Rare Thoughts on a Rarer Neurologic Condition

Episode Transcript

Dr. Daniel Correa:
From the American Academy of Neurology, I'm Dr. Daniel Correa.

Dr. Katy Peters:
And I am Dr. Katy Peters, and this is the Brain & Life podcast. So, hi listeners. Hope you're doing well, hope you're getting up and moving. I'll tell you who's moving, it's Dr. Correa. So, I hear you're training for a marathon. How's it going?

Dr. Daniel Correa:
Well, it's exciting. I'm sore, tired and excited, and sleeping a lot to recover. And like many challenges in our lives, it takes a plan. You got to figure out a way to be consistent, and find a community to inspire you to keep going.

Dr. Katy Peters:
Now, for that community, in prep for your marathon, do you reach out to other runners or to friends that will be participating in that same event?

Dr. Daniel Correa:
It's funny, before I started really running more in 2019, I kept seeing this group run by my apartment with fun music and just looking like they were enjoying themselves. So after a bit, I went and showed up. In New York City, it's a great place because there's community and groups for pretty much every interest and background, or a person's unique situation. Many things that in other places you may only find one or two other people. In New York, it seems like there's a group meeting twice a week.
So, I get together multiple times a week with friends from the Harlem Run group, and have had through them an opportunity for accountability, and really just people to get together with on a Monday night, or Tuesdays, or on the weekends to plan a long run. I mean, you need someone with you often to help you just work through the miles and the steps, and some of the different challenges that you might come up with along the way. I've been able to keep working towards this goal with that group and that support, and it's going to be my third marathon this coming weekend here in New York.

Dr. Katy Peters:
Congratulations, that is so wonderful. And it's great that you found a community, so you don't really have a lone mission. You're not out there alone. And here at Bring & Life we make our own connections, and we have our wonderful listeners, and they often will make their own connections with us via social media. And that's what happened today with our guest, Christina Coates. She actually reached out to us via Instagram to tell us about an organization called Hypertrophic Olivary Degeneration Association, also known as H-O-D-A or HODA. This association brings awareness to a rare condition called Hypertrophic Olivary Degeneration. And we're going to learn more about this condition today, and I think what's really cool about this is how can you be your own advocate? How can you build your own community, and essentially reach across with social media to get the word out to others?

Dr. Daniel Correa:
And we want your help to learn more about who you are, and our Brain & Life community. So, we are starting a brainandlife.org/survey, a survey of our listeners. It's so important that we learn more about who's listening and your interests so that we can continue to grow and improve the show.

Dr. Katy Peters:
Well, hello podcast listeners. I want to welcome Christina Coates to the podcast. Now, this next guest actually contacted our podcast via my Instagram page. So, I wanted to say thank you social media, and thank you to Christina. And she reached out, and we heard from her and we said, "Yes. Let's get you on the podcast." So, Christina is the president and founding member of an organization called the Hypertrophic Olivary Degeneration Association, also known as, do I call it HODA?

Christina Coates:
Yeah, we call it HODA.

Dr. Katy Peters:
HODA, great. This association brings awareness to this rare condition, and we're going to learn more about hypertrophic olivary degeneration from Christina today. So Christina, welcome to the Brain & Life podcast.

Christina Coates:
Thank you so much for having me, Dr. Peters, it's my pleasure to be here.

Dr. Katy Peters:
Oh yes, and please call me Katy. We both got cats, we're hanging out, we're having a nice conversation. So, where are you and your cats joining us from?

Christina Coates:
We are joining you from very hot and sunny, and beautiful Gilbert, Arizona today.

Dr. Katy Peters:
Oh, wow. That must be a little hot and sunny. And tell us a little bit more about yourself.

Christina Coates:
Sure. So, my name is Christina Coates, I didn't always have brain diseases, I have them now. I am a almost 48-year-old woman who lives in Gilbert, Arizona. I've lived in Arizona my entire life. I am now a patient advocate and a patient myself, and learning all about neurology and brains. As for who I am, I am a grandma. I love reading. I am trying to learn French and Gaelic right now, just to keep my brain a little bit healthy. I'm an accountant, I'm a lot of things.

Dr. Katy Peters:
Well, thank you so much. And so, let's just jump right in. So, what is hypertrophic olivary degeneration, also known as HOD?

