Abstract
Background:
Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6.
Methods:
We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage.
Results:
Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation.
Conclusion:
Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.
Keywords: Deglutition, Spinocerebellar ataxia, Aspiration, Neurodegenerative disease
1. Introduction
Spinocerebellar ataxias (SCAs) are a constellation of autosomal dominant diseases associated with degeneration of the cerebellum and related brain structures [23]. Among all SCAs, SCA1, 2, 3 and 6 are the four most common subtypes, caused by an expansion of polyglutamine (polyQ)-coding dominant CAG repeats in the respective genes [23]. SCA1, 2, 3 have disease pathology in the cerebellum as well as the brainstem whereas SCA6 is primarily involved in the cerebellar cortex [22].
People living with SCAs experience progressive incoordination, loss of balance, slurred speech and ultimately severe functional decline. Among all symptoms, dysphagia is one of the most relevant clinical manifestations, [25] which can result in coughing or choking after ingestion, inadequate control of solids or liquids in the oral cavity, and food accumulation in the oropharynx [11]. Dysphagia not only com-promises the quality of life in SCA patients, but also results in one of the major leading causes of death, which is aspiration pneumonia from swallowing dysfunction [16,24]. In fact, a previous pathological study showed that aspiration pneumonia was the cause of death in 89% of patients with SCA3 [15]. Other studies also showed that dysphagia may be a predictor for prognosis in neurodegenerative diseases [26]. Even though dysphagia is an important symptom in patients with SCAs, there is a paucity of literature on the prevalence of dysphagia and its association with other clinical characteristics in different genotypes of SCAs, which is the first step towards understanding dysphagia in SCAs.
The scope of our study aims to answer three specific research questions. First, what is the prevalence of dysphagia in patients with SCA1, 2, 3 and 6? Second, what is the association between dysphagia and other clinical characteristics in SCAs? Third, in which stage of the disease does dysphagia become a prominent symptom? We capitalized on the natural history study of the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) cohort in North America to address these questions.
2. Materials and methods
2.1. Study subjects
The study has been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. A total of 237 SCA patients were recruited from 12 medical centers in the United States participating in CRC-SCA. All the participants signed consent forms approved by their respective local institutional review boards. The inclusion criteria were 1) definite genetic diagnosis of SCA1, 2, 3, or 6, either for the subject or for an affected family member with ataxia, 2) willingness of participation, and 3) age of 6 years and older. The exclusion criteria were 1) known recessive, X-linked, and mitochondrial ataxias, 2) exclusion of SCA1, 2, 3, and 6 by genetic tests, and 3) concomitant disorders that affect ataxia measurement used in this study.
After consent all participants received a detailed clinical interview and neurological examination at baseline visit, including age of onset and disease duration. All ataxia specialists were well-trained neurologists and experts in the field of ataxia and movement disorders from academic medical centers. Participants received standardized assessment of Inventory of Non-Ataxia Signs (INAS), which is a validated scale for non-ataxia symptoms of SCAs [8]. In INAS, dysphagia was one of items, and the presence of dysphagia was ascertained by ataxia specialist based on the patient report, sometimes corroborated by caregivers. While the dysphagia item in INAS was further divided into mild, moderate, and severe based on the severity; there were no objective dividing points in these categories. Therefore, we performed the analyses based on the presence or absence of dysphagia. The severity of ataxia was measured by the Scale for Assessment and Rating of Ataxia (SARA), which constitutes eight different domains of ataxia symptoms. SARA, an ataxia rating scale that has been used extensively in ataxia research, is a continuous variable (0–40), with higher numbers corresponding with more severe ataxia [19]. The cut-off value of SARA for different severities are as follows: mild, defined as SARA ≤ 10, moderate, defined as 10 < SARA <20, severe, defined as SARA ≥20 [10].
2.2. Genetic analyses
All CAG repeat numbers of the respective SCA gene were determined using multiplex polymerase chain reaction, followed by capillary electrophoresis with internal standards in Dr. Stefan Pulst's laboratory as previously described [2]. Ten percent of DNA samples were verified using Sanger sequencing.
