Ataxia Series: Beyond the cerebellum - Non-motor features and multisystem care in genetic ataxias

Today we are discussing the topic beyond the cerebellum, non-motor features, and both system care in genetic ataxias. Chris, thank you for joining us.

Dr. Christopher Stephen: Hi Orlando. Thank you for having me, and it's great to see you after our [00:01:00] success in Houston at the MDS-PAS.

Prof. Orlando Barsottini: Perfect. Chris my first question, we know the motor symptoms of ataxia, but non-motor symptoms are frequently under recognized and under reported. What non-motor symptoms should patient and clinicians be aware of?

Dr. Christopher Stephen: Absolutely. I mean, It's a very important area and unsurprisingly, similar to other movement disorder like Parkinson's disease, the genetic ataxias are associated with a broad spectrum of non-motor symptoms, which can be bothersome, disabling. Significantly affect quality of life. Cognitive and neuropsychiatric symptoms are highly prevalent and these tend to occur after ataxia onset and later in the disease course.

Although there are certain ataxias such as SCA48 where this can be an early feature, that's something to watch out for. Cognitive function is commonly related to [00:02:00] the cerebellar cognitive effective syndrome in the genetic ataxias, as opposed to being based and regarding treatment, this is treated similarly to other degenerative cognitive disorders. Psychiatric disorders are also very common, either rising cerebellar cognitive affective syndrome, the CCS, or reactive to motor concerns, decline and fear for the future, which is very understandable. Indeed, depression was found to be present in 17% in a large SCA cohort, and up to 36% in Friedreich's ataxia. Psychiatric symptoms can be treated either by the patient's neurologist or general practitioner, or PCP or by psychiatry. And as always, clinicians should also query about suicidal ideation as this is a clearly preventable cause of death and should be done with care, but should be done in general. And certainly my clinical practice, I ask about suicidal ideation along with depression, anxiety, and psychosis in all of my movement disorder patients. A cornerstone of my clinical approach.

There's no specific treatment guidance for the genetic ataxias [00:03:00] other than maybe citalopram could be favored for treatment of SCA3, as there is some preclinical evidence for that. I would also say that neuroleptics should be avoided for possible, given the risk for tardive syndromes and drug induced Parkinson, which can complicate the clinical picture and also result in worsened motor symptoms.

Moving on psychosis, is relatively uncommon but can occur in certain subtypes and rarely complicates advanced disease in FA, and hence, if you're to see this in FA, and it wasn't be advanced disease in early stages of disease, then you should look for other causes, substance use and other things like that. As I discussed, antipsychotics should be at the lowest effective dose. Certainly it's easier to get away with that when treating depression or anxiety. It's harder to get away with that when you're looking at psychosis, and really I would say the ideal medication such as in Parkinson's disease should be something like quetiapine or clozapine. And while there's no data for use of pimavanserin, which is FDA approved for the treatment of [00:04:00] psychosis in Parkinson's disease, given data and other neurodegenerative disorders, that could actually be a reasonable consideration for off-label use.

Fatigue is another big one. It's also common and correlates with motor disease severity, but it's also multifactorial. And I would say that undoubtedly psych symptoms play a role in this as well. Stimulants could be considered for this as our group is actually investigating.

Sleep disorder is also frequent. And while REM sleep behavior disorder can occur in ataxias associated with Parkinsonism. The SCA3 is the most common, but can also be present in SCA2 and SCA1. As a result, you should ask about this and treat when relevant to do in terms of my approach, I tend to start with low and escalating dose of melatonin as I do in patients with Parkinson's disease and really relegate benzodiazepines to really severe disease given the inherent side effects.

So you have to put that in the back of your mind as well, and hence that's another reason it's important recommend sleep disturbances and sleep disorders in [00:05:00] the genetic ataxias. Restless leg syndrome is also particularly common in SCA3. So again, you should ask about that and treat as you would for RLS in Parkinson's disease.

Moving on to bowel and bladder symptoms, these are also common and particularly in Friedreich's ataxia where urinary symptoms can occur in a large number, perhaps up to 80% and bowel symptoms in 64%. In comparison, there was 15% of a cohort of SCAs who had lower urinary tract symptoms. Autonomic symptoms, while you may commonly associate this with conditions such as MSA, can also occur in CANVAS, so you have to bear that in mind and treat as indicated. Sexual symptoms are also commonly under-reported, and also I would say that providers and clinicians often do a not ideal job of actually asking about sexual symptoms. But they tend to be most prominent for Friedreich's ataxia and they should be queried, but with care as it can be a sensitive topic for patients. And you can use standard [00:06:00] treatments for that, including PD5 inhibitors, which can be beneficial.

