Peter Fox, MD, Director of the Research Imaging Institute, professor of Neurology, Psychiatry, Radiology and Physiology at UT Health San Antonio talks about children with locked-in syndrome and the effort and research going into improving their treatment and finding the route of the issue.
Interview conducted by Ivanhoe Broadcast News in September 2017.
Can you delve a little bit into the history of how you formed this collaborative relationship with the foundation and with the mother of Conrad?
Dr. Fox: I’ve known Liz Tullis for about six years and she’s the mother of Conrad who has experienced drowning and survived resuscitation after drowning. And Liz came to me asking what might be done to help her son and to help other children who have the same disorder as her son. When she came, she came armed with a lot of information, she had already met with many other parents of children with similar conditions and with similar experience and with similar affliction. She’d set up a registry to allow people around the country to log in and provide their contact information to go on record as having a child who had survived drowning.
I can’t imagine anything more frustrating for a parent. When she came to you and she presented that she and other parents believed, what was your first, not the physician’s response, but the emotional response to that?
Dr. Fox: From the outset this sounded to me like what the parents were describing is some form, some variation of what’s called locked-in syndrome. This is a well-described syndrome that everyone understands is quite frightening and terrible, to be unable to communicate even though you’re conscious. There have been movies made about this, books written about it, it’s a horrible scary thing. The realization that there might be many people, particularly many children, in this situation and that as far as I knew and from what I was hearing from Liz and the other parents is that the medical community was not recognizing this or accepting that this might be the case. So my heart went out to them that this is something that needed attention and it called me to do it.
We were discussing how the families generally recognized this first, I’m assuming because they know the individual more so than the physician or the medical staff does? So they were seeing this themselves?
Dr. Fox: Yes, the literature in locked-in syndrome is quite clear that the families and the in-home care givers are typically the first to notice when the patient returns to consciousness. It’s common and this is true in these children as well, that the syndrome often starts with the person in a coma and then comes out into some twilight level of consciousness. The caregivers and the medical providers have seen the patient in an unaware state or in a very low level of consciousness and may not go on accessing day after day. Yet the families do, the families see the patient every day and so they are the ones that notice when there’s eye contact, when there’s a smile when someone tells a joke. Things like that are often what let the family know first that their child is back.
Is there any such thing as an average period of time between the downing and resuscitation happens and when they get out of the twilight zone into a more conscious state?
Dr. Fox: There’s a lot of variability but one of the things that distinguishes this syndrome say from other stroke syndromes is it’s clear immediately what happened. It’s not a mystery when you pull a limp child out of a pool, what happened, they drown. You know you need to give CPR and to call an ambulance. So the response time in this is typically very fast. Some of children I have seen have been in remote circumstances at national parks on family retreats, but generally the response time is fast. The ambulance crews are not at a loss, it’s no mystery and they hit the emergency room quickly. The speed of delivery is good. The time between drowning and resuscitation varies a fair amount. Some of the kids, we know that it’s just minutes, and other kids it might be twenty minutes. It’s in that range.
How did you get from point A to realizing that this was a possibility and then you isolate it to a region?
Dr. Fox: Actually what I did was I picked out the imaging techniques that I thought were most likely to show an effect. The syndrome, the clinical presentation, suggested that it was going to be isolated to the motor pathways. I still did whole brain analysis, I didn’t just image the motor pathways but it was a battery of techniques that would have the highest likelihood of showing these abnormalities. Then the other is that the analyses that I applied were done two different ways. One was by group where I put all the children together and analyzed them as if they were one case, which is what the clinical radiologists never do. This is a research technique that I applied and it worked in each of the three main protocols I did. The three main imaging protocols, in each case it showed that there was a very clear and focal difference between the patients and the age matched controls. So that confirmed that it was definitely a focal lesion. And this is something that on an individual basis you couldn’t have gotten out of any subjects data, it had to be a group.
How is that?
Dr. Fox: The findings actually are small and subtle and they don’t show well on standard clinical images. Based on what we’ve done, I believe I can develop a protocol which will show this very early on. But I have to prove that, I haven’t tested that yet because all of the patients we’ve done have been chronic, they’ve been six months or more after the injury.
When you’re doing this and they’re at risk are they asleep when you’re doing this?
