Dr. Stacey Clardy, autoimmune neurologist at the University of Utah, talks about a rare disease called “brain on fire” disease.
Interview conducted by Ivanhoe Broadcast News in 2023.
There’s a disease known as the Brain on Fire because of the book. Could you tell me what that disease is?
CLARDY: Yes. Anti-NMDA receptor encephalitis, which is a bit of a mouthful, is the actual disease that the book Brain on Fire was written about. Brain on Fire, of course, was written by Susannah Cahalan who had anti-NMDA receptor encephalitis. She happened to be a journalist, and so was able to then really bring awareness to the condition by writing the book. The disease itself is an immune system attack on the brain. What happens is, you’re perfectly normal one day. It’s usually young people. Think of a sister or a niece or a girlfriend, and suddenly overnight, this person can become paranoid, start having visual hallucinations, auditory hallucinations, strange behaviors that can eventually progress into weird movements, or seizures in some cases. It’s a very challenging diagnosis to make for that reason because often at the onset, it’s primarily what we think of a psychiatric symptoms. Patients will go to see a psychiatrist or be admitted to an inpatient psychiatric unit because it’s sudden onset and it’s severe. Then they often develop neurologic symptoms later, a seizure or sudden drops in blood pressure or abnormal movements. That gets them attention, hopefully of a neurologist, who can then put all these symptoms together and think to test for anti-NMDA receptor encephalitis. The test for that is done on spinal fluid. It requires what we call lumbar puncture or a spinal tap. We look for the specific antibodies in the spinal fluid. If they’re present, then you have the diagnosis of anti-NMDA receptor encephalitis.
Could it be months, even years to get the right diagnosis?
CLARDY: It could be a long time to get the right diagnosis. In most cases, you go from 0 to 60 quite quickly though. For most patients, they’re really normal one day, the symptoms come on fairly quickly and they require hospitalization often within a few weeks.
When you say, young people, are you talking 10 year olds or 20 year olds?
CLARDY: It can affect really almost any age throughout the lifespan. But the most common population affected are children and young adults.
Is there any symptom that is the telltale sign that you have this?
CLARDY: There are a few symptoms that clue us into the facts that this should be considered as a diagnosis. But there isn’t a slam dunk. That’s why some patients go weeks or sometimes even months without the diagnosis. But a few of the symptoms that really clue me in to think of it sometimes are previously a normal person who has had no mental health conditions, who really has acute, severe hallucinations. Often when we think about primary psychiatric disease, or patients will have a history of some mental health conditions, or it will be running significantly in the family. Often these patients have never had a hallucination or a mental health concern whatsoever. It really has a thunderous onset. Beyond that from a neurological point of view, many of these patients, but not all, develop a characteristic orofacial movement where their mouth and lips are continuously moving. It may start initially very subtly, only for some parts of the day, and it can then progress on to be almost continuous. Also, some of them have posturing, we call it dystonic posturing, where maybe a limb moves beyond their control and locks. It could be an arm, it could be a leg. That’s a clue, but that’s not specific only to this condition.
Is there any thought on what causes it? What causes your immune system to attack your brain?
CLARDY: We are developing a much better understanding of what causes this to happen in most patients. For many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma. Now, this is not a particularly rare growth on the ovary, many women have them. Most of the time, these cysts can just be monitored. However, in the cyst, there is a component of tissue that really is brain tissue, it looks just like brain tissue. If the immune system can see inside that cyst for some reason, if it gains access to the inside of that cyst, it will then do what it’s supposed to do and it’ll begin to attack, because it knows that that tissue shouldn’t be there. Unfortunately, when it attacks there, it’s simultaneously attacking the same brain tissue that is actually in your brain, that should be there. That’s the cause in probably about half of patients, especially women, after puberty. For the other patients, we’re not certain. Often for children, we speculate that there may be a post viral component, maybe their immune system saw a virus, effectively fought it off and again made a similar mistake. But we’re less certain how that might happen compared to say, the ovarian teratomas.
What’s the traditional line of treatment?
CLARDY: We have several traditional lines of treatment and this is the essence of the problem. The condition’s been well-known and well-described for over 15 years now by Professor Josep Dalmau who discovered it and then did subsequently a lot of the work to understand the pathophysiology and what’s going on with the immune system. What we don’t have is a single approved treatment for this condition. For the last two decades, we’ve been just trying things that we think might work. We’ve borrowed medications from other fields of medicine where they modulate the immune system or suppress parts of the immune system. We keep doing that. We’ve thought maybe it’s working and we think maybe we’re doing the right thing. But the bottom line is, we’ve never had a single high-quality study to show if we are doing the right thing.
Now you have the study with the drug, so it’s being used for something else, isn’t it?
CLARDY: Yes. So the Extingish Trial is studying many things, but one of the things it’s studying is a specific treatment to see if it helps anti-NMDA receptor encephalitis patients. The drug name is inebilizumab, which is a bit of a mouthful. It’s approved for another condition that neurologists treat called neuromyelitis optica spectrum disease. What the drug does is, it suppress a specific part of the immune system, the part of the immune system that produces antibodies, antibodies that are both good and bad. It is a way to make sure that those anti-NMDA receptor antibodies are produced far less. But it also suppresses other portions of the immune system as well.