Christina Coates:
Well, Katy, I can tell you what it's not. It's not great. It is not great. So basically from my understanding, and I'll keep this at a lower level, there's two small structures called inferior olives at the base of the brain or the brainstem. And these olives with HOD, first they expand or hypertrophy, and then nobody knows for how long, it's estimated anywhere between two and five years, after that cycle then they atrophy or shrink. The olives are like the gatekeepers from the body to the brain. So, everything that is automatic, so think breathing, movement, anything like that can be affected by this disease. We generally have oculopalatal tremors, which I just got my palatal tremor last week, which is odd because I've had this for three years. I just now got my tremor. So HOD, it's an interesting little booger. There's a lot of opportunity for science to be done here, a lot of learning to be done. We as patients tend to know way more about our disease than our actual neurologists do so HODA is hoping to change that.

Dr. Katy Peters:
Well, I am glad that you're advocating, and I'm sorry that it's such a challenging condition. I'm sorry about the tremor. I assume this most likely gets misdiagnosed, and you were initially diagnosed with having a brain cavernous malformation, and then the diagnosis changed. And when I was reading on the website for HODA, it went from a rare diagnosis to begin with to an even rarer one. How did you handle that situation?

Christina Coates:
Sure. So, the cavernous malformation actually was a good diagnosis. I had a cavernous malformation on my cerebellum adjacent to fourth ventricle. So, what happened was I had surgery to get rid of that, and the surgery was a success. However, the lesion, so cavernous malformations are known to bleed or ooze blood. So, the lesion actually bled during my surgery, which they were concerned with. And we don't know if the bleed, the surgery, the previous bleed, we don't know what caused it but something damaged the Mollaret-Guillain triangle area, and that is usually what sets off HOD.

Dr. Katy Peters:
Yeah, and this is a very sensitive part of the brain. It's the deepest part of the brain. And just like you mentioned, it's really a conduit for all function going in and out of the brain. And I'm impressed that you explained that triangle. I'm a neurologist and I get tripped up over that. So what are you doing now for, is there any treatment you're undergoing or any particular monitoring?

Christina Coates:
Sure. So for treatments, we basically work with our team of physicians. Neurology is my quarterback to treat any symptoms. There's no actual treatment or cure for HOD, so we have to treat our symptoms only. As far as therapies, I've done vestibular therapy to help me with the dizziness that comes along with this. And it's not like a vertigo dizziness, it's a very special kind of dizziness that only HOD folks know about. It feels like you're dropping on a roller coaster while also on the carousel all the time. So, it's very special. So for me, as far as therapies go, I've been at this for three years. I try to get outside as much as I can. Obviously Arizona, so it's a little bit more challenging for me during the summer times. And I try to walk on different kinds of surfaces, so not just pavement or asphalt, I try to walk on gravel and anything different to keep my brain working a bit.
I also like to read as much as I can, which is difficult because some of the symptoms that HOD always comes with is double vision and nystagmus, or my eyes just move around on their own. So, that's why I had to stop working actually is because I was in finance and accounting, and it's hard to see spreadsheets and track the lines when your eyes are moving all the time. So, I try to read. Like I said, I'm trying to learn some different languages. Full disclosure, I had to take French in both high school and college, but it never really clicked with me. So, I'm trying now to do that, just to keep my brain exercising. What we've learned is it's really important to exercise both your brain and your body, because if you don't use it, you lose it, and you lose it fast with this disease.

Dr. Katy Peters:
I agree with you, exercise your brain and body, and it sounds like you've gotten some really great tips about walking over the different textures of pavement or ground, that can be really good for the vestibular rehab component. It retrains your brain that you don't want to be feeling like you're out of balance or having that falling sensation. And that has to be quite scary, I would think, to have that sensation.

Christina Coates:
It is. You start to feel like the top half of your body is super heavy and you're always trying to fall.

Dr. Katy Peters:
Oh, wow. Well, tell us a little bit about HODA. What is HODA doing now I guess to not bring awareness, but maybe even bring treatment options and build a community?

