|Year : 2022 | Volume
| Issue : 4 | Page : 647-653
Spinocerebellar ataxia 12 patients have better quality of life than spinocerebellar ataxia 1 and 2
Surekha Dabla1, Divyani Garg1, Rajeev Aggarwal2, Nand Kumar3, Mohammad Faruq4, Roopa Rajan1, Garima Shukla1, Vinay Goyal1, Ravindra Mohan Pandey5, Achal Kumar Srivastava1
1 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
2 Neurophysiotherapy Unit, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, India
3 Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
4 CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
5 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||02-Jul-2021|
|Date of Acceptance||19-Dec-2021|
|Date of Web Publication||06-Apr-2022|
Achal Kumar Srivastava
Room No. 60 GF, CN Centre, Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Spinocerebellar ataxia is a neurodegenerative disease. Information on comparative assessment of quality of life (QoL) among SCAs, particularly SCA 12, is scarce. We aimed to compare health-related QoL in SCA 1, 2 and 12. Methods: We conducted a cross-sectional study among individuals with genetically-confirmed SCAs. Ataxia severity was assessed using Brief Ataxia Rating Scale (BARS), independence in activities of daily living (ADL) using Katz index (Katz ADL) and depression using Beck's Depression Inventory-II (BDI-II). QoL was assessed via Short Form Health Survey version 2.0 (SF-36). Results: We enrolled 89 individuals (SCA1 = 17, SCA2 = 43, SCA12 = 29; 56% males). Mean age at onset (41.0 ± 11.6 for SCA12 versus 24.9 + 7.0 for SCA1 and 28.8 ± 9.8 years for SCA2) was significantly higher among SCA12. SCA12 had lower BARS (mean score 4.1 ± 4.5 versus 10.6 ± 4.6 for SCA1 and 12.5 ± 4.5 for SCA2). SCA12 scored better on all SF-36 subdomains including Physical (PCS) and Mental Component Summary (MCS) scores. PCS score amongst SCA12 was 44.4 ± 9.0 versus 30.4 ± 9.1 for SCA1 and 33.3 ± 8.9 for SCA2. MCS score for SCA12 was 51.4 ± 11.4 versus 41.8 ± 11.5 for SCA1 and 41.8 ± 11.2 for SCA2. SCA12 had lower mean BDI scores (5.0 ± 6.0) versus SCA1 (9.5 ± 11.6) and SCA2 (10.9 ± 10.3). BARS and BDI emerged as significant predictors of most SF-36 subdomains. Conclusions: Our study suggests that despite older age and comparable disease duration, SCA12 patients experience better QoL, less severe depression and ataxia versus SCA1 and SCA2. Severity of ataxia and depression are significant predictors of QoL among the three SCA types.
Keywords: Depression, SF-36, spinocerebellar ataxia, trinucleotide repeats
|How to cite this article:|
Dabla S, Garg D, Aggarwal R, Kumar N, Faruq M, Rajan R, Shukla G, Goyal V, Pandey RM, Srivastava AK. Spinocerebellar ataxia 12 patients have better quality of life than spinocerebellar ataxia 1 and 2. Ann Indian Acad Neurol 2022;25:647-53
|How to cite this URL:|
Dabla S, Garg D, Aggarwal R, Kumar N, Faruq M, Rajan R, Shukla G, Goyal V, Pandey RM, Srivastava AK. Spinocerebellar ataxia 12 patients have better quality of life than spinocerebellar ataxia 1 and 2. Ann Indian Acad Neurol [serial online] 2022 [cited 2022 Oct 3];25:647-53. Available from: https://www.annalsofian.org/text.asp?2022/25/4/647/342613
| Introduction|| |
Spinocerebellar ataxias (SCA) are a heterogeneous group of degenerative disorders with autosomal dominant inheritance characterized by gait ataxia, in association with diverse neuraxial involvement. More than 40 distinct genetic subtypes and 30 genes have been identified., Prevalence estimates range from 1 to 4 per 100,000 individuals, with the most prevalent forms of SCA worldwide being SCA 1, 2, 3, 6 and 17. However, the most common forms in India are SCA1, 2, 3 and 12, with the latter occurring in a specific ethnic group. SCA2 and 12 are common SCAs in India., Life expectancy in these patients may be shortened by six years up to as much as 29 years. Progression of disease limits independence and increases reliance on a caregiver for activities of daily living. The progressive nature of this condition impacts patients' health-related quality of life (HRQoL). Assessment of health related QoL in SCA patients potentially provides useful clinical information, both in terms of disease progression as well as in evaluation of response to treatment.
