Céline Dion’s Doctor Advances Medicine for Patients of Rare Neurological Disorders

This episode features a discussion about autoimmune neurological diseases, 
including the rare stiff person syndrome (SPS) that affects Canadian 
superstar Céline Dion. Our guest is Amanda Piquet, MD, associate professor 
of neurology and director of the autoimmune neurology program at the 
University of Colorado School of Medicine. Piquet, whose team is conducting 
groundbreaking research on autoimmune neurologic disorders, has treated 
Dion’s SPS for over two years at UCHealth University of Colorado Hospital. 
Piquet calls the $2 million philanthropic investment her team received from 
the Céline Dion Foundation a turning point in the understanding of SPS and 
other autoimmune neurologic diseases.

Transcript

Chris Casey:

Welcome to another episode of Health Science Radio, where we talk with researchers at the University of Colorado Anschutz Medical Campus about the ways they are innovating and advancing healthcare. My name is Chris Casey and I'm the Director of Digital Storytelling at CU Anschutz. In studio at the historic Fitzsimmons building, I'm once again honored to be joined by my co-host, Dr. Thomas Flaig, our Vice-Chancellor for Research.

Thomas Flaig:

Hello, and the honor is of course all mine.

Chris Casey:

So our guest today is Dr. Amanda Piquet, who is an Associate Professor of Neurology at the University of Colorado School of Medicine, where she serves as the Director of the Autoimmune Neurology Program, and Associate Program Director of the Neuro-Infectious Disease and Autoimmune Neurology Fellowship. That's quite a mouthful. 

Dr. Piquet completed her medical degree at Penn State University and Neurology residency training at Harvard's program at Massachusetts General Hospital and Brigham and Women's Hospital. She then completed a fellowship in autoimmune neurology at the University of Utah. 

Dr. Piquet's research program seeks to advance our understanding of rare autoimmune neurologic disorders through observational studies, translational studies focused on identifying potential biomarkers associated with neurological outcomes and treatment response, and innovative clinical trials. In support of this program and ongoing research in stiff-person syndrome, Dr. Piquet was recently recognized as the inaugural chairholder of the Céline Dion Foundation Endowed Chair in Autoimmune Neurology.

Thomas Flaig:

Congratulations.

Amanda Piquet:

Thank you. Thank you for having me.

Chris Casey:

Thank you for joining us. And that is quite an honor that you were recently bestowed this first Endowed Chair in Autoimmune Neurology. Dr. Flaig, would you like to kick us off with delving into stiff-person syndrome and Dr. Piquet's research?

Thomas Flaig:

Well, before we jump into this, I think the very interesting conversation and recent tie-ins with recent events and so forth, let's talk a little bit about stiff-person syndrome. Can you start out by just telling us what this is and how does it manifest in patients?

Amanda Piquet:

Yeah, so stiff-person syndrome is a progressive autoimmune neurologic disorder. It has two cardinal features. When patients present, they have stiffness often seen in the trunk – so chest, back, stomach. The core muscles. Also involves the legs pretty commonly and can impact someone's walking because of that. Other features include episodic muscle spasms, and these spasms can be triggered by various things. They can also be untriggered. And these spasms can be quite debilitating. Imagine if you had a charley horse, but having that through your entire leg or in your chest and across the body. The triggers can happen when there's bright lights, there's loud noise, something unexpected happens – like a dog comes running around the corner. Patients can freeze up, and that triggers these spasms, that triggers the stiffness and can impact someone's walking.

Thomas Flaig:

In what age does this usually present in patients?

Amanda Piquet:

That's a great question. Typically, we see this happen on average around the age of 50. It's more common in women than men. Actually about 60% to 70% women, but it can occur even in pediatrics. That is exceedingly rare. Maybe about 5% of cases – or at least that's what's been described in the literature – can occur in the pediatric population.

Thomas Flaig:

And it's a pretty rare entity, I think, in terms of prevalence of one or two per million, something like that?

Amanda Piquet:

That is what has been described, about one in a million. However, as we define this disease better and we study this disease more, I suspect those numbers are inaccurate. For example, we recently did an epidemiology study here at the University of Colorado through the UCHealth system, a population-based study. So it looked at the entire population of the UCHealth cohort over a decade and pulled out those patients that had stiff-person syndrome. And when you do it with that methodology, we found, depending on how you want to define the disease, because that isn't necessarily agreed upon with experts yet, depending how you want to define that, we're looking at one to two per 100,000. And that study is provisionally accepted with neurology.

Thomas Flaig:

As we move over to the story of our talk today, you talked about proximal muscles, those kinds of central muscles in our body. Does it affect the vocal muscles?