Christina Coates:
I am so excited to tell you about HODA, Katy. HODA started October 5th, 2021. So, I had just been diagnosed for a few months and I had finally stopped crying, because when you get a diagnosis like this, what most mainstream folks don't understand is when you get a rare diagnosis and there's no treatment, and there's very little research, they basically just tell you, "Here you go, this is all yours. Figure it out." And I mean, nobody can know everything about everything. But what HODA is doing now is first we are building communities, so we're finding our patients. We have a website, we are on social media, we're really trying to find our patients. Then we're working on education, both for our patients and we're trying to educate neurologists, because the story that we hear most often is that, "I didn't know I had HOD. I found this on my radiology reports from my MRI. My doctor didn't mention it. When I mentioned it to my doctor they said, 'Oh, it's no big deal. It'll go away on its own.'"
It doesn't go away on its own, that's just a common misconception among neurologists. So, a big can of worms that we've opened is trying to educate neurologists worldwide that this is not just going to go away, and please stop telling your patients that it's going to go away, because I get to be the constant bearer of bad tidings for people who come in and say, "My neurologist said this is going to go away," and I have to tell them, "I'm so sorry, it's not going to go away." So, HODA's working on education, right now we're fundraising to create a mouse model with HOD. Once we have the mouse model-

Dr. Katy Peters:
Oh, wonderful.

Christina Coates:
Yeah, then we can start really diving into some research and getting some answers, figuring out why this happens. Sometimes for a reason like mine and also idiopathically, this can happen to anybody at any time.

Dr. Katy Peters:
Well, I think that's wonderful that you're advocating not only to inform communities, but it stretches even to basic science research. So I'm so excited, and if you want to check out that website it's H-O-D-A-S-S-O-C dot org. Am I good?

Christina Coates:
You are good.

Dr. Katy Peters:
I think I'm good.

Christina Coates:
You are good.

Dr. Katy Peters:
So, now you have a role in this organization. What is your particular role?

Christina Coates:
So, I am the founding member. I'm the president, I'm also kind of the acting treasurer at this point. The board is working together to try and build something great. We've got a couple new members that just came on, and we're very excited about our future. We're looking forward to planning a patient conference in 2025, we're hoping.

Dr. Katy Peters:
Oh, I'm really excited, and I'm going to just say that that's going to come together. That's going to happen.

Christina Coates:
Yeah, I think so. Thank you.

Dr. Katy Peters:
Yeah, absolutely. And I guess you're an accountant, so it makes sense that you're in charge of the treasury. What are those skills from your prior roles, what have you brought to HODA to help it flourish?

Christina Coates:
Sure. So, I did work in for-profit private sector my whole life, but I learned there patience somehow, and organization, and what's required of us as far as in the United States with the IRS, what we need to do to file our taxes, things like that. So, really big organization skills came from my previous job.

Dr. Katy Peters:
I think that's wonderful. And I'm always telling my patients, again, I'm a neurologist and I treat patients with brain tumors. And again, it's a rare disease, not as rare as hypertrophic olivary degeneration, but I'm always saying use your skills. Use your skills at what you were trained in, and use your community to advocate for yourself and for others. So, what are your hopes and aspirations for people with hypertrophic olivary degeneration?

Christina Coates:
Let's just call it HOD.

Dr. Katy Peters:
HOD. What's our hope for HOD?

Christina Coates:
My joke is that science plays the worst tricks on people with neurodegenerative diseases by these crazy names that we can't say. My hopes for the community is that first we can provide good research, and education, and community for the people that have HOD, and their care partners. We host groups for both patients, online groups, virtual groups for patients and care partners so that they can just ... There's so much power in just being seen, and heard, and understood. That representation is so huge. And so, we really try to focus on helping keep people's feelings about this above board. It comes with depression obviously. You get this diagnosis, you're thrown out into the middle of the ocean. They basically dump a bucket of chum with you out in the middle of the ocean and tell you, "Okay, good luck." So, we want to be there for folks, that's our number one aspiration.
Secondly, we want to jump into research so we can provide good, accurate, factual information to our folks. Sometimes in our Facebook group of patients we'll get somebody who will find something on YouTube and want everyone to try it, and I really just want to present good factual information, that's important to us. And then we also hope to build out our deck of resources as far as we have a map of where physicians are located around the world that have just seen HOD. There are very few experts in HOD, but just patients around the world have such a hard time finding a doctor who has either seen HOD or is curious enough to learn about HOD. I always say, "My doctor doesn't know anything about HOD, but he's willing to learn" And he's gone on to PubMed, and he's read the research that is available, and he trusts in HODA actually, and we work together on how to move forward with treatment.
For instance, we decided together that an annual MRI is probably best for me just to keep an eye on these olives and see what they're doing, make sure there's nothing else going on up there, because this HOD, it doesn't seem to ever really travel alone. It's part of a complex medical issue. Ataxia usually comes along with HOD. I do not have ataxia, knock on wood, but who knows, it may show up at some point. So, it gets really complicated, which is why it's so important for us to find the physicians around the world that can tackle something like this with their patient, and we'll work with their patient, not just tell the patient what to do.