Neuropathy is common in many ataxia, while neuropathic pain particularly associated with the dominant ataxias, SCA3 and SCA1, but also the recessive ataxias, Friedreich's ataxia and CANVAS.

Prof. Orlando Barsottini: Okay, perfect. Chris, you have mentioned cognitive disorders in ataxia, could you discuss a little bit more about cerebellar cognitive affected syndrome and how to identify these patients?

Dr. Christopher Stephen: Absolutely. And really the nexus of this and the where this was begun is really quite close to home because in cerebellar cognitive affective syndrome, CCS or Schmahmann syndrome has been the life's work of my colleague Dr. Jeremy Schmahmann, and it represents a constellation of both cognitive and affective deficits resulting from cerebellar pathology. Indeed the syndrome reflects the cerebellum's role beyond motor [00:07:00] coordination, and specifically its involvement in higher intellectual function through connectivity with prefrontal, parietal, and frontal temporal cortical areas. Importantly, neuro anatomically, this is associated with lesions or pathology involving the posterior lobe environments of the cerebellum and reflects the anterior sensor motor. As opposed to posterior cognitive and emotional dichotomy. While specific lobes have been linked to distinct cognitive and effective domains.

So when talking about the CCS, core features include executive functions such as planning, set shifting, verbal fluency, abstract reasoning, and working memory. Also, difficulties with spatial cognition including visual spatial organization memory and language deficits.

Neuropsychiatric symptoms can also include personality changes with blunting of affect or disinhibited and inappropriate behavior with difficulties with attentional control, emotional control, OCD spectrum, so obsessive and compulsive thoughts or actions, autism spectrum [00:08:00] or psychosis. Each of these different aspects can have a positive to an overshoot or negative undershoot aspects, which can be present and framed as the dysmetria of thought and as you can imagine, as with other cognitive psychiatric disorders, these symptoms can be very disabling and greatly contribute to morbidity.

There are also thankfully useful scales to identify the CCS, which is published by our group, including the CCS Scale, which was published in 2017 and more recently, the Cerebellar Neuropsychiatric Rating Scale or CNRS, which was published in 2025, although has been used back since perhaps 2016. And that's an observer or caregiver questionnaire. Which has been found to be very useful for detecting the neuropsychiatric symptoms associated with the CCS 

Prof. Orlando Barsottini: Okay Chris, extending beyond the central nervous system what multi-system manifestations occur in ataxia?

Dr. Christopher Stephen: Well, this is [00:09:00] another very important question. While I would say the genetic ataxias, particularly Friedreich's ataxia, are true multi-system disorders, this can be present in a number of different genetic ataxia. Where manifestations extend well beyond the central nervous system and can lead to morbidity or even mortality. As a result, recognizing these and screening for these is very important, as there may be potentially effective treatments or management strategies that can actually mitigate these systemic symptoms.

In terms of discussing these, we first have to talk about cardiac manifestations, which are unfortunately very common in and can be rarely present in early ataxia such as perhaps early onset SCA7. Refsum disease and other ultra rare disorders. And focusing on FA cardiac manifestations occur in up to 85% of patients who develop cardiomyopathy and cardiac disease, the leading cause of mortality, and up to 62% of FA deaths from either heart failure or arrhythmia. And as a result, it's vitally important [00:10:00] that Friedreich's ataxia patients should have regular cardiology follow up with at least annual screening, and also involve treatment of blood pressure, lifestyle changes, devices as appropriate, and even in perhaps select individuals consider cardiac transplantation. It's also notable that there have been encouraging preliminary reports on a gene therapy trial for cardiomyopathy and FA which is also reassuring.

Endocrine symptoms are another important multi-system involvement. Typically include diabetes, which is characteristic of FA, where it can be present in up to 30%. And understandably, this can contribute to morbidity. And there are also rare causes such as the Wolfram syndrome, whether it's also associated with diabetes insipidus. As a result, as a neurologist, caring for FA patients should make sure that they have annual hemoglobin A1C screening. If you detect diabetes, you should treat this as early as possible. In comparison, hypogonadotropic [00:11:00] hypogonadism is characteristically associated with Gordon Holmes and related syndromes and should also be treated. Musculoskeletal manifestations such as scoliosis are well known to complicate the majority of Friedreich's ataxia patients and also foot deformities such as pes cavus are common. These can be present in a minority of other genetic ataxias, but it's important that these may require surgical correction.