Comparisons among different SCA types in terms of QoL are also sparse in literature. However, despite lack of definitive treatment, QoL data is still useful in apprising authorities and clinicians of the impact of such rare diseases on the population and the patient individually. Moreover, although some information of QoL is available on patients with SCA1, 2, 3, 6 and 10, there is no study on QoL amongst SCA12 patients. In the current study, we sought to determine health-related QoL in three different types of SCAs i.e., SCA1, 2 and 12 using the generic 36-item Short Form Health Survey (SF-36). We also aimed to identify association of clinical, demographic and social factors such as age, age at disease onset, disease severity, disease duration, depression and activities of daily living on QoL amongst each of the three SCA types.
| Methods|| |
In this cross-sectional study, we enrolled consecutive genetically confirmed SCA1, 2 and 12 patients of both genders >=18 years of age from Ataxia Clinic of a tertiary centre in northern India over 1.5 years. The method for CAG repeats length estimation has been described in our previous study. The study was approved by the institutional ethics committee. Written informed consent was obtained from participants.
Patients under 18 years of age, those with concomitant co-morbidities that could influence assessment of QoL and those not willing to participate were excluded.
Clinical profiles of participants were recorded and detailed clinical examination was done. Data regarding age, gender, age at disease onset and disease duration were collected. Ataxia severity was assessed using Brief Ataxia Rating Scale (BARS). They also underwent evaluation for independence in activities of daily living using Katz index (Katz ADL) and depressive symptoms using Beck's depression inventory-II (BDI-II). QoL was assessed by completing the Short Form Health Survey version 2.0 (SF-36).
Brief Ataxia Rating Scale (BARS)
BARS is an abbreviated version of the modified International Co-operative Ataxia Rating Scale (MICARS) consisting of five subsets: Walking capacity (0-8 points), heel-shin test for decomposition of movements (0-4, scored for each side), finger-nose test for decomposition and dysmetria (0-4, scored for each side), dysarthria test for rate, rhythm and clarity of speech (0-4 points) and anomalies of ocular pursuit (0-2 points). Total score is 30 points with higher scores implying greater severity of ataxia.
Katz Index of independence in activities of daily living (Katz ADL)
Katz ADL contains six items (bathing, dressing, toileting, transferring, continence and feeding) to assess functional status as ability to perform these ADLs independently. Each is assessed on a scale of 0 (dependence) to 1 (independence). A score of 6 indicates full function and 0 indicates complete dependence in ADLs.
Beck depression inventory-II (BDI-II)
BDI-II is a 21-item questionnaire to evaluate severity of depressive symptoms. Each item is scored from 0 (no symptoms) to 3 (severe symptoms) with total scores ranging from 0-63 scale. A total score of 0 to 13 indicates minimal depression; 14 to 19 indicates mild depression; 20-28 moderate depression and 29 to 63 indicates severe depression.
Short form health survey version 2.0 (SF-36)
SF-36 is a generic health-related quality of life (HRQoL) scale containing 36 items in 8 domains: Physical function (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social function (SF), role emotion (RE) and mental health (MH). For each subscale, items are coded, summed and transformed into a scale ranging from 0 (worst HRQoL) to 100 (best HRQoL) using a software provided by Optum® outcomes. SF-36 also provides two summary scores: Physical Component Summary score (PCS) and Mental Component Summary score (MCS). PCS represents a combination of PF, RP, BP and GH subscales while MCS represents a combination of VT, SF, RE and MH subscales. Scores are norm based (Mean = 50, SD = 10).
Data were recorded on a predesigned proforma and managed on MS Excel spreadsheet. Categorical variables were summarised as frequency and percentage. Continuous variables were summarised as mean ± standard deviation. Chi Square test was used to compare categorical variables amongst the three groups. Demographic characteristics, clinical parameters, SF-36 scores and disease severity scores were compared among SCA1, SCA2 and SCA12 groups using One-way analysis of variance followed by Bonferroni correction in P value for post-hoc comparisons if required. Correlations between patient characteristics and health related QoL parameters (SF-36) were calculated using Pearson correlation coefficient. Analysis of covariance was used to estimate marginal mean scores (standard error) adjusted for age, gender, age at disease onset and depression (0-100 scale; low score represents poor QoL). Stepwise multiple linear regression, with probability to enter as 0.05 and probability to remove as 0.01, was used to determine independent relationship of various patient characteristics with quality of life subscales in each of the three types. Statistical analysis was performed using Stata 14.0 statistical software. In this study, P value of < 0.05 was considered as statistically significant.
| Results|| |
The study included 89 patients with SCA (SCA1 = 17, SCA2 = 43, SCA12 = 29) as shown in [Table 1]. Males constituted 56% of our participants. The mean age at enrolment ± SD was 29.7 ± 7.5 years, 34.3 ± 10.7 years and 45.7 + 12.3 years for SCA1, SCA2 and SCA12 respectively. SCA12 patients were significantly older than SCA1 and SCA2 patients at presentation (p < 0.05). Mean age at onset ± SD was higher for SCA12 patients, being 41.0 + 11.6 years compared to 24.9 + 7.0 years for SCA1 (p < 0.05) and 28.8 ± 9.8 years for SCA2 patients (p < 0.05). SCA2 patients had longer duration of disease at presentation (5.4 ± 2.8 years) than SCA1 (4.4 ± 2.6 years) and SCA12 (4.0 ± 2.3 years) although the difference was statistically not significant. Patients with SCA12 had significantly lower mean scores (5.0 ± 6.0) on BDI compared to SCA1 who had a score of 9.5 ± 11.6 (p < 0.05) and SCA2 who had a score of 10.9 + 10.3 (p < 0.05). SCA12 patients also scored significantly lower on the BARS with mean score being 4.1 ± 4.5 compared to 10.6 ± 4.6 for SCA1 (p < 0.05) and 12.5 + 4.5 for SCA2 patients (p < 0.05). There was no difference in the three subgroups in Katz ADL score.