Dr. Katy Peters:
Well, we appreciate you being here today to inform our listeners, and we're here to amplify, to amplify what is HOD, what is HODA doing, and also Christine, what you're doing. And so Christine, I really appreciate you being here, sharing your experiences and your advocacy for yourself and for others with HOD.

Christina Coates:
Thank you so much for having me.

Dr. Katy Peters:
And thank you very much to our Brain & Life listeners.

Dr. Daniel Correa:
Can't get enough of the Brain & Life podcast? Keep the conversation going on social media when you follow @NeuroDrCorrea and @brainandlifemag, or visit Brainandlife.org.

Dr. Katy Peters:
Hello listeners, and welcome again to the Brain & Life podcast. Thank you so much for joining us today. I am Katy Peters, your co-host. I'm honored to introduce our medical expert, Dr. Vikram Shakkottai. Dr. Shakkottai is a professor of neurology at the UT Southwestern Medical Center in Dallas, Texas. And he is the Dedman Family Distinguished Chair in neurologic disease. The long-term goal of his clinical and laboratory research is to determine whether alterations in neuronal physiology contribute to motor dysfunction and degeneration in patients with cerebellar ataxia. His work in the laboratory has identified dysfunction in cerebellar circuit mouse models of ataxia, with identification of ion channels regulating neuronal intrinsic excitability as key targets for a shared therapeutic strategy. Now, those are his laboratory interests, and his clinical interests are really patients with conditions like cerebellar ataxia, also rare, inherited, sporadic disorders of cerebellar dysfunction, balance, and other movement disorders. So Dr. Shakkottai, welcome to the Brain & Life podcast.

Dr. Vikram Shakkottai:
Thank you so much for having me.

Dr. Katy Peters:
Yes, and can you tell us more about yourself and where you're joining us from?

Dr. Vikram Shakkottai:
Yep, I'm happy to. I am currently at the University of Texas Southwestern Medical Center in Dallas, and I am a movement disorders neurologist. So, I see patients with general movement disorders including Parkinson's disease and dystonia, but my specific both clinical and research interests is in a group of disorders which impair cerebellar function and the cerebellar circuit, which segues I think into what we're going to talk about today, which is a disorder of the inferior olive, which is considered part of the cerebellar circuit.

Dr. Katy Peters:
So, before we get into the specifics of cerebellar ataxia, we're going to go back to the basics because in your introduction I did a lot of scientific stuff, and talked about also some neuroanatomy. What is our cerebellum for, to our listeners, what is the cerebellum?

Dr. Vikram Shakkottai:
Great question. So, the cerebellum is really important for precision of movements. And the characteristic movements that the cerebellum is involved with are what are called ballistic movements. So, when you reach for something really quickly, and you want to precisely know where to move your arm and hit that target exactly right without having to correct yourself, that is the role of the cerebellum. And that there are other things that involve these rapid movements, these rapid precise movements that one often takes for granted. And this includes eye movement. So, when you want to look really quickly, move your eyes over to an object and look at it, and keep it in focus instantly, when you're driving, for example, that requires precise cerebellar function. The other thing that we also are really dependent on the cerebellum for is speech. So, imagine how you have to move your tongue, your palate, all your muscles have to move precisely and time it exactly right to produce a sound of the correct pitch, caliber, volume, and timbre to really make sense. And that is one of the most vital things as humans that the cerebellum plays a role in.
So whenever you think of precise movement, be it coordination of movement, hand movements, eye movements and speech, you require the cerebellum. Another really important role for the cerebellum with bipedal organisms like ourselves is how to walk. So, walking is really falling all the time, but catching yourself before you actually hit the ground, and that's what the cerebellum does. When there's any perturbation in the trajectory of a movement, if you don't anticipate it and correct for it before that happens, then you fall. And the role of the cerebellum is to ensure that you are not falling all the time. And this is also something that we take for granted, and this is somewhat unique because we have such an unstable position when we walk because we walk on two feet.