Visual loss also a cardinal feature in SCA7 where there is the presence of cone-rod dystrophy, but it's also common in Friedreich's ataxia where there's optic atrophy. Also present in Wolfram syndrome and mitochondrial disorder. However, sadly, there are no effective treatments at present for the visual loss associated with these genetic ataxia, but obviously there's hope for the future, and particularly treatments such as gene therapies.

Hearing loss can also frequently involve Friedreich's ataxia, and a few others. In particular, I would highlight SCA 36 and mitochondrial disorders. And this can be treated as you would with any other hearing disorder, with hearing aids, [00:12:00] amplification, and cochlear implants as indicated. In contrast, hepatic dysfunction we know is commonly associated with Wilson's disease, which can present with ataxia. Chronic diarrhea is a common manifestation of cerebral tenderness and renal failure can also occur rarely in genetic ataxias. Such as action myoclonus renal failure syndrome, which is caused by SCAB2 mutations.

Another important consideration is that there are very few genetic ataxias where there can be increased risk for malignancies, but it's very important to be aware of these if you treat these patients. Commonly you'll think of ataxia-telangiectasia and therefore, if you have a patient with AT you should limit the amount of radiation exposure they have for investigation. So for instance, use MRI where possible as opposed to CT or even conventional radiographs. And they should also be monitored closely, including for various different malignancies and treated aggressively as patients can develop lymphoma, leukemia, solid organ [00:13:00] malignancies among others. And similarly AT-like disorders caused by MRE11 variants, it can also be associated with lymphoid malignancies, while myeloid malignancies can be associated with 79 L related ataxia or SCA49, although that's a very rare disorder. I would point you to looking at these various different multi-system involvement ataxia at some excellent reviews that were produced by my colleagues, Malco Rossi and Jose Luis Pedroso, who have offered a number of these reviews and have been very useful for me over the years.

Prof. Orlando Barsottini: Okay, Chris, thank you for the complete answer. Other question, Chris, how should the multidisciplinary care for the genetic ataxia be stricter. What have you and your group at Harvard been recommending or suggesting?

Dr. Christopher Stephen: Absolutely, and this is not new for the genetic ataxia, but is present in the case of any [00:14:00] neurogenerative disorder and particularly rare and complex disorders like the genetic ataxia. What we have to remember here is that as always, the patient is at the center of any management team. And then around the patient, regarding medical management, the neurologist and ideally an ataxia specialist is required for knowledge of the disease management of ataxia and collaborates with the patient's general practitioner. Similarly, other medical specialties may be required to consult or manage systemic manifestations, as I've discussed with, for instance, cardiology follow up essential for Friedreich's ataxia. Similarly, ophthalmology should see patients with or at risk for visual loss, such as an SCA7. Or psychiatry or neuropsychiatry may be very useful to manage more severe psychiatric symptoms as well as psychotherapists and other mental health providers.

Infrequently, you may need to have surgical specialists form part of the team that may be required, for instance, in the form orthopedic surgery for complications of scoliosis in FA or other mechanical [00:15:00] deformities. I would also say that physical medicine and rehabilitation doctors can be very useful as they can help direct rehabilitation to provide important medical input in complex rehabilitation cases, which can characterize some of the genetic ataxia patients particularly later in the course.

Moving on from that, another aspect, aside from medical care, the rehabilitation specialists, which are essential for the management of ataxias are rehabilitative treatment, which I would say should be a maintenance therapy throughout the course of the disease. So not just one single course. One and done. But rehabilitation should be present throughout the disease course with periodic reappraisals and proper treatments as symptoms decline. So these include physical therapy or physiotherapy particularly to work on gaining balance, strengthening and stretching, but also occupational therapy to work on manual dexterity, activities of daily living, ADLs, IDLs and modifications of eating utensils, [00:16:00] pens, other household tools, but also speech therapy to work on dysarthria, the speech intelligibility, and also dysphagia to work on safe swallowing strategies. And also assistive and augmentative communication devices when patient's speech disorders are so severe that they're having difficulty communicating their needs and wants.

It's also important to recognize that in any genetic disorders, genetic counselors are very important members of the team as they provide genetic counseling and also family planning discussions, and they can be very important in these difficult decisions for family members and understanding the risk for the next generation and for other family members. Palliative care may also be required mainly in the setting of greater morbidity. Also, social work is very important for counseling resources and family support, and that should be either through the general practitioner or as indicated through the patient's neurologist.