2.3. Statistical analyses
We assessed the basic demographics of SCA patients with and without dysphagia. Chi-square was used to compare non-continuous variables. For normally distributed variables, we used the Student t-test to compare dysphagia groups with non-dysphagia groups. For non-normally distributed variables, we used the Mann–Whitney U test to compare dysphagia groups with non-dysphagia groups. Logistic regression models were employed to assess the odd ratio of having dysphagia when other covariates (gender, age of onset, disease duration and CAG repeat number) being controlled in different SCAs. A p-value less than 0.05 was considered statistically significant in these analyses. Each subtype of SCAs were considered a separate cohort in statistical analyses, other than studying the overall point prevalence of dysphagia. All analyses were performed using SPSS software (version 23).
3. Results
There were 237 SCA patients (SCA1:40; SCA2:55; SCA3:91; SCA6:51) in the current study. Among these patients, the point prevalence of dysphagia was 59.9%. When comparing to the non-dysphagia groups, the dysphagia group had on average 3-year longer disease duration (14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001) and higher ataxia severity (SARA: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). However, the dysphagia and non-dysphagia groups were not different with respect of age of onset, or gender, or CAG repeat number. (Table 1). When stratified ataxia severity into mild (SARA ≤ 10), moderate (10 < SARA <20), and severe (SARA ≥20), SCA patients had a step-wise increase in the point prevalence of dysphagia (39.4%, 63.0%, and 74.6%, respectively), indicating the dysphagia can represent a clinical manifestation in the later stage of the disease.
Table 1.
Clinical characteristics of SCA patients with and without dysphagia.
| Dysphagia | No dysphagia | p-value | |
|---|---|---|---|
| n (%) | 142 (59.9%) | 95 (40.1%) | |
| Age of onset (years) | 40.53 ± 12.57 | 41.56 ± 13.01 | 0.297 b |
| Median = 39.00 | Median = 42.00 | ||
| Sex, M: W | 68: 74 | 54: 41 | 0.176 a |
| Disease duration (years) | 14.51 ± 8.91 | 11.22 ± 7.82 | 0.0001* b |
| Median = 14.00 | Median = 9.00 | ||
| Ataxia severity (SARA score) | 17.90 ± 7.74 | 13.04 ± 7.51 | 0.000* b |
| Median = 17.25 | Median = 12.50 | ||
| Ataxia severity (SARA) | |||
| Mild (%) | 26 (39.4%) | 40 (60.6%) | |
| Moderate (%) | 63 (63.0%) | 37 (37.0%) | |
| Severe (%) | 53 (74.6%) | 18 (25.4%) |
Abbreviations: SCA = Spinocerebellar ataxia; SARA = Scale for assessment and rating of ataxia.
Mild was defined as SARA ≤10, moderate was defined as 10 < SARA <20, severe was defined as SARA ≥20.
Values represent mean ± standard deviation or number, and for variables with non-normal distribution, the median is reported as well.
p < .05
Chi-square test.
2 independent samples Mann-Whitney U test.
We next asked whether different genotypes of SCAs could have different point prevalence of dysphagia. We found that dysphagia was most common in SCA1 (70%), followed by SCA3 (62.5%), SCA6 (54.9%), and SCA2 (54.5%). In SCA1, the dysphagia group had a higher SARA scores compared to non-dysphagia group (17.43 ± 7.72 vs. 9.54 ± 7.92, p = .009). In SCA2 the dysphagia group had a longer disease duration compared with non-dysphagia group (17.03 ± 8.89 vs. 11.96 ± 6.33, p = .017). In SCA3, the dysphagia group had a higher CAG repeat number (71.84 ± 3.92 vs. 70.09 ± 4.68, p = .012), a longer disease duration (14.36 ± 8.58 vs. 10.69 ± 6.95, p = .037) and a more severe disease (18.68 ± 8.86 vs. 11.43 ± 6.81, p = .000) compared to no-dysphagia group. Interestingly, none of these factors differed in SCA6 patients with and without dysphagia (Table 2). These data suggested genotype-specific regulatory factors in dysphagia.
Table 2.