Amanda Piquet:

Yes. And so everything's controlled by the muscles when you talk, when you sing. And so for example, when you take a deep breath and want to push that air over the vocal cords in order to sing, that requires coordination, muscles to the vocal cords, as well as coordinating taking that deep breath, opening that chest cavity, lowering your diaphragm, and being able to push all that air out. That is all muscles across the trunk, the rib cage. That can go into spasm and be affected in stiff-person.

Chris Casey:

It's only been a few weeks since the conclusion of the Paris Olympics, and I can't help but note that a rather well-known patient of yours, Céline Dion herself, sang Hymne A L'amour to conclude the opening ceremonies, which was a very dramatic moment. I'm just curious, given your experience with Céline Dion, Amanda, what was that moment like for you to see her finally, after all this struggle, and you've been very involved with her therapy, to see her triumph like that in front of the world?

Amanda Piquet:

That was just an incredible moment to watch. She did a phenomenal job, and I was just so proud to watch her do that. Céline, like a lot of my patients with stiff-person syndrome, works incredibly hard with this disease. It is, like I said, a chronic disease. We need to manage symptoms on a day-to-day, week-to-week basis. It requires a lot of effort on the side of the patient. When we do non-pharmacologic therapies such as exercise, physical therapy, for Céline's case, vocal therapy, those things are essential. And so that performance is just a reflection of her incredibly hard work.

Chris Casey:

And I understand you were traveling that day when that performance happened. Could you talk about where you were? I'm sure you were wanting to watch, but how did it transpire with you watching?

Amanda Piquet:

Yeah, so I was scrambling to watch it in a United Airline line to board my flights to Minneapolis. I serve on the conference subcommittee with the American Academy of Neurology, the AAN. We meet once a year in the summer to put together our big annual meeting, in terms of the educational material for that. And so that was interesting as I was sitting there with my headphones and trying to watch that boarding the plane.

Chris Casey:

Oh my. I know you can't get into too many particulars about her case, but could you talk about just how stiff-person syndrome presents? And it's a very mysterious kind of onset and it gets confused with other illnesses, correct? Maybe touch on a little bit how the onset occurred with Céline and just the struggles of the diagnosis process?

Amanda Piquet:

It's an incredibly hard diagnosis to make. It is not uncommon that patients have this diagnostic odyssey where they go years without getting to a diagnosis. Many times patients are misdiagnosed, especially women, with things like multiple sclerosis, fibromyalgia, chronic pain syndromes. For men, sometimes we see a misdiagnosis of Parkinson's disease or another type of movement disorder because of that walking impairment. So it is a challenge. It requires expertise in that disease because it's a clinical diagnosis. Like I said, we don't have international consensus criteria for the diagnosis of stiff-person syndrome. That is something that myself and others are actively working on. However, there are diagnostic guidelines that we use. These still need to be validated across institutions, but generally that includes the clinical syndrome. That includes antibody testing, both in the blood and the spinal fluid. That includes ruling out other things with diagnostic imaging, like MRI. And that includes something called an EMG, which is to look at the activity of the muscles.

The time to diagnosis on average when you look through the literature is about seven years, just to give you a sense of how long this diagnostic odyssey could be.

Thomas Flaig:

At the top, we mentioned that you were the first holder of this new Endowed Chair. Can you just talk a little bit about that, maybe what the Endowed Chair is focused on and your engagement in that? And it's a gift from the Céline Dion Foundation, I believe?

Amanda Piquet:

It is an incredible honor to be awarded this Endowed Chair from the Céline Dion Foundation. 

This chair position will support my role as the Director of the Autoimmune Neurology Program and support the program itself. And the mission of this program is twofold: focusing on clinical and research and really bringing them together for patients. 

So one of the foundational components of the Autoimmune Neurology Program is our autoimmune and paraneoplastic neurologic disease registry. As you can tell, we use a lot of big words in neurology and long titles.

What this is, is this is a registry where we have an observational study, and we are learning from patients. Because these are rare disorders and they need to be defined better, we learn directly from the patients. So in that registry we capture things like symptom onset, different antibodies we find in a patient, different findings that we see on imaging, any association of other autoimmune diseases like rheumatologic diseases or other related cancers in the setting of paraneoplastic neurologic disease – that's defined by an autoimmune disease with an underlying cancer. 

And so we collect all that information from patients in an organized database and we follow patients longitudinally so we can understand as we try different treatment approaches, what works for patients. We're also collecting blood, spinal fluid when it's available, to advance our biomarkers for these diseases.