It sounds like you might be giving up one for something else. Are you though? If you have less antibodies, could that be dangerous especially in the time of pandemic?
CLARDY: Anytime we suppress the immune system, we think it’s a risk and we’re concerned, and that’s why this study is so important. Currently there is no approved treatment, and what often happens is these patients are subjected to multiple immunosuppressives at a time. We so much want to do something when we see patients this sick. The practice historically has been to try one immune suppressant, then another one and another one. We don’t necessarily know if any of them are working or what the timing is. You can imagine that could be a very dangerous situation because instead of targeting one piece of the immune system and waiting to see if that’s having an effect, the tendency has been to layer on multiple immunosuppressants. Yes, the risk of that can be significant infection or worse.
Have you seen patients go from zero to 60 and then basically, are you able to stop this progression? Are you able to reverse some of the problems? Are you able to stop the symptoms?
CLARDY: I’ve seen and been able to treat a large number of these patients over the past decade or more. The whole reason for this trial is, I am tired of walking into the room after I’ve made the diagnosis and not knowing what to tell the families the best treatment. They ask, how we are going to approach this, is their loved one going to get better, if they’re going to get better, how soon will they get better, will it get worse first, and why did this even happen in the first place? I don’t have answers to those questions and that’s why we’re doing this trial. We do think suppressing the immune system helps here, and we do it by various different mechanisms, again, that we’ve borrowed from other conditions, but we need to know if we’re doing it the right way and we need to do as much immune suppression as we do sometimes. Sometimes we could do more, sometimes we could do less. The tricky part is everyone that gets this condition gets a slightly different flavor. Some of these patients probably need less immunosuppression and more supportive care. Others of these patients may need more immunosuppression. For some, they’ll recover quickly over the course of weeks. For others, it will be months to years for the recovery and we don’t know how to predict who is going to fall into what category and who needs what treatment and that is why we have the extinguished trial.
Once you get it, do you always have it where you always have to be treated, or can it be cured?
CLARDY: When you get NMDA receptor encephalitis, for most patients, they will often keep what I call the scar, a little bit of a marker. They will keep that antibody for many of them in their spinal fluid at a low level, but the condition itself should be able to be brought under control in the vast majority of these participants over months to years. Again, recovery for most is very slow to really get back to the high level of functioning. These are young people, they’re often students or early professionals. To really get back to where they tell us they’re really right on the top of their game can take months to years, but for most patients, we are able to get them there over a long period of time. The question is, have we exposed them unnecessarily to risks in the meantime, infections, too much immunosuppression, too little immunosuppression? We don’t know.
I just talked to Katie before. How was she when you first met her? What was she like?
CLARDY: When we first met her, she was like many patients. She had been a very successful student doing quite well and really declined quite quickly and ended up in the intensive care unit rather rapidly.
Was she was treated with this drug or others?
CLARDY: You can’t get this drug outside of the study.
How did the treatment work for her? Is she back to normal, is she’s still recovering?
CLARDY: She’s recovered quite well. I think it would be interesting to ask her exactly how long she thought it took until she really had the essence. What I say to the patients and their loved ones is the spark back in your eye and really the subtle parts of your wit and your sense of humor can take many months. There is the piece of recovery that is getting out of the ICU and the next piece of recovery graduating from rehab, but for many of these participants, it’s that last part, the really getting back to the essence of who you are with every aspect of your personality that can take many, many months. I would actually be interested to see how long she says it took for her to really feel that was back.
For your trial nationwide, are you still enrolling, how many patients? How long will it last?
CLARDY: The extinguished trial is enrolling at 26 sites all across the United States. We will have two sites in Europe as well. One in Barcelona, where Professor Down Melies who discovered the condition, one in Rotterdam, the Netherlands. In the US 26 sites, it’s not every hospital in the country. The important part is this is such a rare disease that what we really need is for all of our clinician colleagues. The second they suspect this diagnosis and confirm this diagnosis on spinal fluid to call us. We’ve set up a 24 hour hotline and an email, to call us as soon as they have identified a patient who they think may benefit from being in the trial.
What should patients do? Where should patients go?
CLARDY: They should just talk to the doctor and ask if they have heard about this trial.
Anything you would want to add?
CLARDY: The key is, we’ve finally gotten NIH to fund this after years and years of lobbying. Somehow if we can convey and really what I’m passionate about is getting the word out to the patients and their loved ones, it’s really their loved ones, the patients are in the ICU. Getting the word out right at the time of diagnosis is what we have to do to get them enrolled in the trial, otherwise, they miss that opportunity.
Because they can’t be on other drugs before?
CLARDY: All of the participants in the trial receive multiple first-line immunotherapies. They also have the option to receive rescue therapies if their doctors think that’s necessary as well. What we’re testing in this trial is whether embolism ab, in addition to all of that, is beneficial or not.
END OF INTERVIEW
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