Autoimmunity After Brain Injury

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Chronic neuroinflammation after a head injury has been linked to accelerated neurodegeneration and could contribute to the pathogenesis of chronic traumatic encephalopathy. Research suggests that this persistent neuroinflammation may result from a central nervous system-directed autoimmune response, but this phenomenon is not yet fully understood. In today's episode of Neuro Pathways, we're discussing current knowledge about autoimmunity following brain injuries and what ongoing investigations are hoping to discover. I'm your host, Glen Stevens, a neurologist/neuro-oncologist at Cleveland Clinic's Neurological Institute. I'm very pleased to be joined by Dr. Greg Hawryluk. Dr. Hawryluk is a neurosurgeon serving the level one trauma center at Cleveland Clinic Akron General and medical director and chair of the Scientific Advisory Board of the Brain Trauma Foundation. Greg, welcome back to Neuro Pathways.

Gregory Hawryluk, MD PhD:

It's a pleasure to be back with you.

Glen Stevens, DO, PhD:

So I know we discussed this when you're here last time, but maybe with a different audience. Just again, tell us a little bit about your background and how you made your way here.

Gregory Hawryluk, MD PhD:

Most certainly. So I am educated well beyond my level of intelligence. After med school up in Edmonton, I did neurosurgery training in Toronto, did clinical subspecialty in neurotrauma complex spine in San Francisco, and stopped along the way to do a basic science PhD. So that sent me back another five years. So I ultimately got asked to come join the crew in Akron General back this past summer. So it's hard to believe I've already been here for almost a year.

Glen Stevens, DO, PhD:

So last time you joined us for our episode on neurotrauma-related treatment guidelines, you talked about the science of TBI and how it could potentially be built on a faulty foundation and that this may be impending progress as we're trying to move forward. So when we last spoke, you mentioned, autoimmunity is contributing to this faulty foundation. Can you give us a quick refresher on your thoughts on this topic and area?

Gregory Hawryluk, MD PhD:

Yeah, so this is, to me, something I just love to think about, and what I would say, us neurosurgeons, we're usually pretty conservative people, and we're not generally good at creative thought, and I don't think people want a creative neurosurgeon. You want someone that follows the textbook pretty closely. So what I would say is that there's some things that I think stick with us as we train, and some things as we're learning our craft. What I would say is that it's a golden opportunity before you are endowed with the biases and the common thoughts and customs of your specialty as you're first acquiring information. It really gives you a chance to question things, and it is really just a part of acquiring that knowledge. I still remember being back in medical school, and we talked a lot about sympathetic opthalmia. So this idea that the eye, which, of course, is a central nervous system structure, that if an eye is ruptured, that can be a very serious thing because not only it can be a problem, of course, for that eye, but it can be a problem for the intact eye.

So it was said that you could form an autoimmune response that would attack not only that injured eye but also the good eye. You could end up totally blind. So the idea was that you would consider potentially removing that ruptured globe to prevent a sensitization from happening that might attack that good eye. I remember being in medical school, asking our ophthalmologist, "Okay. If it's a central nervous system structure, we know that the brain and the spinal cord are immunoprivileged. Of course, the other thing in the body that's immunoprivileged, that is the testicle. The question is, 'If you have a head injury or a spinal cord injury, wouldn't you potentially get an autoimmune response to that?'" Of course, the problem is that we can't remove the brain or the spinal cord the way you would an injured eye. But I remember the ophthalmology professor looking a bit blankly at me and saying, "You know what? That's a really good question, and I don't know the answer to that."

It's one of those things where if you were to suggest to the average neurosurgeon, "Don't you think that if the brain is immunoprivileged and we spill brain antigens into the blood, we now know that happens, don't you think that the body could start to attack the brain?" And so if we start to think about this possibility, it actually could explain all sorts of different observations that are described out there. So we know that there's way too much inflammation in the brain. It's been clocked at at least 17 years after a head injury. We know, for instance, that in preclinical models, that if there's an isolated injury to the spinal cord, we can see way too much inflammation in the brain that's not explained by just a spinal cord injury. It could potentially go so far as to explain what's been reported to be the transmissibility of Alzheimer's disease in patients that are getting human growth hormone extracts to treat hypopituitarism.

So there's a long list of different circumstantial pieces of evidence that I'd love to talk about. I think neurologists tend to be a little bit more attuned to autoimmunity to the nervous system, but I certainly think it's something neurosurgeons don't think enough about.

