Written By Dr. David Bushart Edited by Celeste Suart
The RISCA study will help researchers design smarter, more efficient clinical trials by teaching us about the very early stages of SCA
Ataxia research has grown significantly in recent years. Although much work still remains, we are gaining a better understanding of how ataxia affects patients. Several exciting, new therapies are currently being studied. These advances would not be possible without the involvement of ataxia patients in clinical research studies. Some clinical studies are drug trials, where patients are enrolled to help researchers determine whether new therapies are effective at treating ataxia. However, other equally important types of clinical studies also exist. Ataxia patients play a critical role in the success of these studies.
What would an ideal treatment for ataxia look like? Ideally, we would be able to treat patients when their symptoms are very mild, or perhaps even before their symptoms appear at all. However, there are several obstacles to developing and testing this kind of hypothetical treatment:
First, it can be hard to know which patients to treat if symptoms are not yet present! There are many people who descend from patients affected by SCA of some kind. They have a 50% chance of being affected. While some of these people have been genetically tested, many have not. This makes it difficult to predict whether they will eventually develop SCA at all.
Second, along those lines, it could be very difficult to predict whether a drug is working to prevent symptoms from appearing if we don’t know precisely when symptoms should appear. It is much easier to tell if a drug is working when it is given to a patient with obvious symptoms – if their symptoms improve, the drug works.
Third, it can be difficult for researchers to enroll enough patients into clinical trials to get a meaningful result. This is complicated by the fact that we don’t know the answers to the first two questions above. Until recently, it remained unclear how a trial to test such a hypothetical treatment would need to be designed.
Thankfully, recent work has helped us better understand the answers to these questions. Results from the RISCA study were recently released. RISCA, which is a prospective, longitudinal, observational cohort study, was designed to study individuals who are at-risk for developing SCA, and how SCA symptoms might first appear.
Individuals enrolled in the study were children or siblings of SCA patients who were receiving care at one of the study centers. This study was limited to children and siblings of patients with a diagnosis of SCA1, SCA2, SCA3, or SCA6. This was decision was made since together these SCAs are the most common. It would allow the researchers to enroll enough participants to make meaningful conclusions. Since this study was designed to observe how initial ataxia symptoms appear, the study was also limited to individuals who did not have ataxia symptoms at the time of enrollment. Participation was also limited to patients who fell within age ranges of when SCA symptoms typically first appear. This includes 18-50 years old for SCA1, SCA2, and SCA3, and 35-70 years old for SCA6 (which can appear later in life than the other SCAs).
This study was a collaboration between a large number of physicians and researchers in hospitals and research centers across Europe. RISCA enrolled individuals from 2008-2015, and these individuals were observed until March 2018, at which point the study ended. Overall, 302 participants were enrolled in the study, but only 252 were able to attend at least one follow-up visit. Thus, only these 252 participants could be analyzed for the study. Most of these participants were from families with a known diagnosis of SCA1 (83 individuals, or 33% of the study) or SCA2 (99, or 39%), while SCA3 (46, or 18%) and SCA6 (24, or 10%) had fewer individuals enrolled.
Researchers used SARA, the Scale for the Assessment and Rating of Ataxia, to assess participant ataxia symptoms. During the 8-year observation window, close to 50% of participants at-risk for SCA1 or SCA2 “converted” to ataxia, or began to show disease symptoms. The doctors in the study were asked to determine, based on their clinical experience, whether they though each participant showed signs that were consistent with a diagnosis of SCA. This “conversion rate” was lower for SCA3 (42%) and SCA6 (13%). But this is likely due to a small number of these participants enrolled in the study, rather than a lower rate of ataxia in those at-risk for SCA3 and SCA6.
Other important parameters were also assessed in the RISCA study. The physicians were asked to give a “confidence rating” of each patient. This means that they were asked how confident they were that a participant did or did not have SCA, simply by their clinical observations. Additionally, two coordination tasks were performed: the SCA Functional Index (SCAFI) and the Composite Cerebellar Functional Score (CCFS). Like SARA, the SCAFI and CCFS tests help determine the severity of ataxia symptoms in each participant, although each test uses different tasks to measure motor performance.
The study also used the Inventory of Non-Ataxia Signs (INAS) to assess for neurological function unrelated to ataxia in each participant. This is an important control test since other types of neurological disorders can also cause symptoms of ataxia. It was important for researchers in this study to be confident that ataxia symptoms were likely due to a diagnosis of SCA, and not a different neurological condition. Finally, a subset of patients underwent MRI analysis to determine whether specific brain regions may be affected early in SCA and could therefore serve as a way to help make a clinical diagnosis.
A main goal of the RISCA study was to determine which kinds of early symptoms might appear in these different types of SCA. This might help doctors make an earlier ataxia diagnosis in some patients. Researchers found that in participants at-risk for SCA1, the factors most associated with progression to disease were increasing age, longer CAG repeat length, and ataxia confidence rating. For SCA2, these factors included increasing age and longer CAG repeat length. For SCA3, factors included increasing age, ataxia confidence rating, and double vision. Unfortunately, analyses could not be made for SCA6 patients due to a low number of SCA6 at-risk individuals enrolled. After study enrollment, SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased. The SARA scores remained stable in the non-ataxia range for non-carriers. Changes in SCAFI and CCFS were also observed, while most of the non-ataxia (INAS) signs were not affected in these individuals.
In SCA1, SCA2, SCA3, and SCA6, longer CAG repeat length usually results in earlier disease symptoms. So, CAG repeat length can be used by researchers to predict when symptoms might be expected to first appear in patients. Interestingly, the RISCA study found that SARA scores may start to change in SCA1, SCA2, and SCA3 patients even before the predicted disease onset. This means that SARA may be a sensitive way to predict the onset of ataxia in individuals are at-risk for these SCAs.
Additionally, MRI results indicated that several brain regions may begin to change in SCA patients very early in disease. However, further research will be needed due to a small number of participants in this portion of the study. Importantly, RISCA was able to give us new information about how many participants might be required in future clinical trials designed to test preventative therapies for SCA, which was a main goal of the study.
Overall, the RISCA study has given us important information about how ataxia symptoms begin and progress in patients who are at-risk for developing SCA. This will help doctors support patients when symptoms are starting to appear. It will also help patients and family members understand what changes they should look for in the early stages of disease. RISCA, and other studies like it, provide critical information for ataxia researchers as new therapies are planned and tested.
Prospective study: Patients are enrolled in a study before the onset of a disease. In this case, patients were enrolled before the onset of ataxia symptoms.
Longitudinal study: Participants in a study are followed over a period of time, during which they are tested for the same variables over and over. In this study, patients attended at least one baseline and one follow-up visit, although some patients were followed for up to eight years.
Observational study: Researchers are not testing any type of treatment – rather, they are simply observing patients to look for specific outcomes. In this study, patients were observed for different clinical signs related to ataxia, along with other non-ataxia neurological signs.
Cohort study: Patients with a similar distinguishing feature are studied. In this study, the cohort was defined as individuals who are at-risk for developing SCA due to having a direct relative affected by SCA.
Conflict of Interest Statement
The author and editor declare no conflict of interest.
Citation of Article Reviewed
Jacobi H, Tezenas du Montcel S, et al.Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study. Lancet Neurology, 2020. 19, p. 738-747. (https://pubmed.ncbi.nlm.nih.gov/32822634/)