Clinical characteristics of SCA patients with and without dysphagia, stratified by genotypes.
| SCA 1 |
p-value | SCA 2 |
p-value | SCA 3 |
p-value | SCA 6 |
p-value | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
n = 40 |
n = 55 |
n = 91 |
n = 51 |
|||||||||
| Dysphagia | No dysphagia | Dysphagia | No dysphagia | Dysphagia | No dysphagia | Dysphagia | No dysphagia | |||||
| n (%) | 28 (70.0) | 12 (30.0) | 30 (54.5) | 25 (45.5) | 56 (61.5) | 35 (38.5) | 28 (54.9) | 23 (45.1) | ||||
| Age of onset (years) | 40.21 ± 10.32 | 40.08 ± 10.99 | 0.972 b | 37.03 ± 11.09 | 36.76 ± 13.48 | 0.936 b | 37.32 ± 12.18 | 39.37 ± 12.59 | 0.346 c | 51.00 ± 11.68 | 50.87 ± 9.70 | 0.965 b |
| Median = 37.00 | Median = 40.00 | |||||||||||
| Sex, M: W | 12: 16 | 7: 5 | 0.369 a | 16: 14 | 16: 9 | 0.425 a | 25: 31 | 21: 14 | 0.154 a | 15: 13 | 10: 13 | 0.473 a |
| CAG repeat (numbers) | 46.96 ± 4.00 | 45.33 ± 4.85 | 0.512 c | 39.27 ± 1.98 | 40.80 ± 4.31 | 0.111 b | 71.84 ± 3.92 | 70.09 ± 4.68 | 0.012* c | 22.32 ± 1.02 | 22.39 ± 0.89 | 0.512 c |
| Median = 47.00 | Median = 46.00 | Median = 72.00 | Median = 70.00 | Median = 22.00 | Median = 22.00 | |||||||
| Disease duration (years) | 10.79 ± 6.00 | 8.92 ± 6.56 | 0.407 b | 17.03 ± 8.89 | 11.96 ± 6.33 | 0.017* b | 14.36 ± 8.58 | 10.69 ± 6.95 | 0.037* c | 15.82 ± 10.98 | 12.43 ± 10.75 | 0.166 c |
| Median = 12.50 | Median = 9.00 | Median = 15.50 | Median = 10.00 | |||||||||
| Baseline SARA score | 17.43 ± 7.72 | 9.54 ± 7.92 | 0.009* b | 19.08 ± 6.60 | 16.09 ± 6.95 | 0.110 b | 18.68 ± 8.86 | 11.43 ± 6.81 | 0.000* c | 15.52 ± 6.12 | 14.02 ± 7.90 | 0.462 b |
| Median = 18.50 | Median = 9.00 | |||||||||||
Abbreviations: SCA = Spinocerebellar ataxia; SARA = Scale for assessment and rating of ataxia.
Values represent mean ± standard deviation or number, and for variables with non-normal distribution, the median is reported as well.
p<.05
Chi-square test.
2 independent samples t-test.
2 independent samples Mann-Whitney U test.
In a clinical setting, it is important to have an understanding of the timing to screen patients for dysphagia. Therefore, we stratified the patients into mild, moderate, and severe disease stages based on SARA scores (see Methods) and studied the point prevalence of dysphagia in each subtype of SCAs. Interestingly, we found that the occurrence of dysphagia in SCA1 increased from mild to moderate stage but remained similar in moderate to severe stage (mild: 42.9%, moderate: 86.7%, severe: 81.8%, p = .022). SCA2 patients had a trend of a stepwise increase from mild to severe stages but this did not reach statistical significance (mild: 33.3%, moderate: 50%, severe: 70.6%, p = .210). SCA3 patients, on the other hand, demonstrated a robust stepwise increase in the occurrence of dysphagia from mild to severe disease stage (mild: 38.2%, moderate: 67.9%, severe: 82.8%, p = .001). Finally, SCA6 patients had similar occurrence of dysphagia throughout the disease course (mild: 41.7%, moderate: 60%, severe: 57.1%, p = .566). (Table 3) These data suggested that dysphagia may play a different role in different subtypes of ataxia during the disease evolution.
