Neuropsychiatric Challenges Facing Patients with Huntington’s Disease

Podcast Transcript

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

Glen Stevens, DO, PhD:

Although Huntington's disease is conventionally characterized as a movement disorder, it is clinically defined by a triad of motor, cognitive and behavioral symptoms with the neuropsychiatric features of the disease often preceding motor dysfunction. In this episode of Neuro Pathways, we're discussing the neuropsychiatric challenges facing patients with Huntington's disease and the importance of a multidisciplinary approach to care.

I'm your host Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to be joined by Dr. Kasia Rothenberg. Dr. Rothenberg is a geriatric neuropsychiatrist in the Cleveland Clinic Neurological Institute's Lou Ruvo Center for Brain Health in Cleveland, Ohio. Kasia, welcome to Neuro Pathways.

Kasia Rothenberg, MD, PhD: Thank you very much. Thank you for having me.

Glen Stevens, DO, PhD: Tell us a little bit about yourself, how you came to Cleveland, those types of things.

Kasia Rothenberg, MD, PhD: Of course, its a long story, so I don't know if you have enough time. I'm European. Obviously, you can't tell probably by my accent. I'm Polish and I'm a cognitive neurologist from my previous life, from my education back there in Europe. I came to US in 2006. It was a project that we had with Case Western Reserve. To make a long story short, I met a very nice American engineer and after a couple of years I relocated to US. As you probably know, like any other international graduate, I had to start fresh, take all the exams and decided on a new, or second, residency program. This time I was looking at psychiatry as my future career. I think it was a good choice because from the beginning, I decided that I want to develop into more neuropsychiatry to combine those two types of training and it did happen.

I did a fellowship in geriatric psychiatry at Yale. I really wanted to stay there, although in 2015 when I was ready to start, in fact, working in the field, the Cleveland Clinic decided on establishing Center for Brain Health. Those days, Dr. Cummings was a director of a center whom I knew, and it seemed to be a really good fit for me. Since then, I'm here working for Center for Brain Health. What I do, it's probably as close as it gets to neuropsychiatry. I take care of people with Alzheimer's disease, Parkinsonisms, Lewy body. And since 2017, I joined the team, our movement disorders people at Center for Neurological Restoration to take care of Huntington's population.

Glen Stevens, DO, PhD: Well, it sounds like Yale's loss is our gain, so we're happy.

Kasia Rothenberg, MD, PhD: Absolutely.

Glen Stevens, DO, PhD: We're happy.

Kasia Rothenberg, MD, PhD: They know it. They know.

Glen Stevens, DO, PhD: So, let's move forward and tell us a little bit first before we get into the neuropsychiatric specific aspects of it, just Huntington's disease in general so that our audience can understand the disorder a little better.

Kasia Rothenberg, MD, PhD: In fact, I have two stories for you. First very brief story takes us back to 1870s. Imagine young man with a brand-new degree, medical degree from Columbia is coming back to his family medical practice in Long Island. He's very bright, very observant, but he's particularly intrigued with one family. He notices that multiple people in this family, they present more or less in the early adulthood with some weird changing, increasing in severity movements. He knows that this type of a movement, it was a term already coined for this type of a movement, chorea, but he notices something more. He notices that this chorea is in fact hereditary, that multiple different generation, they present with the same thing. Of course, George Huntington did not have a good grasp of genetics because just to remind everyone, Mandel published his first "genetic paper" in 1866, so Huntington couldn't really a good understanding of genetics, but he knew it's hereditary.

And of course, immediately after publishing it in 1872, his publication was extremely thorough, so certain type of expressions. The terms that we use even nowadays come from this paper. And of course, he made a name for himself. Since then, this type of a hereditary type of chorea, it's called Huntington's chorea. And now let me fast forward a hundred years. Now we are in 1972, and there is this celebration of his paper and neurological conference. During this congress, people, neurologists from Venezuela, present a movie and a paper about multiple different small villages around the Lake Maracaibo in northern Venezuela where almost every household, every family has somebody with chorea form movements, Huntington's chorea, generations after generations after generation, after generation. Interestingly enough, there is one person who attends this congress, neuropsychologist, and this is a first link to neuropsychology and psychiatry in Huntington's.