Dr. Katy Peters:
That is fascinating. I think now for all of our listeners, now when we walk we know how complicated it is, and I just want to say thank you to my cerebellum. It's actually one of my favorite parts of neuroanatomy, to be honest with you. And I'm sure it's yours.

Dr. Vikram Shakkottai:
It absolutely is mine. And the coding that happens in the cerebellum is I think next to, the precision involved, is actually relatively unique in the rest of the nervous system. And that's really what my laboratory studies as well.

Dr. Katy Peters:
And I guess it's so important, because that cerebellum is going to give us the refinement to really all of our movement, whether it's the movement of our eyes, the movement of our palate, and even the more complex interactions which will require, such in walking and also in talking. And sometimes you do it at the same time, you walk and talk.

Dr. Vikram Shakkottai:
Exactly. And in fact, one of the things that's compromised relatively early in somebody who has cerebellar impairment is the inability to do that, to walk and talk at the same time. And I think some of the rehabilitation strategies are to really focus on walking, because we're so used to taking for granted the ability to walk and do other things at the same time. And that's really compromised when this unconscious role that the cerebellum plays is no longer present.

Dr. Katy Peters:
Well, thank you to you and thank you to our cerebellum. So, when the cerebellum goes awry, so you study this, you study a phenomenon called cerebellar ataxia. Can you just tell us a little more about that? What is cerebellar ataxia?

Dr. Vikram Shakkottai:
So, the cerebellar ataxias I think are a really heterogeneous group of disorders. And I think oftentimes people think of them as primarily genetic conditions, but I think it's really any of those conditions that impair cerebellar function. And the causes are really quite diverse, and in some ways from the perspective of a neurology resident or a trainee, it's very daunting because there's so many things that can affect cerebellar function all the way from autoimmune disease, tumors of various sorts, strokes, as well as genetic conditions. So, I think parsing out what the etiology is or what the cause is for cerebellar ataxia is so challenging that people relegate the cerebellum and cerebellar ataxias to a little black box that they don't really want to think about too much. And I think that's unfortunate, because I think the cerebellum in all its roles has a relatively uniform set of things that it does. And it's really understanding function, I think can tell you, give you a lot of insight also into what is the etiology for why it's gone wrong.

Dr. Katy Peters:
I'm a neuro-oncologist, so we see it of course with tumors that involve the cerebellum, but also for patients that have a phenomenon called paraneoplastic disorders, where you can get a degeneration of the cerebellum and lead to ataxia and eye movement problems, and also speech problems. Now, I just listed some symptoms. Can you tell us some more symptoms that patients may see if they have cerebellar dysfunction?

Dr. Vikram Shakkottai:
Yeah, I think based on natural history studies that we've done, primarily in the inherited cerebellar ataxias, the earliest symptom of global impairment and slowly progressive cerebellar impairment is balance. So, balance seems to be one of the earliest symptoms that is impaired. And what patients typically say is that when they're walking often in a hallway, in a straight line, in a crowded environment, that they veer off and just feel off balance, and bump into the walls. And subsequent to that, there's often changes in speech, which are I think the second most common impairment. And the changes in speech in cerebellar ataxia start out with the same slurring of syllables that one often experiences when one is inebriated, when there's too much alcohol in the system.
And that's interesting because we do think that the effect of alcohol on speech is mediated by cerebellar impairment. So, it is in some ways the same physiology that happens with alcohol that you also see with the dysarthria of cerebellar ataxia. And then there's changes in coordination in the hands, changes in the handwriting. Typically, the letters are variable in size as opposed to say Parkinson's disease where there's more of an impairment in producing big letters. And where there's a micrographia, a reduction in the size of the letters, and difficulties with handwriting are often followed by other changes in hand dexterity, including buttoning and other tasks.

Dr. Katy Peters:
It's interesting because as you were listing off everything, I was thinking about how we document the neuro exam. And we usually start with mental status and it's the top of our brain, and then we go to cranial nerves, which is our midbrain and brainstem, and then we move to motor and sensation, and the cerebellum becomes at the bottom. But if you can think about it, everything that you just mentioned really connects even to the top, because we talk about speech, we talk about also your cranial nerve function. Now, our brainstem, right next to the cerebellum, how are they involved? What are the connections there?