And it's also important to mention community resources. Such as important patient advocacy groups, including organizations such as the National [00:17:00] Ataxia Foundation in the US or at Ataxia UK in the uk and other specific organizations that are country specific. Their services can include providing patient and caregiver support groups, meetings, connect patients and families such as the National Ataxia Foundation annual meeting. They produce understandable medical information relevant to the ataxia, and also clinical and research updates among many other services that they provide.

Prof. Orlando Barsottini: Okay, Chris, is there evidence for exercise in the treatment of ataxias?

Dr. Christopher Stephen: So yes, there is. And a bulk of this prior to more ataxia specific evidence came from other movement disorders such as Parkinson's disease, where there is growing evidence, supporting exercise and rehabilitation to slow the progression of disease. And in fact, at the moment in Parkinson's disease exercise is the only treatment been shown to slow progression disease. But also it's becoming increasingly important for the treatment of cerebellar ataxia.[00:18:00] 

Some recent randomized control trials demonstrating meaningful benefits. If you're talking about why this may be the case, potential putative explanations include leveraging neuroplasticity by performing motor tasks over and over again or buffering symptomatic worsening by the patients having greater physical conditioning and stamina. So in terms of the evidence, a multicenter clinical trial published in Neurology last year involved a cohort of 71 genetic ataxias that were assigned to either six weeks of outpatient PT, followed by a 24 week home exercise program, including balance and aerobic as opposed to their usual activity. And this revealed improved ataxia severity and functional independence, which was actually sustained in 30 weeks. Subsequently, another trial comparing at home high intensity, I stress high intensity aerobic training to balance training. Found that this high intensity aerobic training improved ataxia symptoms, fatigue and aerobic fitness more than the balance training alone. And of note, for those in [00:19:00] the aerobic group who continued to train regularly, these benefits were also maintained at one year. So this suggests that we're feasible high intensity rehabilitation, so we're talking five days a week is beneficial. However, in other ataxia, a less frequent exercise was still beneficial. So even if you can't do this high intensity exercise, which certainly may not be for everyone, and it may not be possible in some more advanced ataxia, doing less frequent exercise still yields benefits. In addition, I would also suggest to promote adherence. They should try and make exercise fun, and this could be a useful strategy.

So there is some data using video games which could be beneficial. I tend to advocate including a variety of different exercise modalities, including balance training and aerobic. And some patients have also enjoyed using a video game system to work on balance training. Which, as I mentioned, can be fun. ' cause ultimately, if you want to have someone keep to a goal of doing regular exercise, you need to make sure that it's [00:20:00] not a chore, it's not an ordeal that they're doing nothing but exercise.

Prof. Orlando Barsottini: Chris, now I would like to address a more sensitive topic. When should we consider palliative care in ataxias and how do I discuss this with the patient and their family?

Dr. Christopher Stephen: Absolutely, and I think over the years our thinking about palliative care has certainly evolved. However, this tends to be sensitive, mainly because patients do not really understand the purpose and goals of palliative care. So really palliative care should be considered early in the disease course, not just at the end of life. But earlier palliative care and advanced care planning are particularly important. It's notable for more rapidly progressive disorders, which can include Friedreich's ataxia, where patients can be wheelchair bound, in their late teens or early twenties in the classical form of disease, but especially for very rapidly progressive conditions such as the genetic acquired diseases. Where certain patients, for instance, those with genetic [00:21:00] CJD may even die with months of symptom onset. So that's a little bit of a separate case.

I'll speak more in terms of palliative care for the general genetic ataxic patient. So I would say the specific triggers to consider a palliative care referral, including intense or refractory medical or psychiatric symptoms, emotional, spiritual, or social struggles, complex goals of care, or advanced care planning needs, caregiver distress or burnout and severely diminished quality of life or function. In contrast, hospice care is really intended for those with very advanced disease, with considerable functional impairment and independence. But it doesn't mean that patients can go on and come off hospice care. But given the stigma associated with palliative care, it's important to be open frank when discussing a referral with patients and really explain what palliative care is and is not, and try to dissuade misconceptions which can actually be common because most patients would think palliative care, oh, this is end of life care. That's not what palliative care is. Hence, it's our job as a clinician to explain the goals of [00:22:00] palliative care are to maximize and focus on quality of life, which can be present at any stage of disease, and also actually any person that should be the goal to maximize and focus on quality of life and also adequately managing symptoms.