She has this crazy idea that maybe if we study those people from Maracaibo, because there is a chance that they would have both parents with a disease, so a chance to learning something about genetics of this condition. Yeah, it's a larger chance, correct, to find the gene. And of course, it's 1972. We have a good understanding of molecular genetics already. Just to remind everyone, 1953, Watson and Crick well, told us how really genetics works. So she does go there and starts the Maracaibo study, which leads to first mapping. After that, encoding the gene for Huntington's disease. Interestingly, of course, well, there is a question why this woman is so devoted, because it's not easy. We know, of course it's not easy to get funds for such a project. Her project lasted like 22 years.

Every single year, the team was going there collecting epidemiological data, blood for genetic analysis, et cetera, et cetera, et cetera. Even neurological teams were joining the group to assess how people change within this disease. So she is, in fact, a person who was living in a family with Huntington's disease. Her mother and all her uncles developed symptoms, so she was in fact living in this fear of eventually developing the disease. So entire life, life really well lived, extremely devoted. She in fact created the whole culture that now we follow. The culture of taking care of people with Huntington's disease.

Glen Stevens, DO, PhD: So, we learned that it's an autosomal dominant disorder.

Kasia Rothenberg, MD, PhD It is.

Glen Stevens, DO, PhD: We learned that 90 percent of the patients have inherited and sporadic is a small percentage of the patients versus some diseases, it's a 50/50. And we learned later, I guess, about trinucleotide repeats.

Kasia Rothenberg, MD, PhD: Correct.

Glen Stevens, DO, PhD: And the CAG repeat length can influence the extent of disease. Can you talk a little bit about that?

Kasia Rothenberg, MD, PhD: Yes, and this is very interesting topic. In fact, we don't really fully understand how really what is happening in neuronal cell of people with this particular mutation. But we know that the gene, which later on was called Huntington gene, is located on a short arm of a chromosome 4. In fact, it's a quite large protein which is being encoded by this gene. On a five prime ending, there is kind of an interesting repeat of free nucleotide, CAG and now a mutation is in fact the situation when this triple nucleotide repeats itself. Normal gene has this tail, in fact. So normally we have like six up to 35 repeats, but if the repeats keep adding the protein, which is basically produced based on this gene becomes extremely unstable and clumps and leads to neuronal demise, leads to neurodegeneration.

Glen Stevens, DO, PhD: So, let's move into your specific area of interest. I mean obviously the chorea, people can see the chorea, but before the physical manifestations, psychiatric manifestations may present much earlier. So, let's talk a little bit about the neuropsychiatric manifestations of Huntington's disease, and when does it start, the implications of it, those types of things.

Kasia Rothenberg, MD, PhD: In fact, you know what? It starts really early. Here comes the problem that of course certain symptoms may in fact go unnoticed. I still don't think that we fully understand how disease may present early, but we know for a fact that the degeneration, which starts in the brain of patients with Huntington's disease, we noticed it mostly in certain areas, basically basal ganglia, which this type of a neurodegeneration is responsible for chorea. But we know by now through all kinds of pathological studies that the same type of degeneration happens in our frontal lobes. So immediately, even earlier than chorea, certain type of behavioral changes may occur. Behavioral, I use it rather broadly, not only sense of strictly psychiatric symptoms, but cognitive as well. So, imagine somebody with this dysfunctional frontal lobes. Sometimes people may become disinhibited. Control is different than it should be people become repetitive, obsessive, compulsive. So, there is this lack of a top down control of behavior. So yes, psychiatric and cognitive symptoms starts really early.