Thomas Flaig:

So you've mentioned your work in autoimmune disease and neurology. How does this fit in this umbrella of autoimmune diseases? 

Amanda Piquet:

So autoimmune disease in general, we usually think about it as the immune system behaving badly and attacking oneself. In the setting of an autoimmune neurologic disorder, your immune system attacks either the central or the peripheral nervous system, so it can look like many different things. You can have inflammation of the brain. That's encephalitis. You can have inflammation of the spinal cord. That's myelitis. You can also get neuropathies from inflammation of the peripheral nerves. 

Another forgotten entity of the nervous system is the autonomic nervous system, so you can have inflammation and antibodies that attack the autonomic nervous system, and that's basically the part of the nervous system that controls all the other vital organs that we don't think about: heart, breathing, gut.

For stiff-person syndrome specifically, we don't understand the exact path of physiology, but the proposed thought is that many patients have this antibody biomarker called GAD65. With that antibody, we believe that your immune cells, your B cells, make that antibody inappropriately, and then that antibody attacks the central nervous system. Your spinal cord, your brain stem, parts of your brain are rich in something called a GABA receptor, and that GABA receptor is a function of the nervous system that inhibits signal. So you can imagine that's like putting the brakes on the nervous system. So when you have that GAD65 antibody causing problems, it interferes with the function of the GABA receptor and it interferes with the ability to put the brakes on the nervous system.

If you can imagine, there are some patients with GAD65 antibodies that have seizures because they're always on go and you can't activate that brake, so you can have a seizure. For stiff-person syndrome, if you're not putting the brake on signals from the spinal cord or from the brain stem or perhaps the motor cortex, then your muscles are always on. And so one of the core features, like I said of stiff-person, is that you have muscle spasms because they're being triggered inappropriately, and stiffness because you can't relax the muscle – since you don't have that brake function.

Thomas Flaig:

Stiff-person syndrome also runs in families, so is there a genetic component to it?

Amanda Piquet:

It's actually uncommon for it to run in families. I've certainly seen it. There are certain unique groups that perhaps it clusters. What does tend to run in families is just being predisposed to autoimmunity in general. So we tend to see a cluster of different diseases in families with someone with stiff-person. And that includes type 1 diabetes because that's also associated with those GAD65 antibodies, autoimmune thyroid disease, and something called vitiligo, which you lose that pigment in your skin.

Chris Casey:

And you've already touched on this a bit, but could you just elaborate a bit more about what kind of therapeutic regimen somebody with stiff-person syndrome might face, and how is that parsed out? The options of immunotherapies, symptomatic therapies, then you've mentioned physical therapies. Hydro? Hydrotherapy?

Amanda Piquet:

Yeah, hydrotherapy. Physical therapy in a pool.

Chris Casey:

Could you just kind of address the array of therapies?

Amanda Piquet:

Yeah. When you think about the treatment approach to the patient, put them in two big categories. So you have your immune therapies, and the immune therapies target the underlying dysfunction or the autoimmune disease. Your symptomatic therapies, which are targeting things like the muscle spasms, the stiffness, to make patients feel better. And so looking at the immune therapies, the first line therapy, the go-to therapy for stiff-person syndrome is something called IVIG or intravenous immune globulin. Oftentimes we can see a good response with IVIG, but it may not be sustained. There is some literature out there that suggests that about a third of patients continue to progress years after the initiation of IVIG. So we definitely need better therapeutics. 

Oftentimes in the clinic, we are using off-label immune therapies because we have no FDA-approved therapies for stiff-person syndrome. And a common go-to is an anti-CD20 therapy called Rituximab used in other rheumatologic disorders.

When you look at the symptomatic therapies, on the other hand, those are medications like benzodiazepines because of their action on that GABA receptor. That is our first line symptomatic therapy, but we use other different types of muscle relaxers and anti-spasm agents like Baclofen. And then outside of medications, there's the therapy that we use, so the non-pharmacologic approaches. Like you said, physical therapy, hydrotherapy, which is physical therapy in the pool. We can do balance therapy, among many other different types of approaches. 

One thing that we do see with stiff-person – and it's not uncommon – is phobias and a lot of anxiety around this disease. A lot of patients can have some PTSD and medical trauma just because they took so long to get to a diagnosis. And in that setting, having a psychologist as well as therapists can be super helpful.

Thomas Flaig:

So just thinking about the rarity of stiff-person syndrome, some of the limitations in current therapies, what sort of research do you see in this area is going to be done in the future?