Dr. Vikram Shakkottai:
Yeah, so I think the cerebellum, and as you just mentioned, the cerebellum is really integral to the rest of the brain, and receives input really from the limbs to match up what you want to do with what you have to do. And the cortex, where the commands for the movement come in. And this is mediated through fiber tracks that traverse the brainstem, which is this important area that integrates, I mean, has all the cables essentially from the legs and the thinking part of the brain, and connects them up for motor tasks with the cerebellum. So, I think the important input into the cerebellum from the periphery, from the limbs is through these spinocerebellar tracks which receive the sensory input from the limbs. And then there's an outflow tract from the cerebellum, which then goes through the thalamus, a relay nucleus close to the brainstem, that then projects to the motor areas.
We think the cerebellum may actually have a non-motor role, which is still being worked out in cognition and maybe affect as well. And so, the cerebellum does project to more than just motor areas, including the prefrontal cortex. But the role of the cerebellum is to integrate all this and regulate a motor command that makes that movement precise. And there's a nucleus in the brainstem that has a really important teaching signal for the cerebellum, and that's the inferior olivary nucleus. The inferior olivary nucleus in the rostral medulla in the top of the medulla, which also houses the respiratory center and other really important functions for cardiac, and breathing and other things also has this inferior olivary nucleus, which projects into the cerebellum and provides a really important teaching signal for the cerebellum.

Dr. Katy Peters:
I love the idea of a teaching signal, that it's telling it what to do and refining it. I love that idea. And you mentioned the inferior olive, and we're not talking about olives like you would see, I guess in any Greek salad-

Dr. Vikram Shakkottai:
Or in a martini.

Dr. Katy Peters:
Or in a martini, since we're talking about ... I was trying to think what are olive dishes? But I actually love olives, but we are actually going to talk about what's going on in the brain, not necessarily what's going on in my kitchen later on tonight. So, we're going to talk about a rare disorder, it's called hypertrophic olivary degeneration. And our guest on the podcast, Christina Coates, has this condition, and she really developed a foundation to really help others with this condition and bring awareness, called HODA. So, can you tell us a little bit more about hypertrophic olivary degeneration?

Dr. Vikram Shakkottai:
Yeah, no, and just to take off a little bit on the olive and the olivary nucleus, it's funny how when somebody looks at the brain we can't forget about food. So, the reason the olive is called an olive is somebody, I mean, I guess these were the classic neurologists, I think who imagined this-

Dr. Katy Peters:
Absolutely.

Dr. Vikram Shakkottai:
... in France, who saw this little bulge in the brain stem that looked like a little olive. And so they said, "Oh yeah, that looks like an olive," and it's inferior. It's like in the bottom of the brain, so let's call it the inferior olivary nucleus, and that's why it's the olivary nucleus. But the inferior olivary nucleus plays this really important role in learning. But the reason why it's important, I guess from a neurologic standpoint, is that in some individuals it develops into, there's this condition known as hypertrophic olivary degeneration that you mentioned.
And this often happens when there is a lesion in the brain stem, often in the middle of the pons, most commonly because of hemorrhage, a cavernous malformation or multiple sclerosis, which causes a lesion in the pons that dissociates the olive from the cerebellum. And when the cerebellum and the olive lose this connection due to this lesion that disconnects them, the olive, not to anthropomorphize things, make it a individual that really behaves of its own volition, but the olive undergoes this unusual form of degeneration known as hypertrophic olivary degeneration. And in many other parts of the brain, when in the course of degeneration cells shrink, or they have what's called atrophy, they get smaller and then ultimately they disappear. In the olive, for whatever reason, and this may be unique just to the inferior olivary nucleus, instead of getting smaller, olivary neurons get bigger, and the cell size gets bigger, and the dendrites get more profuse.
And in many cases, it's almost an incidental finding on a brain MRI that there are these enlarged olives that have these characteristic signal chains. But in a number of individuals with hypertrophic olivary degeneration, because that teaching signal from the cerebellum to the olive is partially disconnected, it's actually unusual in that it's not the connection from the olive to the cerebellum that's disconnected, it's the connection from the cerebellum to the olive that's disconnected. If it happens both ways, then you often have very profound cerebellar ataxia, but when this unidirectional contact between the cerebellum and the olive is disconnected, the olive undergoes this hypertrophy. And that can be accompanied by ataxia, but more characteristically, and this was first described by German neurologists, I think way back in the 18th century, late 18th century, and in the early part of the 19th century by French neurologists, where this is associated with an unusual movement disorder known as oculopalatal tremor or oculopalatal myoclonis, and this is a condition where there's an oscillatory activity of the eye that's somewhat irregular and low frequency with a synchronized movement of the palate as well.
And many patients who develop oculopalatal tremor have loss of visual acuity because their eyes are moving all over the place, and they sometimes have a clicking sound because of the palate moving constantly. And in addition to that, this tremor can then propagate and involve muscles involving important for speech, and can also produce in coordination in the limbs and the tremor in the limbs. And this can also be associated with ataxia depending on how isolated this loss of connection is, whether it affects the connections from the cerebellum to the olive, and also affects the connections between the olive and the cerebellum, and other pathways that the cerebellum regulates.

