Rules of engagement: Nullifying neurotrauma

From mild concussions to a sustained loss of consciousness, how do we improve outcomes?
08 October 2024
Presented by James Tytko

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A X-ray image of figure clutching their head, with their brain glowing in red.

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Today, we're going in depth on traumatic brain injuries. James Tytko speaks with Dawn Astle, daughter of former England striker Jeff Astle, about the finding that his death was linked to head trauma sustained during his playing career. Also, Prof Peter Hutchinson gives an overview of head injuries, and Adel Helmy talks about changing the rules of some sports to reduce risk. Then, Alexis Joannides describes one of many new technological innovations to support medical staff dealing with TBIs, before Prof David Menon describes the path towards better drug treatments and diagnostic tools. If you like this programme, you can hear more podcasts from James dedicated to our brains and nervous systems by subscribing to Naked Neuroscience wherever you get your podcasts...

In this episode

A football stadium

Jeff Astle: How a career of heading footballs led to death
Dawn Astle

In the UK, 1 million people come to hospital with a head injury each year. Damage to the scalp or the skull is usually relatively easy to deal with, but the most pernicious problems arise for the people who have done damage to their brains. What’s particularly concerning is that what can seem like a relatively minor injury at first can cause some patients to deteriorate very quickly. Here’s Dawn Astle, daughter of West Brom and England footballer Jeff Astle, who died in 2002 aged 59 from accumulated brain trauma likely sustained during his playing career…

Dawn - When my dad was about 54, in 1997, we noticed that he was just acting a little bit strangely, and saying things that were odd. He couldn't remember my son's name when he was born. He asked whether his mum was still alive and my grandmother had died some 16, 18 years before. And we didn't really understand what was happening to him. My mum was really worried. Mum said to him 'please go and see the doctor, Jeff. I'm worried about you'. And he agreed. So mum literally rang the local medical unit up and they did some tests with him there. The doctor said to my mum, 'I'm sorry Lorraine, but I think Jeff's got early onset dementia.' Mum was just absolutely devastated as we all were. And so tests and scans followed and they basically said that dad's frontal brain cells were dying and there was nothing anybody could do. From that day on, really, the disease took more of a hold as the weeks and months passed. He was incredibly restless still. He became aggressive at times and he was never like that. He was on the sofa surrounded by everything that he'd won in football, you know, England caps, FA Cup winner's medal, League Cup winner's, medal. But he remembered none of it. And I always say that sort of looking back now, everything football gave him, football took away. The day he died, it was 19th of January, 2002. And I remember that day as if it were yesterday. And to be honest, that day continues to haunt me every single day. It was while we were eating this little birthday tea I'd put on, he started to cough and it was getting worse. And I remember my partner and my brother-in-law helped him to his feet, but then his legs gave away. We took him outside, just to get some air. But this coughing just seemed to get worse. And we were screaming at him, literally screaming for him to spit the food out. You could tell there was food there, but he wouldn't spit it out. We were trying to open his mouth to get this food out. We just couldn't do it. It was just horrendous. And then there was that realisation as, 'oh my God, is he breathing?' And I remember calling 999 and myself and my partner were giving him CPR and it was just the most horrendous thing. Sadly dad ended up choking to death. There was nothing any of us could have done to stop it. And believe me, God believe me, we tried.

James - I can only imagine how difficult, thank you so much for sharing that. You mentioned it was the game he loved and lived for that eventually ended up taking his life. Is that something that was at the forefront of you and your family's minds after the diagnosis and as his condition got worse?

Dawn - I don't know. I don't know whether it was at the forefront because, to be honest James, we didn't really talk about it very much. I guess in the background, there was always that 'I wonder if,' 'could it be' type of question that we all had. Dad didn't have many opinions on many things, probably apart from football, cricket, and horse racing, to be honest. But one thing that he really believed in and was quite passionate about was, believe it or not, organ donation. And mum, when asked about donating dad's brain after he passed away, she had no hesitation. I guess little did we know all those years ago how much his brain would reveal. And thank God we did.

James - What exactly was it that came to light after your dad had passed away and his brain was handed over to the doctors?

Dawn - Mum had already had a phone call from somebody from the coroner's court saying that there was going to be an inquest into Dad's death. And it was during the inquest when the pathologist, Dr. Robson, stood and described how badly damaged my Dad's brain was, and it was something we weren't ready for and something that was very hard to listen to. And he found that there was considerable evidence of trauma to his brain, and it looked like the brain of a boxer. But he said that the main candidate for this trauma, which apparently was right through the brain, right from front to back, left to right, was the heading of footballs. But it was the repeated heading. I think that was the key that appeared to be the problem. And then having listened to that, it was her Majesty's Coroner, then Andrew Hague, who actually said, 'Mr Astle's type of dementia is entirely consistent with heading footballs and his occupational exposure has made at least a significant contribution to the disease, which has caused his death.'

