the variation and the injury severity and variation in outcome. But if you want to just look at what happens to a molecule that's responsible for inflammation, you can do that in smaller numbers, typically tens of patients. But instead of doing it in one centre, TBI reporter allows us to do that in 6, 8, 9 and eventually a maximum of 16 centres. Again, doing small numbers of patients, but getting through the studies much more quickly than we would if we were just doing it in Cambridge, for example. And that's important because there are so many questions to answer. The second part of it is there's been, as I said, a lot of studies in traumatic brain injury, both observational, where patients didn't get any specific drug, but also the past interventional studies where drugs or other interventions were trialled. The data was collected, we got the information, the papers were published, and then the information was never looked at again. Now, across all of these studies internationally, we calculated that there were over a hundred thousand patients and bringing all of those together would provide the weight of numbers that would allow us to answer questions that were simply impossible to answer in any individual study.

James - So it was all sort of just sitting there, that information, waiting to just be assessed by neuroscience researchers like yourself and the network you've set up?

David - Correct. So for example by combining two studies, we got together 5,000 patients and understood the genetic contribution to the outcome from brain injury. And the bottom line is we found that about 25% of the variance in outcome is genetically driven. The card you've dealt with when you're born, the genetic cards that is, have a huge bearing on how well or badly you do after the same sort of injury, but varying across patients.

James - You mentioned biomarkers. I wonder if you could just paint the picture of the diagnostics scene in traumatic brain injury.

David - So we are familiar with biomarkers and the setting of heart disease or cancers. For heart disease, if you're coming in with a chest pain, people will do a blood test to look at a protein called troponin, which is released by injured heart muscles. And that's now so well established that it's a key diagnostic tenet to diagnose whether someone's had a heart attack or not. Now with traumatic brain injury, it's been very crude. So far we've classified traumatic brain injury as mild, moderate, or severe, which is ridiculous. If you went and asked a cancer patient whether they had mild, moderate, or severe cancer, you would get laughed out of court. What we need to do is to understand the precision diagnosis and apply precision medicine to these patients. Classically, we've used CAT scans to diagnose whether there is injury to the brain, but biomarkers are turning out to be very sensitive, perhaps even more sensitive than CAT scans. And the protein biomarkers we are talking about are proteins like GFAP or UCHL1. These are now approved for use to diagnose traumatic brain injury. The second is that it's important for prognosis. If you add in these protein biomarkers and look at their magnitude and the trajectory of appearance and resolution, they typically add between 10 and 15% to our precision of saying how well people are going to do. But the third and perhaps the most important in the context we've been talking about is to identify which treatments to attach to which patients. If we want to talk about what the body is doing in response to the injury, then understanding which inflammatory mediators and molecules are upregulated or increased in the blood and how these affect the ongoing process is very important. And using drugs that have been used, for example in Covid high dose of steroids or drugs that modify the inflammatory response would be very effective in patients perhaps who had a very excessive inflammatory response, but might only have detrimental effects in people who didn't have much inflammation to start with. And we are starting to employ that in clinical trials.