Dr. Katy Peters:
Oh, wow, that was a lot. So, what is that clicking? What is the sound?

Dr. Vikram Shakkottai:
So, if it involves the tensor veli palatini, the muscle that tightens up the tympanic membrane, the eardrum, and that moves, basically your eardrum is oscillating. And so it's vibrating, and that's how we hear sound, so it produces the sound.

Dr. Katy Peters:
Fascinating. And I mean, this has to be a rare condition. I mean, how often do you see patients with this phenomenon?

Dr. Vikram Shakkottai:
So, we actually don't know how rare it truly is. I think many times it's not recognized and in some cases it's included in a diagnosis of cerebellar ataxia, for example. So, I direct a dedicated ataxia clinic. So in my clinic, it's less common among the overall ataxias that I see, but I not uncommonly see individuals with hypertrophic olivary degeneration with an ocular palatal tremor. Many times the individuals who have a hypertrophic olivary degeneration, particularly identified on MRI, who don't have an oculopalatal tremor but may have ataxia may just be diagnosed with ataxia and may not end up seeing a specialized center. So, I think what Christina Coates is doing is trying to develop a registry through the HODA to really look at how common this entity is, and really look at what the natural history is.
Because the other unusual thing about HOD, or hypertrophic olivary degeneration, is that it's a delayed response to this injury. So, individuals often will have a cavernous malformation that bleeds, but the identification of both the tremor, the oculopalatal tremor, and the increase in the size of the olives on brain MRI can be delayed often by many months, six or more months. And sometimes the reason I see some of these patients is because they've had worsening of symptoms in the delayed fashion and this onset of this new tremor many months after their bleed when they thought they were actually getting better from the ataxia and the brainstem hemorrhage, and they have this new movement disorder and there's concern about, "Oh, now is this something else? Is there a degenerative condition superimposed?" Or is there something else going on separate from that hemorrhage that they already had six months prior?

Dr. Katy Peters:
And that has to be scary for the patient if they've already had a hemorrhage and had a cavernoma that involved the brainstem or the cerebellum, whatever it may be, to then have those symptoms. What I think is so fascinating though, is there I guess a variation, like you'll have a little bit of symptoms? Or does it correlate with the radiographic findings? What is the day-to-day when you see someone with this? How do you prognosticate?

Dr. Vikram Shakkottai:
Yeah, yeah. No, that's a great question. And really it's incompletely understood. So, a lot of the work was done in individuals who had these hemorrhages, and then we happened to have brain material in the 1980s looking in a delayed fashion as to how this evolved. And what we know from those studies is that in a delayed fashion there is this olivary hypertrophy, and then with the development often of tremor that is progressive, that gets worse as this hypertrophic response, which we think is a maladaptive but potentially compensatory response because the olive seeking direction from the loss of the cerebellar input. And that can happen over many years actually, with progression and worsening of motor impairment and tremor.
And then it often plateaus, and at least in some cases there is then degeneration, frank degeneration where there's cell loss and then scar tissue formation, but then attenuation of the tremor, but that's not necessarily the case. So, that's one set of kind of possibilities that can happen. Otherwise, I mean, this palatal tremor and the motor impairment can persist indefinitely after progressing, but it often plateaus typically a few years after the onset of the phenomenon.