James - It was given his position on the pitch, perhaps, right at the business end where he was being asked to head the ball a lot, unknowingly putting himself at extra risk compared to some of his teammates.

Dawn - Oh, definitely. We know now, our footballers are five times more likely to die with Alzheimer's disease than you and I, and they're four times more likely to die with motor neuron disease than you and I and twice more likely to die with Parkinson's disease. But that data, which the Field study uncovered, also showed us that a former professional footballer's length of playing career and player position is tied to higher neurodegenerative disease risk. So the centre halves, five times more at risk. Again, centre forwards, nearly four times more at risk. So dad was a centre forward, and his professional career was I think about 17 years.

A X-ray image of figure clutching their head, with their brain glowing in red.

What is a traumatic brain injury?
Peter Hutchinson, University of Cambridge

The challenges that need to be overcome to improve outcomes for the many patients who suffer brain injuries were discussed at a recent meeting of the International NeuroTrauma Society here in Cambridge, which is looking to lead the global push for better TBI treatments. We’re going to hear now from Professor of Neurosurgery at the University of Cambridge Peter Hutchinson, who was there, and he gave me an overview of traumatic brain injuries…

Peter - These injuries can be divided into two parts. They can be what we call focal, so that's like a blood clot, which is either between the skull and the membranes or the membranes and the brain, and big blood clots need urgent neurosurgery and an operation to remove them. The second type is what we call diffuse injury, where the brain is swollen and bruised within the confines of the skull. Now if you bruise your knee or your elbow for example, that will swell. It will then go down. The problem when the brain swells is that it's swelling and it's confined by the tight skull. So the consequence of that is the pressure will go up inside the head, and if the pressure goes up, the amount of blood flowing into the brain will reduce delivery of really important nutrients for the brain, like glucose. And the gas, oxygen, that we need to survive on, delivery is reduced. So there is cell death and swelling, which compounds the problem. This vicious cycle of brain swelling in the tight skull, increased pressure, reduction in blood flow, reduction in oxygen, glucose, cell injury, further death and more swelling.

James - And it's a case of the bigger the impact to the head, the worse the injury?

Peter - Diffuse brain injury has a range of severity. The mildest is called mild traumatic brain injury, and the mildest variant of that is called concussion. So that is an injury that can occur with or without loss of consciousness. We don't fully understand what's happening to the brain, but this is usually a transient disturbance of brain function from a number of causes, to more severe diffuse injury through what we call mild/moderate, and the most severe is called diffuse axonal injury in pathological terms. And that's when there is quite severe injury to the structure of the brain, to the nerves and the supporting cells, that is associated with loss of consciousness, which can often be very prolonged and these can be very challenging to treat.

James - It's alarming what you said there about the concussions, on the more mild end of the spectrum, not necessarily having any symptoms, us not being able to detect when they've happened?

Peter - As you say, concussion may be so mild and transient that it may not even be picked up. You sometimes see that on the rugby field where somebody may or may not have a knock. They may be transiently dazed, but that can be quite a difficult diagnosis to make. Sometimes it is more obvious: there's a short period of loss of consciousness. Sometimes people have very few symptoms after a concussion. But classically, patients do have a number of symptoms. These can be what we call physical; so headaches, visual disturbance, dizziness, impairment, imbalance. They can be what we call psychological or cognitive; impairment of memory, impairment of concentration, thought processing and planning. And then quite challenging can be what we call the neuropsychiatric symptoms; changes in behaviour, the way we respond to others. And mood disturbance, particularly depression, can be quite a big problem for some of these patients.

James - What do we know about how neurodegenerative complications relate to traumatic brain injuries?

Peter - This is quite a difficult topic and something that we don't fully understand. There is a concern that particularly after multiple concussive injuries or even one severe traumatic brain injury, following the acute stage, that there is an impact on the brain in the longer term. So the risk of getting what we call neurodegenerative disease, probably the most cited is some form of dementia, but there are other complications such as seizures or even Parkinson's disease. And there's quite a lot of work going on now to try and relate that initial insult to these problems in life. The challenge is how do you do those studies? We can try and control people who've had brain injuries against the normal population and compare their brains, but in order to answer these questions accurately, we need to do what's called longitudinal studies where we need to follow patients who've had a brain injury for many, many decades, and those who haven't.