Dr. Fox: They’re asleep. I’ve done a good number of studies in children before and with the focus of trying to develop diagnostic procedures for toddlers. For very early onset, autism, ADHD, stuttering, different conditions that occur, mental retardation syndrome is when you’re trying to make an early diagnosis but the child is too young really to cooperate or follow directions so what we’ve been doing is studying the kids at night asleep. Typically we give them a little bit of Benadryl but we bring them in at bedtime and give them the Benadryl and let them fall asleep. They’re in a mildly sedated sleep or drug-aided sleep. I mean Benadryl is pretty mild. So that’s what we do and that’s what we did in this group, they were all studied at night, in the first phase of sleep.
These are MRI images?
Dr. Fox: Yeah, this is all MRI.
So there’s that sound going on it?
Dr. Fox: Yes
But with the Benadryl they are sure to calm down a little bit?
Dr. Fox: What we learned actually fairly quickly and before we got to this study was that certain sequences are rhythmic enough and continuous enough that they don’t wake the kids up. And other things that are too dis-rhythmic do wake the kids up. So we got rid of the ones that would wake the kids up and we put in the ones that are more droning in sound and some that are kind of waxing and waning but slowly and it’s a big racket but it’s not startling. And so we typically got an hour of MRI in each child, just a continuous hour of data.
When you made this discovery and had your “ah ha” moment if you will what were you thinking? How did it impact you?
Dr. Fox: Well one was that we predicted right, that we made a guess, we bet on it we got a grant, we put in a lot of time and effort. We didn’t know exactly where the lesion would be but the bet from the start was that it would be a focal lesion because the syndrome appeared very restricted to the motor system. The analyses weren’t really biased toward that, they could have shown a lesion anywhere but the clinical syndrome really suggested that so that was very nice to see. But one thing to realize is that the analyses take a long time and so we did the simplest one first and published it and then moved on to the next one. And so more it was a series of “ah ha’s” like, well we made this prediction and we published that first but then we did a new analysis on some of the additional data and that showed the same thing but more clear. Then we moved on to the functional analyses which were really quite difficult and took a long time and those confirmed it. Each time it was just reaffirming the original prediction.
So a timeline of the project if you will, on when you got okay to go ahead and pursue this and where we are right now. And also the second part of that is exactly where are you at now in the process as far funding, and approval and testing?
Dr. Fox: We began the project in 2012 and it took us two years to do it. We hoped to do it in a year but that’s a lot of work to do in a year so it took us two years to get all of the data acquired. Some of the kids we had to bring back because ultimately we found their data had too much motion and so we brought them back. These are children that flew in from all over the country. We have kids from both coasts; one kid is from Paris, France. There was a lot of time getting all the data together and then analyzing it, writing it up and publishing it. The publishing took us about a year and a half to get all three of the papers published. Where we are now is getting ready to submit the grants for the next round of funding. I want to study more children with this disorder and get a more complete characterization of this disorder in children. The other approach that we want to do is to study a non-human primate model to see if we can develop a lesion like this in an animal model so that we can test new treatments in an animal before we try and implement them in the clinic. You can’t really try unproven treatments in real kids, that’s not going to happen, so we’re doing an animal project. And we would like to move as well on the acute imaging front of getting research quality scans on children that have downed and been resuscitated the day they get in the hospital. So we’re in negotiations to get approval to do that but still all of this will require additional funding.
You’ve got to have parents with just go ahead and do it, whatever you’ve got just go ahead and do it but you can’t do that of course, or can you?
Dr. Fox: No, for this they would have to be consent, everyone that participates in the study it’s informed consent from the parents. As an aside all the parents who participated in this study when they got the results of the study a hundred percent said they would come back to be studied again, they were very happy that they participated and so I know that we can scan on a two or three year follow up all the children that we’ve scanned already. But for the acute imaging that would be something of course that the parents would need to want to participate in. And so I’d say the next phase is developing imaging protocols that could be done in the hospitals shortly after admission. And then the other is developing and testing treatments that we would want to be implementing. So maybe we’ll be testing treatments four or five years from now.
These kids that you’ve discovered the locked-in syndrome described, we don’t want to give people the idea that they know everything that’s going on and they’re ready to respond but they can’t move their mouth, this is not quite that sophisticated of a level that they’re at? Or do you know that?