Table 3.
Dysphagia in different SCA subtypes, stratified by ataxia severity.
| Dysphagia | SCA1 |
SCA2 |
SCA3 |
SCA6 |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mild | Moderate | Severe | p a | Mild | Moderate | Severe | p a | Mild | Moderate | Severe | p a | Mild | Moderate | Severe | p a | |
| Present (%) | 6 (42.9) | 13 (86.7) | 9 (81.8) | 0.022 | 2 (33.3) | 16 (50.0) | 12 (70.6) | 0.210 | 13 (38.2) | 19 (67.9) | 24 (82.8) | * | 5 (41.7) | 15 (60.0) | 8 (57.1) | 0.566 |
| Absent (%) | 8 (57.1) | 2 (13.3) | 2 (18.2) | 4 (66.7) | 16 (50.0) | 5 (29.4) | 21 (61.8) | 9 (32.1) | 5 (17.2) | 7 (58.3) | 10 (40.0) | 6 (42.9) | ||||
Mild was defined as SARA ≤10, moderate was defined as 10 < SARA <20, severe was defined as SARA ≥20.
p<.05
Chi-square test.
Finally, we investigated the factors that can influence the occurrence of dysphagia by constructing logistic regression models to assess the relationship between clinical and genetic factors, including age, sex, disease duration, and ataxia severity, and the presence of dysphagia. We found that dysphagia was associated with ataxia severity in SCA1 (β = 0.171, p = .014) and SCA3 (β = 0.171, p = .014), confirming that ataxia severity played a major role in the development of dysphagia. (Table 4)
Table 4.
Logistic regression for dysphagia status.
| SCA 1 |
p-value | SCA 2 |
p-value | SCA 3 |
p-value | SCA 6 |
p-value | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
n = 40 |
n = 55 |
n = 91 |
n = 51 |
|||||||||
| β | OR | β | OR | β | OR | β | OR | |||||
| Ataxia severity* | 0.171 | 1.186 | 0.042* | 0.098 | 1.103 | 0.124 | 0.094 | 1.099 | 0.020* | −0.001 | 0.999 | 0.990 |
| Sex | 1.009 | 2.742 | 0.260 | 0.528 | 1.696 | 0.404 | 0.551 | 1.735 | 0.269 | −0.366 | 0.694 | 0.535 |
| Age of onset | 0.089 | 1.093 | 0.229 | −0.056 | 0.946 | 0.239 | 0.025 | 1.026 | 0.487 | 0.018 | 1.018 | 0.616 |
| Disease duration | 0.093 | 0.911 | 0.349 | 0.060 | 1.062 | 0.281 | 0.011 | 1.011 | 0.747 | 0.019 | 1.019 | 0.587 |
| CAG repeat number | 0.344 | 1.410 | 0.095 | −0.395 | 0.674 | 0.069 | 0.126 | 1.134 | 0.233 | −0.042 | 0.958 | 0.899 |
OR = odds ratio.
p < .05
Assessed by Scale for ataxia rating and assessment (SARA).
4. Discussion
This is the first large-scale study surveying the prevalence of dysphagia in the four most common genotypes of SCAs. Our study shows that dysphagia is a common symptom among SCA1, 2, 3 and 6. In SCA1 and SCA3, Patients with dysphagia have more severe ataxia than patients without dysphagia. The association of ataxia severity and dysphagia is less robust in SCA2 and 6. Ataxia severity thus can serve as a practical guidance for clinicians to identify dysphagia and to take timely and appropriate steps to improve clinical care, particularly in patients and SCA1 and 3.