James - There are also genetic and lifestyle factors at play here. That's the difficulty with ensuring we're addressing the causation here rather than just a correlation?

Peter - Exactly. So just to break that down a little bit: the genetic makeup, our genes, do influence our outcome from brain injury. There is a sort of protein, lipoprotein E, and the type of this protein you have can influence how well you recover from injury. But in the longer term, I think some of the consequences, particularly professional people who play high level sport and then they suddenly stop playing it for whatever reason, maybe they've got another injury, has a profound effect on them because this is their wellbeing, this is their life. So whether that is a result of brain injuries or whether it's that dramatic change in lifestyle is something that we really need to try and get to the bottom of.

James - In that pursuit, do we have a good working hypothesis? People might be aware that dementia, Alzheimer's, it's because of this buildup of abnormal proteins in our brains. Do we have any guesses as to the mechanism through which traumatic brain injuries or even mild concussions lead to that?

Peter - So there's a number of studies trying to address the pathology and the pathophysiology of the link between the initial trauma and the dispositions in the brain later. But I don't think it's something that we do fully understand. And there probably is some population link between brain injury and these later problems. But of course, how do you relate that to each individual? And that's of course the challenge where you are trying to differentiate between population studies and what in effect is a case report for each individual patient.

photo of women playing football

14:36 - How can we reduce head injuries in sport?

The healthcare research at the forefront of treating sporting head injuries...

How can we reduce head injuries in sport?
Adel Helmy, University of Cambridge

Given we do see some association between sport and brain injuries, and with head knocks a common feature of many sports like football and rugby, attention has turned to how we can make them safer. Adel Helmy is an Associate Professor of Neurosurgery at the University of Cambridge…

Adam - So there's lots of important research going on about the burden of concussion in sports and thinking about how that might be reduced in a practical way. The issue with changing the rules or dynamics of sport is getting the balance right. We don't want to take away the competitive element or the essence of the sporting endeavour in itself. But at the same time, having recognised that there may be these risks in the very long term, we want to appropriately risk mitigate. And that's different for different sports. Probably the best example that people will have come across is the change in tackle height rules in rugby. We had a talk about that within the public session. And one of the things that came out within that talk is the enormous resistance in the first instance to a new approach such as this, but the fact that in the longer term it actually gains great traction because people have recognised that although it is a change to the way that the game is conducted, it may in the longer term accrue substantial benefit. Another example would be the change in heading rules, particularly for grassroots football. This was first taken up by the Scottish FA, but also the English Football Association from this year has introduced those new heading rules. And those will be filtered through at the different age groups, such that in three years time, no primary school children will be heading the ball. It does require a change to the sport. It does require engagement of parents, coaches and so on. But I think in the longer term, until we better understand the risks that are associated with these endeavours, it does make sense, particularly at grassroots, particularly for young people, that we try and minimise the risk of concussion in the longer term.

James - We heard about Jeff Astle's story earlier in the programme. I'm thinking of a BBC documentary where Alan Shearer, another prominent footballer, underwent an MRI scan to have a look at his brain. He must have headed the ball as much as anyone in his professional career. And the MRI scan showed a very healthy brain. We don't really know enough yet about who is affected, and that's why people show this initial aversion to the rules being changed, maybe?

Adam - I think in different contexts, there are different reasons. It's not a simple problem. And you're absolutely right: the absolute risk is not that large. There's definitely an increased risk, but many people may not be affected by these conditions. And the other risk factors, whether they be genetic or some other aspect, are critical. And because we don't understand these and we have to be upfront about that, it's very difficult for us to counsel people in a reliable or confident way.

James - We've been talking a lot about dangers associated with participating in contact sports, but the huge raft of health benefits that have been proven again and again in study after study associated with doing sport and levels of physical activity shouldn't go amiss in our conversation.

Adam - Clearly, as scientists and doctors working in this field, we're very interested in the pathophysiology, how repeated concussions may injure the brain and lead to this increased risk in the very long term of conditions such as dementia. But it's really important that this is put in context. So we recognise that sport is an important part of British national life, and that there are huge benefits that accrue from that to individuals in terms of team building, learning discipline, teaching our children how to win and lose in the right way. We shouldn't dismiss all of those things. And the difficulty that we have, particularly when we're talking to members of the public, is to balance those risks. What we don't know yet is how big a risk is it to an individual? And clearly a lot of the evidence has come from professional sports for very good reasons. Those are the people with the highest exposure to these things like concussions. But it's really important to recognise that for grassroots or amateur sport, both the dose (the number of concussions that you might be suffering) and also the magnitude (how bad those concussions are) are likely to be much reduced. And really we need to look at this in much greater detail before we can give you an idea of the relative balance of risks.