Dr. Fox: Some I think are exactly at that level and others I think are below that level. They’re aware of the people around them, they know the difference between different people, most of the kids that we studied listened to audio books, watched TV, and made it known whether they don’t want to listen to this book. Some are disappointed when somebody that they were expecting to come that day can’t come. The parent’s descriptions of what kinds of interactions they have are pretty clear and indicate a pretty high level of consciousness. I’d say that’s not in a hundred percent but that’s in the majority.
So this isn’t just an emotional reaction to people this is a thought-process thinking reaction?
Dr. Fox: Some of the children with this syndrome are classic locked in. They answer by eye blinks, they can spell things out by eye movement control on a computer. They can demonstrate to you quite clearly that they know what’s going on.
Had this not been scientifically or medically proven at all before this?
Dr. Fox: I can find no evidence of it. It’s been shown in adults with a stroke, not from drowning. But its surely been shown in adults that this type of syndrome can occur with a lesion in the motor pathway. No question what so ever. And the lesion that we found is about half an inch away from where it’s been described in adults to produce locked-in syndrome, and in the same pathway. Thereby it’s in the same wiring, it’s just slightly uphill. So the plausibility of all this is extremely high.
You said reachability wise it’s reachable?
Dr. Fox: Yes it’s very reachable.
If we get to it sooner in their kids and their cells regenerate faster than adults do, whose cells are dying off, are you going through all of that in this thought process?
Dr. Fox: Yeah. One reason I think we’re seeing this is that kids’ hearts and lungs and kidneys are healthy enough so that they can get effectively resuscitated right? So this may well be a level of drowning that an adult wouldn’t come back from, but if we can treat this acutely because it is so restricted in size that we may be able to prevent this. One thing I think that needs to be on the table as well is that 70 percent of the families that participated in this study indicated that in the acute setting when the child was first admitted to the hospital the recommendation that they were given by their neurologist was to withdraw care because their child would never recover in any meaningful way. That’s the expectation, based on literature that is a cogent recommendation. I think many children are not being supported, the care is being withdrawn. Depending on the parent’s wishes that’s fine but they should know that the child might recover not with global brain damage but with a restricted lesion. That this is in fact a very likely scenario is that the child would be paralyzed but conscious. So no parents have been told that. They don’t really know what the future would hold for their child and their choice to maintain care or withdraw care. Then the other issue is that if it is such a focal lesion could we develop a treatment for it? In adults with stroke, we rush them to the hospital to the stroke center and we give them tPA to the clot and if we do that within three hours the outcomes are significantly better than allowing the stroke to progress. So in this population it’s easy to get to these kids within three hours. Three hours is forever, these kids are often in the ER within half an hour, within in 45 minutes. So if there were an equivalent treatment, now tPA is not what we need here that’s to break up clots and this isn’t a clot but is there some neuroprotective agent that we could give at this site.
Would that then dissolve, that neuroprotective agent, would that protect it from further developing or dissolve it or prevent it, what would they do?
Dr. Fox: There are different agents; this is a very active area of research of neuroprotection both for stroke and for traumatic brain injury. The range of neuroprotective agents is broad and they have different mechanisms of action but they’re trying to do a number of things. For instance, clean up the area so that toxic material isn’t building up and causing more cell death. Supporting the neurons that are suffering and might die to provide the necessary nutrients for them to survive and make it past this insult. Or to decrease cytotoxicity in the area that can make cells die. There are different approaches but none of them have been tried because no one knew that this was a focal injury. If you tell me that the whole brain is stroked that’s a bad picture. But if you tell me that it’s a small area, that’s very different, and it’s a reachable area; it’s an area right near the major blood vessels entering the brain. That creates a different set of possibilities that haven’t been entertained before.
Chronologically if you would walk us through a child who is swimming and they drown; the parents call emergency services, can you walk us through the process of what happens to the kid medically and then where you think you might intervene in that process?