Our study found that the overall prevalence of dysphagia was 59.9%, which is similar to a prior studies on dysphagia in SCA3 (63.5%) [9]. Among SCAs, SCA1 patients have the highest prevalence of dysphagia (70%). Clinically, SCA 1 patients may more commonly have bulbar symptoms, The postmortem examination of SCA1 patient brain often demonstrated the loss of motor neurons in the brainstem [1,14,20], which may additionally contribute to dysphagia, in addition to cerebellar dysfunction [13]. Importantly, the development of dysphagia can be a negative predictor for survival in SCA1 patients [4]. Therefore, screen and recognizing dysphagia is important to care for SCA patients. A prior study of a smaller cohort (n = 34) suggests that a SARA score exceeding 15 points warrants a videofluoroscopy in the clinical routine in order to detect aspiration [17]. Our study also supports the notion that clinicians should raise awareness of dysphagia in SCA 3 when the SARA scale exceeds 10 points since the likelihood of dysphagia increases once the disease stage progresses into moderate to severe stage.
Age of onset can be an important predictor for disease progression and severity in SCAs. Early onset SCA patients usually have more severe disease phenotypes and often have a longer pathological CAG repeat size [9]. Therefore, one might expect that dysphagia is more common in early onset SCA cases. However, we did not find such association in our study, and the possibly explanations are 1) our sample size is modest to reach statistical significance 2) our cohort does not include childhood onset cases, which are more likely to have prominent disease burden, 3) dysphagia could be by other factors besides age of onset. Further detailed studies are required to answer these questions.
Swallowing is a complex physiologic function, which requires sensory input as well as sequential and coordinated activation of both voluntary and involuntary movement along the oropharyngeal-esophageal tract [18,21]. Normal swallowing ensures a safe transfer of alimentary material from the oral cavity to the stomach. Malfunction in any of the components during the swallowing process could result in malnutrition, dehydration, penetration or aspiration of food to the airway and even death [3]. The cerebellum plays an integral role in fine-tuning voluntary movement of the muscles and coordinating motor control [12]. Our study highlights the importance of the cerebellum and related brainstem structures play a role in swallowing, and further exploration of the details of dysphagia in SCAs will shed light on what aspect of swallowing is controlled by the cerebellum. Interestingly, SCA1, 2, and 3 patients nonetheless demonstrate a trend of increasing point prevalence of dysphagia as the disease becomes more severe whereas SCA6 patients have similar point prevalence of dysphagia throughout the disease course (Table 2), which might be due to the additional involvement of disease pathology in the brainstem structures in SCA1, 2, and 3. Future studies of clinic-pathological correlations will be important to answer this question.
The present study has several novelties. First, we directly compared dysphagia in SCA1, 2, 3, and 6 patients and highlighted the genotype-specific prevalence of dysphagia, Second, we assessed the association between ataxia severity and the prevalence of ataxia in a genotype-specific manner, which may inform clinicians regarding the timing to screen SCA patients of different genotypes for dysphagia. Finally, we capitalized the largest cohort of SCAs in North America and this study may serve as a basis to further develop dysphagia into an outcome measure for future SCA clinical trials.
There are several limitations to our study. First, we ascertained dysphagia by detailed history taking and physical examination, but we did not use other objective diagnostic tools such as videofluoroscopic swallow studies, which is considered the reference gold standard [5-7]. In addition, we did not assess other parameters which might be associated with dysphagia such as body mass index. Furthermore, we were not able to follow up with the patients long enough to assess the mortality among this cohort. Nonetheless, this study could serve as an initial step towards more comprehensive understanding of dysphagia in patients with cerebellar ataxia. Also, an independent quantitative scale for dysphagia which may be closely related to hospitalization and death due to aspiration can be constructed based on further research.
In summary, dysphagia is a common clinical symptom in SCAs, especially in the moderate to severe disease stage among SCA1 and SCA3. Understanding of dysphagia in SCA patients can advance the knowledge of the roles and implications of the cerebellum in regulating swallowing.
Acknowledgement
The Clinical Research Consortium-Spinocerebellar Ataxia (CRC-SCA) natural history study is supported by the Rare Disease Clinical Research Network (RC1NS068897), and the National Ataxia Foundation. Dr. Stefan Pulst is supported by National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS033123, R21NS103009, U01NS103883 and R37NS033123. Dr. Kuo is supported by the NINDS R01NS104423, R03NS114871, K08NS083738, Louis V. Gerstner Jr. Scholarship, Parkinson's Foundation, Brain Research Foundation, and International Essential Tremor Foundation.
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