Glen Stevens, DO, PhD:

I think last time you were here, we talked about the concern that Alzheimer's was related to head trauma. So pack the bags and go home. We're done. I guess that's the problem. We look at it too simplistically and we don't really look at the bigger picture. Why do we need to do any further research? It's done. That's what the cause is. I guess that's your concern, that it's never that simple.

Gregory Hawryluk, MD PhD:

No, and that's a big part of it. Some of the stuff as I was doing the fundamental learning about some of these things, you look at it and you say, "I'm sure someone checked on that. I'm sure they made sure that dementia that can happen after a head injury is really Alzheimer's disease." And as you peel back the layers, you realize, "No one actually did that." So I think Alzheimer's disease has really been an inappropriate label for cognitive decline after neurotrauma. The reality is that we're now recognizing things like CTE, and in the past we recognized things like dementia pugilistica, and the reality is that the neuropathology of these conditions is very different there. There's commonalities. There's tau and amyloid deposition, but that the pattern of tau deposition, for instance, in CT is quite a bit different from Alzheimer's disease. I think what's happened is that calling things Alzheimer's disease, it's been a bit of a false label. It's implied a false understanding.

When the textbook says, "Oh, they've got Alzheimer's disease." You don't question that. It sounds like it's known. We all know what Alzheimer's disease is, and it keeps you from questioning it and actually investigating what's really going on. So I think that's been certainly an important setback in the field, amongst others that we talked about last time.

Glen Stevens, DO, PhD:

So this is a very unfair question, but how much trauma is too much trauma?

Gregory Hawryluk, MD PhD:

That is a really good question. This gets very complicated very quickly. What I would say is that in the preclinical models, there's an additive effect. You start to see some effects with one injury, and you see more effect with more injury. One of my collaborators, Dr. Kevin Wang, has been one of the leaders in CNS autoimmunity. After a head injury, what he's found is that you really start to see a lot more autoimmunity if you have an injury severe enough to make you lose consciousness. But what's really interesting is, in the preclinical studies that I've done, there is always some degree of CNS autoimmunity there. So you can see neurons and oligodendrocytes staining with autoantibodies, albeit at a low level, but in subjects that have never actually had a trauma. That raises, to me, the question, "Is the first trauma really the first time that the body might actually be seeing those immunoprivileged organs?"

So I think a lot of us in medicine would think that probably, if you hit your head even gently, perhaps there's some microtrauma, maybe minimal disruption of blood-brain barriers. It's quite possible that in any human being, for instance, during development or as we're getting older, maybe there's some very small amount of autoimmunity that's always there.

Glen Stevens, DO, PhD:

In brain tumors, head injury has been posited for many years as a cause of brain tumor. But, of course, when you talk with patients, everybody will give you their head trauma story. And it could be multiple, "I did this, I did that." Trying to separate that out is, as you could imagine, just about impossible. Tell us about autopsy studies on people that have had head injury.

Gregory Hawryluk, MD PhD:

What was a real surprise, everyone knew that after a head injury, there's inflammation, and it sticks around for a while. But I don't think that anyone ever thought it would stick around for 20 years. So the real classic study here, it's Genta Adel, back in 2012, first described this, and that raised some real questions 20 years out. Why is there too much inflammation? What is going on? And I've thought that could have two explanations. One is that there's just something about the head injury, something self-perpetuating. The other possibility is that that specific thing is an autoimmune response. I think when we start to think about the fact that the brain and spinal order are immunoprivileged, maybe that's going on, it would certainly explain an awful lot of things.

Glen Stevens, DO, PhD:

So even for a neurosurgeon, an autopsy is a bit extreme. In a live person, how are we determining this neuroinflammation?

Gregory Hawryluk, MD PhD:

I think we really struggle to do that. I would argue that maybe we aren't doing that well at all. Maybe one of the reasons that if this really is a problem, one of the reasons we aren't detecting it is, it might almost be like a post-polio syndrome. So a lot of these patients will already have some level of debility. They'll be spastic in a lot of cases. A slight decline in their function. Is that normal aging? Is it just their spasticity getting worse? Hard to tell. But I would tell you that I have a good friend with an incomplete cervical cord injury, and she tells me that she is slowly losing respiratory function over time. She's wondered. She's a very bright person, very highly educated. She's wondered to herself, "Is this like a post-polio syndrome?"

I talked to her about this autoimmune idea, and she says, "You know Greg, that's really interesting. That could also potentially explain what's going on." I don't think that we have a lot of good tests of this, and really, in preclinical models, we can look directly at the brain and the spinal cord, but we can't do that in people. So very tricky.