And it's also important to note that palliative care is commonly provided alongside active medical treatment, which a lot of patients and their families may not be aware of. As a clinician, you should use compassionate communication and active listening to elicit the patient's perception, preferences, emotional reactions and values. It's also important to discuss the trajectory of disease to support decision making. This discussion should also address advanced care planning and goals of care. And acknowledge the disability paradox. So the disability paradox is that patients may perceive future states as unacceptable, so such as being wheelchair bound, having difficulty with speech, things like that.

But actually when they reach that stage, they find them acceptable once this becomes a reality as they adapt to a new normal. So you have to [00:23:00] think about that as well. And I would say in my experience, palliative care has been very useful for patients and their families and as a support to the neurologist as well.

And fortunately, we have a wonderful palliative care, neuro palliative care team here at Mass General.

Prof. Orlando Barsottini: Okay. And Chris, should we discuss brain donation in ataxias, what is your opinion on this?

Dr. Christopher Stephen: So I would say yes, we should absolutely discuss brain donation on genetic ataxias. I always see brain donation as really the greatest gift that patients in the next of kin can give. And I always explain this in such terms because this is a gift of knowledge that will contribute to the better understanding ataxia and hopefully ultimately a cure at some point.

I would say that in addition to an altruistic goal of improving scientific knowledge, it's also important to acknowledge that autopsy remains a gold standard for a detailed neuropathological diagnosis. I also explicitly explain that while there is now the possibility of studying disease using patient derived stem cells, which can [00:24:00] maybe make patients think since you have all this technology, why do you need to have brain donation and study brain tissue. And while these patient-derived stem cells can be differentiated into neurons, our understanding of the biochemistry and tissue changes caused by these devastating disorders will only be achieved through the use of postmortem tissues. It is also important to remember that it may be possible to do post-mortem genetic testing from brain tissue, for instance, if it was not possible to do so during life. However, what I would say is that the main limiting factor for brain donation is really the lack of donation requests made by physicians. And indeed studies have shown that half of clinicians never approach patients about brain donation at all. Some of the reasons for not seeking consent often include, particularly discomfort broaching the subject, but also a lack of awareness of the medical and scientific benefit of post-mortems.

Sometimes organizational constraints, but also overestimation of families assume negative reactions, so thinking, oh there's no way they'll go for this, because that may not be the case. [00:25:00] Also, I would say from the patient and family perspective, if there are also barriers which we have to acknowledge, and these can include perceiving donation as intrusive or causing physical injury to the body, or viewing donation as incompatible with spiritual or religious beliefs, or concerns by the loved one being maintained as a whole. You know, this can be held by certain individuals. We also have to think of historical mistrust stemming from organ retention scandals. I would say the timing is also important if you're gonna broach the subject of brain donation, and it should ideally be discussed while the patient still has mental capacity so they can have an active role in making this kind of decision and not just prior to imminent demise. I would also say that once you bring it up, the topic should also be revisited in outpatient visits during the course of the disease. But there are several aspects to consider.

In addition, individuals with rare genetic disorders also understand the limitations of science. Brain tissue may truly be able to help scientists for the next generation, including their family members or their children. So that can be a major motivation for [00:26:00] them to be interested and consent to brain donation. Seeking consent often a process rather than the aim of one interview. And as I indicated, both the patient and the family members should be included in discussions were relevant. I also personally provide patients and the family members or next to kin with written information regarding the process upfront so they can have this documentation to mull over home. It's also important to address potential concerns in advance, such as costs, disfigurement, and religious beliefs, as I mentioned.

So costs can certainly be an issue. It's important to be upfront about this. However, certain academic center funds and patient advocacy organizations such as the National Ataxia Foundation may provide funding to cover all costs of transportation and brain autopsy. While the donor family would still be responsible for regular funeral or cremation expenses. It may also be concerned regarding religious beliefs.

However, it's notable that while most major religions support organ and tissue donation. If the patients have specific questions or concerns about their religion's position on this [00:27:00] issue, they may want to talk with a religious leader of their faith, and so certainly you should advocate that they do that because as a neurologist, you have to be the greatest advocate for your patient.

Prof. Orlando Barsottini: Okay. Thank you, Chris for sharing these insights and thank you to our listeners for joining us. We hope this episode helps you approach non-motor symptoms in genetic ataxias with greater confidence and precision. Thank you.

Dr. Christopher Stephen: Thank you so much, Orlando. [00:28:00]