James - To bridge this gap between the crucial research that people like you are doing and the public understanding, what can we do? I'm referring, really, to the event not so long ago here in Cambridge.

Adam - We are very lucky to host one of the largest neurotrauma meetings that runs. It's something called the International Neurotrauma Symposium. It brings together both head and spine trauma, and it also brings together both basic scientists, those people who work within universities, perhaps in model systems looking at head injury, but also the doctors like ourselves who treat head injury in an active way. The conference covers absolutely every aspect of neurotrauma. That can be inflicted violence, it can be military trauma, it can be modelling biomechanics, it can be looking at blood biomarkers, it can be looking at scans and imaging, it can be looking at new trials. But we're very acutely aware that this research is not just for us, it's not an ivory tower within the university system. It's really important that this has direct applicability to people's lives. And given the recent advances and the public perception and the media coverage of sports concussion and dementia risk in particular, we chose a number of speakers from a range of sports: football, Rugby Union, Formula One and also the Paralympic movement. this is essential both to engage with the public and learn what the priorities are for them to allow us to draw in funding and engagement from different charities, but also to shape the sort of research that we do.

Rugby match

The tech looking to combat sporting brain injuries
Alexis Joannides, Addenbrooke's Hospital

Whatever changes to the rules of sports we make, we’re not going to eliminate head injuries from happening altogether. That’s why innovations from pitchside to ambulances to intensive care units are also needed to help avoid as many deaths and serious disabilities as possible. Alexis Joannides is co-director of the Health Tech Research Centre at Addenbrooke’s Hospital, which won £3 million pounds of funding earlier this year from the National Institute of Health and Care Research to support the development of medical devices, diagnostics and digital technologies. He told me how they were going to use the funds…

Alexis - If you try to make a difference, you have to take a structured approach. There are different parts of the patient pathway that you could tackle. There's preventing the injury in the first place, there's stabilising the patient on the scene and on their way into the emergency department, then there's protecting the brain from further injury in the hours and days after an injury and that happens usually in intensive care, and then there's a whole piece of work and effort around rehabilitation and making sure after an injury you recover back to normal life as far as possible.

James - A lot of different stages then, let's zoom in on one particular part of the timeline as you've outlined it for us, and how we are working to make an improvement there.

Alexis - If we look at acute monitoring, this is usually happening once the patient has come to the emergency department, they've been stabilised, then there is a very vulnerable period, a critical period, that the patient will usually be in critical care or the intensive care unit for severe head injuries. And there your focus is making sure the brain doesn't sustain any extra damage from what has already happened. So historically, neurosurgeons and intensive care physicians focus on brain pressure and making sure that doesn't go over a certain level that affects blood flow to the brain. But there are also other parameters, such as how much oxygen is getting into the brain from the blood, and also the metabolic status of the brain in terms of respiration and general metabolism. What we've been championing for a number of years now is a concept called multimodality monitoring, which is where you can have different readouts of the brain pressure, oxygen levels, chemistry, and metabolic demand. So how do you tackle that? Well, the most important thing is to know what are your readouts in terms of sustaining further injury.

James - Could you just take me through why it's that combination of factors that is critical for medical professionals to have at their disposal during that time.

Alexis - So if you have this combination of factors that enables you to tailor your treatments with the patient, be that giving salt solution to reduce the pressure, increasing the amount of oxygen delivered in the ventilator. So in order to customise what you give, you need to measure it. Now if you say, well, how do we do that? Well, again, there's a number of stages. First, you need a device that allows you to put a number of different probes or thin wire into the brain safely. And then you also need to be able to measure the data and analyse it to work out what best to do. So for example, we've just completed a phase two trial on having an algorithm for optimising the pressure that the brain should be at, with an individual patient. We're also working on a sensor that allows the chemistry, the metabolism to be measured in real time, because historically this would be done as a readout with a four hour time lag. So now we have more up to date information. And then really the ultimate outcome is looking at how the patient does down the line. And this is something that you would start doing at the critical phase before you start looking at what difference you've done down the line.

An outline of a human head, filled with connections like vessels or nerves.

The future of treating head injuries
David Menon, University of Cambridge

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.

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