Glen Stevens, DO, PhD:

Yeah, that's where I was going next. So if you have trauma to the brain, do you measure the neuroinflammation in the spinal cord? And if you have a spinal cord injury, do you measure it in the brain at an autopsy?

Gregory Hawryluk, MD PhD:

I think maybe we should start. I don't think that we're doing that routinely. I think this would also be news to pathologists that I think that the one pathologist out there who really has been very inquisitive is a gentleman by the name of Dan Perl who's down in Pennsylvania, and he's really asked that question, "What's going on here? Is this really Alzheimer's disease we're seeing?" I think it's something we need to start looking at. I think PET scanning is getting much, much better, and in ulcers, new ligands. I think in the future we may be able to do antemortem studies where we can actually quantitate the number of inflammatory cells in the brain and things like that. But I think at the moment, I would argue that potentially, we've had our blinders on so much about this phenomenon that we really haven't been looking for it.

I recognize that as a neurosurgeon, if we were to consider the idea of immunosuppression, if you said, "Okay, well you hit your head and that inflammation is a problem, we want immunosuppression." I'd say, "That sounds really crazy." These people are at high risk for infection. In a lot of ways, it might be a radical idea, and I'm certainly not a rapid adopter. I think this really needs to be thoroughly looked at, but I do think it needs to be looked at. I think there's just too much evidence that maybe there is something going on that's been overlooked, that I think we need to look under that stone now.

Glen Stevens, DO, PhD:

So neurosurgeons, neurologists, do they look at CNS autoimmunity the same, or do they look at it differently?

Gregory Hawryluk, MD PhD:

You might even be so bold as to say that I think neurologists look at it, but I don't know that neurosurgeons do. What's so interesting to me is, for instance, as I've written grants and I say, "I'm really interested in autoimmunity after head injury." I don't think it was looked at that. Usually there's at least one neurologist that reviews the grant, and they say, "This is boring. We know this happens. We know that after a stroke, autoimmunity is well described." In fact, there's a view that, for instance, if you had not just a stroke but a bladder infection, that infection might act like an adjuvant does when you're getting a vaccine, ramping up that immune response. That's the tricky thing. I think neurologists, I respect you guys, you are very thoughtful about autoimmunity and recognize it in many places that people like us neurosurgeons don't. I've done that. I've talked to some very senior, respected neurosurgeons and neurotrauma specialists and said, "Hey, what about this autoimmunity stuff?" And you often get a lot of blank looks.

Glen Stevens, DO, PhD:

Can you talk a little bit about the evidence that's out there supporting the autoimmunity?

Gregory Hawryluk, MD PhD:

I think it's all circumstantial. Let me, I guess, give you a couple more lines of that circumstantial evidence. So one of my favorite stories paints a picture that, really, brain antigens might be harmful for you as important as they are. This was a fascinating story. There was an abattoir in Minnesota, and they had just instituted a new practice in their slaughterhouse. So apparently, there is a market somewhere in the world for pig brains. What they would do at the time that they sacrificed the animals is blow compressed air up the frame and magnum, and that would take the brain inside the cranium and essentially liquefy it. It was a new practice. But then, shortly after they instituted this, people started to get sick in the plant. In fact, it was such a striking event that the CDC flew in, just like we've all learned in medical school about Legionella, Legionnaires' disease. The CDC flew in and started to look at the transmissibility, all the different factors, what was going on here.

What was fascinating is that for these individuals that got sick, the closer you were to that station, the more sick you got, and there was almost like a gradient in terms of distance within that plant. They really did find evidence that this was an autoimmune problem. So the people got better with steroid treatment. Even more remarkable, there were some investigations done looking for specific antigens that might have triggered this. They actually found a specific potassium channel protein that seemed to be the instigator of this problem. So I think that was really important in demonstrating that there really could be a problem with autoimmunity to the brain. Gosh, shouldn't we maybe be thinking about this after a head injury? Now, one of the other bits of evidence, it's now very well established that brain proteins enter the bloodstream after a head injury. In fact, it's now approved as a point-of-care test.

The FDA approved that on Valentine's Day a couple of years ago. So it proves beyond a shadow of a doubt that you spill brain proteins into your blood, those immunoprivileged antigens. Moreover, the worse your head injury, the more you spill. So very interesting. It's possible that this autoimmunity may tie a lot of things together. Another really fascinating potential example of this is this issue of the transmissibility of Alzheimer's disease. So it used to be that if you had pituitary dysfunction and you needed growth hormone supplementation, now we have recombinant technologies and we can make these proteins in a lab, but it used to be that you had to take cadaveric sources, and undoubtedly there was some brain contamination in those specimens. There was a very high-profile paper a number of years ago that raised that possibility that some of these patients that were receiving human growth hormone supplements, it seemed like they were all of a sudden getting Alzheimer's disease.