Amanda Piquet:

So we have clinical trials on the horizon for this disease. This includes a clinical trial that will likely open up this fall, or at least that's the projected date, in which we're going to be studying CAR T therapy in stiff-person syndrome. With that trial, one of the outcome measures is going to be looking at walking, so seeing if this therapy could functionally make patients better in terms of their gait.

Thomas Flaig:

I'm an oncologist by training, so I think of the CAR T therapy in terms of one of our therapeutics where we take out those immune cells, sort of hardwire them to attack a specific cancer antigen and a marker on the surface. So this sounds like a way to actually impact the immune system by using a similar approach of these CAR T cells.

Amanda Piquet:

Correct. And the target will be those B cells. Those B cells are the cells making the GAD65 antibodies. So taking one's own immune cells, those T cells, putting a little flag on them, so that way, they target and destroy those B cells that are misbehaving and making that antibody. That is the rationale for why to study CAR T and stiff-person syndrome.

Thomas Flaig:

So with the autoimmune nature of this, you've lost that natural inhibitor in the system, and so the CAR T will sort of override that and serve that purpose of limiting that action?

Amanda Piquet:

Correct, by eliminating the antibody.

Thomas Flaig:

Very interesting.

How did you end up getting into that particular area and what do you think about being a researcher in a rare disease setting?

Amanda Piquet:

I am a very curious person, and I think that's how I ended up here. I always had a passion for understanding the brain and the nervous system and that is what led me to neurology. At the same time, I think one of the most complex organs outside of the brain is the immune system. So putting those two together, it's incredibly fascinating to be on the cutting edge and just learning new diseases during my career. In terms of stiff-person syndrome, I saw a lot of patients during my fellowship with this disease. I was surprised at how patients presented because individuals can look very different. Even though you see those core features, some of the additional symptoms that we see can be truly a spectrum across the disorder. I really felt that seeing these patients, there were just so many more questions than answers, and that really just drove me from my curiosity and research side to dive into that disease more.

Thomas Flaig:

I can just imagine the personal level when someone's been searching for an answer to explain their symptoms for years, and you are the expert in that area that can do that. That must be quite rewarding.

Amanda Piquet:

It is. It is. It's amazing.

Chris Casey:

And also quite rewarding must be the fact that of all the other research areas around the country that are delving into SPS (stiff person syndrome), other neuro autoimmune illnesses, that here your program was selected for the Céline Dion Foundation Endowed Chair. Could you explain what that meant to you and your team?

Amanda Piquet:

I almost have no words for that because it's just, like I said, an incredible honor. It just is a reflection and shows the passion our team has in the Autoimmune Neurology Program and our dedication and our search for answers and our determination to do so. It's amazing. There are very few places in the country that do autoimmune neurology, but to be chosen as the one to lead this effort is incredible.

Chris Casey:

And I'll follow up with another sort of pop culture related question because I enjoy the pop culture, you know. I like the pop culture question. So getting back to another thing related to Céline Dion who, without question, is an international superstar. Everybody knows her. A documentary just recently came out as well, I Am Céline Dion, and they did the big premiere, a couple months ago, maybe now it's been, in probably New York.

Amanda Piquet:

New York.

Chris Casey:

I believe you attended.

Amanda Piquet:

Yes, I did.

Chris Casey:

We've seen the YouTube clip and it's very emotional where Céline is up there addressing the audience, and then begins discussing her own journey with SPS and talks about...I believe she's quoted as saying she had help through CU Anschutz and alluding to yourself as solving the mystery about her health. And then she got quite emotional and said, "Dr. Piquet has replaced my fear with hope." That was a very powerful statement. How did that hit you on an emotional level when she said that?

Amanda Piquet:

Oh, absolutely. We go through with patients. We see them at their most vulnerable periods. And to be able to work with someone over time and help them move forward with their life and get back to doing what they love is amazing. And that statement of replacing fear with hope, I hope I'm doing that for all my patients when I see them in clinic.

Chris Casey:

Well, is there anything else, like a bottom-line issue here for you, Dr. Piquet, in terms of study of autoimmune neurological conditions and where it's going and what needs to happen for even more breakthroughs to occur?

Amanda Piquet:

I just want to say that autoimmune neurology is a new field, really not even well described until 2004 with one of the first landmark antibodies of neuromyelitis optica, or NMO. And the field has just exploded since then. And I am so excited and so happy to be part of a rapidly evolving field. It keeps me on my toes and I really think the future is bright for bringing better therapies to patients.

Thomas Flaig:

It's been such a helpful discussion today to understand your work in autoimmune neurology, the impacts in stiff-person syndrome, but the broader work you're doing as well, so they can move forward in the best possible way.

Amanda Piquet:

Thank you. Thank you again for having me.