Dr. Fox: The majority of these drownings are swimming pools but not all. Some are in natural bodies of water but mostly it’s backyard swimming pools, it’s in areas with EMS services. Usually the child is with family and the family pulls them out and likely will start trying CPR while they call the EMS. Depending on how long they had been there, when you drown you stop breathing, when you stop delivering oxygen at some point your heart will stop right? So some of the children that have been coming in, have had no heartbeat. Your blood pressure will drop either way and so some have been resuscitated quickly enough so they still had a pulse but they weren’t breathing. Others had no pulse and EMS would cardiovert them, so shock them, get a pulse back, and ambulate them. They get them to the emergency room as quickly as possible where they are generally intubated. They have a tube put down the trachea to help them breath. Frequently the children begin seizing; they often go rapidly into a coma so they have epileptic seizures. The typical treatment protocol is to sedate them, to chill them to decrease metabolic demand of the brain so they’re made hypothermic. They’re given other support if they have pulmonary problems, from having inhaled water then they need that maintained. But generally they are sedated, chilled, and maintained and they’ll be a comatose state for two weeks, four weeks, a while. A typical hospital admission for this, for children like this would be six weeks, sometimes longer. At a certain point they wake up to a degree and start showing sleep wake cycles. That would be called vegetative state; showing sleep wake cycles but not really being aware of your environment. Often at that stage they’re discharged and so it’s after that they really start showing a return of consciousness, so after a period of months really. Where I’m talking about an intervention would be as they first come in to the hospital. Trying to minimize the stroke as early as possible, they likely would still go through that same course but would come out of it hopefully much faster and with a better ultimate outcome.
And out of all of what you just described, the resulted injury is this lesion, focal lesion, and that’s it, that’s where it is contained?
Dr. Fox: It’s in the basil ganglia for gray matter and it’s in the white matter fibers that connect the motor system to the spinal cord. All of the children I have seen are paralyzed in all four limbs and in the face. They can’t talk, can’t swallow. I’ve seen a few more since this study but typically they can’t eat and so they need a gastric tube. And the problem is that their muscles that coordinate swallowing don’t work. They can’t talk and they can’t eat but they typically have a reasonable eye movement control, some are jitterier than others. Some have perfect eye movement control to the point of being able to spell things out with their eyes with a letter board.
Can you describe let’s say a really high-functioning child, how they’re communicating and how much stimulus they’re receiving?
Dr. Fox: Yes. So the highest level I’ve seen one child with this who can talk some and can eat. He doesn’t talk well it’s nasal speech, it’s dis-coordinated but he can talk. Others that can’t talk can spell things out with eyes, with their eyes can indicate choices by blinking, by moving their eyes, by looking at things that they want. Many of them like to take food by mouth even though they can’t swallow it for the flavor. All of them respond to sounds, touch, sights, they clearly recognize faces. Most of them listen to audio books, they listen to TV, they have preferred shows that they watch. It’s quite clear the parents have on their website; many of these kids have websites, one patient they showed him watching the Ellen DeGeneres show before the lesion and after the lesion, the same response. The kid loved Ellen, likes the music, as soon as the sound track to the music to the show comes on the kid picks right up and starts laughing. Some of the parents, this is a story I’ve heard more than once, started to realize how much their child was understanding when they would be talking and telling jokes and the kid would laugh. One mother said she had her friends over and they were talking, it’s her group that meets in the morning after the kids are dropped off at school, and they were talking about one of the other neighbors and that she was getting into more trouble than she really bargained for and the kid starts laughing. He was twelve, and they’re like, this is only for women stuff, what is he laughing at. They realized that he absolutely knew quite in detail what they were talking about. And other parents said yeah, well he has the same sense of humor that all my other boys do, anything that’s body humor busts him up. It’s like so that’s quite clear to you.
There has to be a part of you that’s emotionally connected to this superior outcome if you will?
Dr. Fox: We need to do something better than we’re doing for these children. There’s a recent study that was done in adults with locked-in syndrome, the ones that could be communicated with and they actually asked them questions about their quality of life; did they regret that they had been supported. Should they have withdrawn support. Just quality of life and would you preferred to be saved and supported or not. And the overwhelming response it was really a very high percentage, like ninety percent plus, were initially very afraid, gradually became used to it. But you have to realize this is a situation where the people around them understand that they’re awake and are happy that they are alive and wouldn’t want things to change. To get better would be wonderful but are they accepting their circumstances, the answer is yes. I think we need to take that to heart and realize that these kids from what I’ve seen they mostly seem to be happy kids and that they’re interacting with their family and they are drawing social and emotional support and this needs to be taken seriously. They need to have a rich and stimulated environment. And that’s the first response to parents of children like this, is to be aware of this possibility and to give your child a life that he or she can enjoy as fully as possible.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Will Sansom
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here.