I want to be clear, that's possible. It's absolutely possible that there's something transmissible about Alzheimer's disease, but an alternate explanation could potentially be that it's simply an autoimmune response that's damaging the brain, leading to cognitive decline. So it's a fascinating world of circumstantial evidence of false labels, Alzheimer's being slapped on things maybe where it shouldn't. I often find, if you peel back the layers on these things and you start to consider that possibility that an autoimmune attack to the brain after some form of brain injury could be problematic, it potentially could explain an awful lot of stuff.

Glen Stevens, DO, PhD:

So I'm not suggesting that anybody with head trauma would then be donating blood, but I wonder if there's any data out there with patients that have had recent head trauma then donate blood, any risk or concern? What do you think?

Gregory Hawryluk, MD PhD:

That is very interesting. Beyond a shadow of a doubt, we know that there's brain proteins there that the levels fall off pretty quickly, some very rapidly within hours. I think as long as you waited a week, it's probably okay. But it raises very interesting questions. Maybe the same thing could happen with a blood transfusion, as seems to be happening with this growth hormone purification.

Glen Stevens, DO, PhD:

Before we get to potential treatments in some of your specific research, I'm just curious, you work at a Level 1 trauma center. What's your take on contact sports?

Gregory Hawryluk, MD PhD:

It's a great question. I think that the first point is that simply having people think about this issue is really healthy. Frankly, I think it's reinvigorated a discussion around the importance of sports. I think the resounding answer from the medical profession has been that sports are good for you. Obesity is a big problem. We think, on the whole, contact sports and sports of any kind, are a good thing. The principle, though, that's really important is respect for one's own body and respect for your opponent's body. Yes, in hockey and football, contact and collision's going to happen. But I think people are abiding by that principle of respect that the health benefits, we think, far outweigh the risks.

I would go further to say that although there's no question that there's something happening with these recurrent brain injuries, that the formal diagnosis of CTE remains controversial. So I would certainly say that my laboratory's efforts to try and understand this autoimmunity really have the primary goal of trying to better understand this dementia that can happen. But I think that what fell out of the news fairly quickly is that as scientists really did start to explore CTE, a lot of the constructs in terms of grading and some of those things, it'd be too strong to say they fell apart, but they haven't been robust. So I think, for the moment, get out there and compete.

Glen Stevens, DO, PhD:

So do you think the bigger issue is a couple of big traumas, or is it microtraumas? Personally, I would be more concerned about repetitive microtrauma.

Gregory Hawryluk, MD PhD:

Yeah, no, and there's published research that has found that, in fact, you don't even need to meet the threshold for a concussion diagnosis. These microtrauma probably are important and probably do accumulate. So it's really been a shame that there's been a noteworthy decline in football participation, for instance. I'm really saddened by that because I would say that obesity is a very big problem, and I think that there's a way to do these sports safely. I have a lot of colleagues that are very involved with the NFL, and I really admire and respect all of the things that they put in place. I think we're now very attentive to the issue of head injury. I think the single biggest thing, and this is maybe a really good point for your listeners, I think one of the biggest things with sporting is the recognition of not returning to play after an injury.

So the real index case here was a gentleman by the name of Lystedt. So he was concussed, went back to the game, was injured a second time, and almost died. There's this florid cerebral edema that seems to happen in rapid repeat injury. I would say that I've considered the possibility, could that be an analogy, like an autoimmune response to at least that edema? So that's something I've thought about. But the bottom line is that I think one of the very best things that's happened with head injury over the last 10 years in sport is this recognition. In fact, laws passed, I think, in 48 states. The last I heard, that these players, by law, can't go back to playing the same game. They have to be assessed by a physician before they can do that. So I think we're making progress in making sporting safer and get out there and be fit.

Glen Stevens, DO, PhD:

So it's amazing, a couple of old hockey players like us could even have this discussion.

Gregory Hawryluk, MD PhD:

That's exactly right. Fortunately, I have all my teeth.

Glen Stevens, DO, PhD:

Yeah. Can you tell us about calcineurin inhibitors?