Glen Stevens, DO, PhD: So, things that specifically we should think about that someone may have, other than there's a genetic predisposition, but when should we be concerned that someone might have Huntington's that's just presenting with a psychiatric disorder that doesn't have a movement disorder? Or that's the secret sauce?

Kasia Rothenberg, MD, PhD: It's not easy. It's not easy because so many different things might influence people behavior. But if we have a good suspicion that the genetic mutation may play a role here, we of course look for certain changes in human behavior and we of course treat it symptomatically as early as possible. There's another aspect which influences everything, but predominantly behavior. Other psychiatric symptoms would be sleep regulation, sleep disorder. We very rarely talk about it, but the degeneration of a Huntington type happens really early in certain areas which regulate our circadian rhythm. So, it may be a good sign for us to pay attention to how people sleep, how they regulate themselves. Can they follow natural circadian rhythm or is it hard for them?

Glen Stevens, DO, PhD: So maybe it's a good thing for the sleep folks out there to be paying attention to this when they see this very disrupted pattern in young individuals with psychiatric disorder because my understanding is that suicide rate, even before diagnosis, can be quite high in these patients.

Kasia Rothenberg, MD, PhD: Correct. This is really very early observation. I believe George Huntington, himself, noticed that people with Huntington's chorea are very impulsive, compulsive and they present with a lot of self-harming behavior. Now we understand it as a combination of a two thing, being really quite disorganized in their thinking and having trouble with control regulation due to lack of executive function.

Glen Stevens, DO, PhD: And that impulse control.

Kasia Rothenberg, MD, PhD: Impulse control.

Glen Stevens, DO, PhD: So, "Hey, I don't want to continue this way." Just make the impulse and done.

Kasia Rothenberg, MD, PhD: There is an interesting, interesting thing about this self-destructive behavior, compulsive suicidality. It doesn't go really with mood because normally we think about suicidal ideation as a byproduct of depression, low mood. Not necessarily here. Many, many times we see people may present with such a behavior and their mood would be normal or unchanged.

Glen Stevens, DO, PhD: I assume, I may be wrong, but do you see increased cognitive mood, psychiatric problems with a greater number of repeats? And then do you get anticipation with generations that the grandson would have more repeats than the two generations before?

Kasia Rothenberg, MD, PhD: Yes. This is something we learned over 150 years observing people with Huntington's chorea that indeed, every consecutive generation, the symptoms tend to present earlier and they tend to be more severe. So, this is a general thing that we see when we work with people with Huntington's disease. It is related to numbers of those CAG repeats. So, the longer the tail of a protein, the more dysfunctional protein, thus the symptoms, degeneration happens much earlier and progresses faster, thus more symptoms earlier, most severe.

Glen Stevens, DO, PhD: So, it sounds like you have a very difficult job in treating the neuropsychiatric symptoms. So, what do you do for these patients? How do you approach it? What do you offer? What type of options are there?

Kasia Rothenberg, MD, PhD: It is a challenge, although there is a very interesting group of people that we put together. Let me take a step back and tell you that Huntington's organizations here in the country are very, very efficient and help us a lot. The best example of it would be that Huntington's Disease Society of Americas came up with the whole idea of creating Huntington's Centers of Excellence. They support the institutions who want to participate, but the goal is to create those interdisciplinary teams for those people. The requirement is to have a movement disorder. Neurologists, psychiatrist, social worker, all kinds of therapies available for the patients. So yes, we have a group of people, we work together, we see patients together, we take history together, we meet and discuss, compare notes. We decide not only on all the metric aspects of a patient, but as well on a therapy.

Glen Stevens, DO, PhD: Drugs that are available other than just standard psychiatric drugs. Any specific drugs for treating neuropsychiatric?