Dr. Katy Peters:
So, what can you do to help treat these patients that are definitely coming in with symptoms that are concerning? Some of them can be very serious. What are the next steps after you really identify this?

Dr. Vikram Shakkottai:
Yeah, and this is unfortunately one of the areas that where we don't have great treatment. So, we now know a lot of pathogenesis, including in cats if you do something similar, if you lesion the cerebellum where you get rid of those inputs from the cerebellum to the olive, in cats you could develop hypertrophic olivary degeneration or olivary hypertrophy. And we've identified a similar process that happens in a mouse model of an inherited ataxia, where we previously didn't know that it happened, but maybe part of the pathogenesis in these disorders that are not directly because of a lesion in brain stem but a degenerative disorder in the cerebellum that selectively seems to affect also the connections between the cerebellum and olive. So, we're hoping that that will give us insight into mechanisms for how this happens, and how to either prevent or attenuate that tremor. So, traditionally for the treatment of oculopalatal tremor, which can be really disabling in some individuals-

Dr. Katy Peters:
Absolutely.

Dr. Vikram Shakkottai:
... things that are tried are things like anticholinergic medications, like Artane, medications like primidone, which we also use for things like essential tremor. But we know that these treatments are really not very effective. They're often associated with significant side effects and don't really impact the tremor. So, in the laboratory we're trying to identify, at least initially, agents that we can use maybe clinically off-label to try and address some of the underlying mechanisms, which we think are related to what you mentioned in your introduction, intrinsic neuronal excitability in the olive. So, our work in a mouse model of a spinocerebellary ataxia type I, where we see hypertrophic olivary degeneration, or a phenomenon similar to hypertrophic olivary degeneration, is that this is associated with an increase in the excitability of the membrane of the inferior olive neurons. And if we can know what that's due to, what ion channels to target to reduce that excitability, maybe that would be a way to both prevent the worsening of symptoms, the progressive hypertrophy and hyper connectedness that causes the oculopalatal tremor, but also treat and attenuate the tremor.

Dr. Katy Peters:
And I think this is so important with your work, Dr. Shakkottai, as a physician, scientists, you're taking not only what you're doing in the laboratory, but observations in clinic about what's happening to your patients, and then partnering that with the advocacy that Christina is doing. I think that really there's an opportunity that in the next coming years we can see some definite benefits for patients, not just with hypertrophic olivary degeneration, but for any kind of injury in the nervous system, because it's all about connections.

Dr. Vikram Shakkottai:
Absolutely. I think it's been so rewarding for me to see the patients where we have models in mice, where we can study in much greater granularity as to how these cells behave following this injury. And this is true for hypertrophic olivary degeneration as well as more broadly the cerebellar ataxias and impairments in the cerebellar circuit.

Dr. Katy Peters:
Yeah, and it's those connections that we get from social media that lead to what you're studying in the laboratory. So, I just want to thank you so much for joining us today, for being our expert, and for really shining a light on a rare disease and helping your patients.

Dr. Vikram Shakkottai:
Thank you so much. Thanks for having me.

Dr. Daniel Correa:
Thank you again for joining us today on the Brain & Life podcast. Follow and subscribe to this podcast so you don't miss our weekly episodes. You can also sign up to receive the Brain & Life magazine for free at brainandlife.org. Don't forget about Brain & Life in [Spanish 00:47:42]

Dr. Katy Peters:
Also, for each episode you can find out how to connect with our team and our guests, along with great resources in our show notes. We love it when we hear your ideas or questions. You can send these in an email to blpodcast@brainandlife.org and leave us a message at 612-928-6206.

Dr. Daniel Correa:
You can also find that information in our show notes, and you can follow Katy and me, and the Brain & Life Magazine on many of your preferred social media channels. We are your hosts, Dr. Daniel Correa, connecting with you from New York City and online at NeuroDrCorrea.

Dr. Katy Peters:
And Dr. Katy Peters, joining you from Durham, North Carolina, and online at KatyPetersMDPhD.

Dr. Daniel Correa:
Most importantly, thank you and all of our community members that trust us with their health and everyone living with neurologic conditions.

Dr. Katy Peters:
We hope together we can take steps to better brain health, and each thrive with our own abilities every day.

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