Gregory Hawryluk, MD PhD:

Yeah, so this is an interesting story. So there were days where I said, "Is this a tree that is worth barking up?" Because a lot of head injury patients, they've got barnyard injuries, they've got open limb fractures, and what's the point in figuring out that you've got an autoimmune problem? Because we probably couldn't immunosuppress these people. What's the point? What's really interesting is, one of my mentors, a very respectable gentleman by the name of Ross Bullock, used to practice in Richmond, Virginia. When I visited him there, he actually wanted to do a trial of cyclosporine for a head injury. There you go. So he's doing it, and he's published a small series. What he actually found was that giving cyclosporine to a head-injured patient, at least in his study, didn't increase the rate of infectious complications. So at least it seemed to be safe.

What's interesting is, I always say that I think the Achilles heel of neurotrauma is the mitochondria because we can fix the oxygen, we can fix the blood pressure, but at the end of the day, what the basic scientists have taught us is that the mitochondria become dysfunctional, and then it doesn't matter if you get them enough blood pressure, oxygen because they're not using the energy that you're giving them. So one of the reasons that mitochondria become dysfunctional is, they develop something called the mitochondrial transition megapore. What's really interesting is that cyclosporine inhibits that from happening. So that was the main reason that Dr. Bullock wanted to investigate that drug. But the byproduct of that is that it's paved the way to potentially try the drug again or potentially more targeted agents, which incidentally have had effect in sympathetic ophthalmia, TNF-Alpha antagonists. Maybe there's now a pathway that's been cleared to start trying these agents and head injury.

Glen Stevens, DO, PhD:

Interesting. So you've been doing some interesting research, so give us a little bullet points on your research and what you're looking at, what you're finding.

Gregory Hawryluk, MD PhD:

Yeah, absolutely. So what I would say is that I've had a two-pronged approach. I've been looking at some preclinical models, and in an inoculation model where subjects are getting spinal cord antigens under the skin, we're inducing brain inflammation, and it's having functional deficit problems with more water maze function, which is a good test of memory. So we really have been able to make the case that potentially peripheral exposure to CNS antigens is a problem. But I've also been trying to look at human patients, and I think we did a very interesting study. Of course, the problem in humans, again, we can't take out the brains and look at them until they're done with them. So we've been stuck analyzing autoimmune antigens to brain antigens in the bloodstream.

What we did is we did a study looking at some normal controls. We looked at head injury patients, spinal cord injury patients, and brain surgery patients, people that had big, big tumors in their brains. What we found is that there absolutely is a spike in autoimmune antibody titers to brain antigens, which tends to happen at about two weeks. That's really interesting because that marks the end of that critical window that is described for sympathetic opthalmia. So that fits. What we found is that the titers go up and stay up in head injury patients. That's not what we found in spinal cord injury patients. So in spinal cord injury patients, the worse your spinal cord injury was, the lower your titers were. We think that the reason for that may be because spinal cord injury by itself is actually an immunosuppressant. What was interesting in the tumor patients is that whenever we looked, they had a slightly higher titer, but after the surgery, it didn't go up, didn't go down.

I don't know. That could be because our brain surgeons were so good and precise that we're not spilling brain antigens. It could be because these patients are all on steroids to reduce brain edema. So that was really valuable. I think if we are going to consider exposing patients to the risk of immunosuppression, we want to pick which patients are most at risk for this problem. I think, based on my study, head injury is the way to go. I think that those are the patients that we need to be looking for this phenomenon in.

Glen Stevens, DO, PhD:

It'd be interesting if the brain tumor patients had lymphopenia-

Gregory Hawryluk, MD PhD:

Absolutely.

Glen Stevens, DO, PhD:

... initially, and maybe they just couldn't mount a response. So any final takeaways?

Gregory Hawryluk, MD PhD:

Yeah, I think you know what I would say to any of your listeners out there that might be junior docs or perhaps neurosurgeons in training, the thing that I really feel strongly about is that I really do think there's a lot of preconceived notions in head injury and then, frankly, within neurosurgery. I think we really need a new generation of people that's not scared to say the emperor has no clothes, to really question everything, and to really say, "Is that really true? What's the evidence behind that?" I think the brain is a hard thing to study. It's perhaps our most important organ. That presents a lot of challenges to study. But I think that a lot of the people that gravitate to neurosurgery and neurology, I think there's a lot of smart people. I think if we could get neurosurgeons thinking a bit more creatively, we may learn some things.

Glen Stevens, DO, PhD:

Greg, thanks for joining me again in this very insightful conversation. It's always great to talk to you, and we appreciate the fine work that you're doing.

Gregory Hawryluk, MD PhD:

Thank you, sir.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.