Kasia Rothenberg, MD, PhD: Unfortunately, not across the field of neurodegeneration, we don't really have specific medication to treat specific conditions. In all aspects, we have only symptomatic treatments for Huntington's disease. It may change. I hope it will change very soon. There's a lot of good development in the field of new treatments for Huntington's disease, genetic treatments. But as of today, we have two medication which are specifically approved to treat chorea or suppress, control, chorea I had better say. In terms of psychiatric and cognitive symptoms, we use medication that we have from other fields. So no, we do not have anything specific, although I believe that if we are really, really careful and prepare ourselves for treating patients with Huntington's disease and all kinds of symptoms, we can really help control symptoms.

Glen Stevens, DO, PhD: ECT have a role with.

Kasia Rothenberg, MD, PhD: Nothing that will specifically start it. Yes, it happened that in certain situations we referred people for ECT.

Glen Stevens, DO, PhD: And so, a patient comes to be seen. Do you run multidisciplinary clinics?

Kasia Rothenberg, MD, PhD: Correct.

Glen Stevens, DO, PhD: Who's involved with that?

Kasia Rothenberg, MD, PhD: It's our movement disorder neurologist. We have two psychologists. Recently, we acquired a social worker who is helping us navigating through all kinds of biopsychosocial problems because our patients eventually need a lot of help with everyday life things.

Glen Stevens, DO, PhD: There's a lot of moral questions with this disease of course and navigating the genetic landscape.

Kasia Rothenberg, MD, PhD: Correct.

Glen Stevens, DO, PhD: How do you guys deal with that?

Kasia Rothenberg, MD, PhD: Yes. This is another good question because I didn't really mention all the members of our team because we do have a genetic counselor who is working with us. So we do test people, we provide genetic testing. Now, it's a very sensitive subject. Yes, we have testing available. So people are born in families where Huntington's disease happened could be tested. Definitely we utilize testing much more for people who are symptomatic. But yes, it's a persona, private decision.

Glen Stevens, DO, PhD: So, children can be tested as well if the parent wants.

Kasia Rothenberg, MD, PhD: Yes. But it's a much, much, much longer process.

Glen Stevens, DO, PhD: Any research at all in the area of Huntington's to share with us today?

Kasia Rothenberg, MD, PhD: Yes, there is a lot of development. Once again, specifically with genetic ways of lowering the level of Huntington production, so multiple different antisense oligonucleotide studies. We here in our group, we participate in a large observational study. It's a biobank study of a name Enroll-HD, and we are part of a Huntington's study group. So, we try to develop ourselves into the center, which is being recognized as a center, which not only helps people with Huntington's disease, but is able to participate in research projects.

Glen Stevens, DO, PhD: So if anybody's out there listening that has Huntington's patients in their practice and would like to have them seen, I assume that your belief would be that this should be the type of disorder that should be managed probably at a center for excellence because of all the nuances of the neuropsychiatric.

Kasia Rothenberg, MD, PhD: I believe so. We see it happening because obviously it's a familial hereditary disease, so many of our patients come with our cousins and family members. So yes, we treat entire families, and we still gather new families, new people are coming, many. Many Huntington's patients are being treated, followed, taken care of in the community. Neurologists, community neurologists, are doing a great job. We try to help with testing. So yes, sometimes we see people, assess people predominantly for testing.

Glen Stevens, DO, PhD: And anything regarding the Huntington's population that we haven't discussed that you feel is important for our listeners to hear?

Kasia Rothenberg, MD, PhD: Let me tell you a little bit about novel things I implemented as a part what we do in Huntington's clinic. I am trying to be more sophisticated in terms of pharmacology, be mindful that basically I use medication, which is coming from other fields of psychiatry, symptomatic medication. I try to guide myself a little bit better to be more effective. The best example would be the fact that for this population, for Huntington's population, I try to do a lot of pharmacogenomics studies to guide myself by pharmacokinetics properties of patients and to be able to combine or to pick better combinations of medications for them. I do see the difference.

Glen Stevens, DO, PhD: I'm really happy to have you here today and share with our audience your thoughts and look forward to continuing to work with you.

Kasia Rothenberg, MD, PhD: Thank you very much.

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