|Table 1: Comparison of various patient characteristics amongst three SCA types|
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In the QoL domains, patients with SCA12 had significantly higher mean scores, representing better QoL, in nearly all domains compared to patients with SCA1 and SCA2 including overall Physical Component Summary score (physical functioning, role-physical and general health) and Mental Component Summary score (social functioning and role-emotional) [Table 2]. PCS score amongst SCA12 patients was 44.4 ± 9.0 compared to 30.4 ± 9.1 for SCA1 (p < 0.05) and 33.3 ± 8.9 for SCA2 (p < 0.05). MCS score among SCA12 patients was 51.4 ± 11.4 compared to 41.8 ± 11.5 for SCA1 (p < 0.05) and 41.8 ± 11.2 for SCA2 (p < 0.05). Bodily pain, vitality and mental health domains were statistically comparable amongst the three SCA subgroups.
|Table 2: Comparison of quality of life (QoL) subscales (mean + SE) amongst SCA types|
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Correlation among various patient characteristics and SF-36 domains is shown in [Table 3]. Age correlated negatively with physical functioning among SCA1 patients and social functioning and role emotional among SCA2 patients. Age at onset correlated negatively with social functioning and role emotional domains for SCA2 alone. Age at onset did not show any correlation with SF-36 domains in SCA1 and SCA12 patients. Disease duration did not show any correlation with SF-36 domains in SCA1 patients. Disease duration showed negative correlation with physical functioning, role physical, general health domains and physical combined score in SCA2 patients. All domains except role physical showed negative correlation with disease duration in SCA12 patients. CAG repeat length did not show any correlation with SF-36 domains and summary scores in any of the three SCA types.
|Table 3: Correlation coefficients between different variables and Health related QOL and patient characteristics (Using SF36)|
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In ADL score, positive correlation was found in several domains (PF, GH, VT, SF, MH and MCS) for SCA12 patients and in vitality, mental health and MCS in SCA2 patients but no correlation was noted in SCA1. BDI scores demonstrated significant negative correlation with all SF-36 domains in SCA2 patients and for most domains (GH, VT, SF, MH and MCS) in SCA12 patients but no correlation was found in SCA1.
BARS had highest degree of negative correlation with most SF-36 domains and summary scores in SCA12 patients. Except bodily pain and mental health in SCA1 and several domains (RP, BP, GH, SF, MH and PCS) in SCA2 patients, all other domains correlated negatively.
[Table 4] shows results of multiple linear regression analysis and it demonstrates independent significant association of various factors (age, age at onset, disease duration, ADL, BDI, BARS and CAG repeats) with QoL subscales including component scores as dependent variables. BARS showed significant negative association with nearly all domains of SF-36 for the three SCA types, particularly for SCA12 in which association was demonstrable with all QoL domains. Similarly, BDI showed significant negative association with nearly all QoL domains, and this association was strongly seen for SCA2 in which all QoL domains associated with BDI. A strong positive association was also seen with ADL for several domains (bodily pain, social functioning, vitality, mental health, MCS) for SCA12 patients. Age, age at onset and disease duration also showed significant association with QoL subscales but to a lesser extent than BARS, BDI and ADL. CAG repeats had significant negative association with general health, mental health and MCS only for SCA1 patients. For QoL domains and component scores, the coefficient of determination ranged from 32 to 92% explaining substantial variation in the QoL subscales.
|Table 4: Association of factors with QoL Subscales: Results of multivariate linear regression analysis|
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| Discussion|| |
We report HR-QoL among three common SCAs in India (SCA1, 2 and 12) using the SF-36 questionnaire. In our study, patients with SCA12 were significantly older at disease onset than SCA1 and SCA2. Older age at disease onset has been previously described for SCA12. In our previous description of 5 Indian families, mean age at disease onset was 37.2 (range 26-50) years. In another cohort of 21 patients with genetically confirmed SCA12 from eastern India, mean age at onset was even higher (51.33 ± 8.98 years). Negative correlation between age at onset and length of pathological polyglutamine repeats has been definitively demonstrated, although there is substantial variability in age at onset in SCAs as such. However, length of pathological repeats may only contribute 50 to 90% variability in age of onset and there may be other reasons in SCA12 as well.,, This is also supported by our previous study demonstrating that intermediate length pathogenic repeats did not clearly correlate with age of onset, suggesting that other contributory factors exist.
We observed less severe ataxia amongst SCA12 than SCA1 and SCA2 patients. SCA12 patients have a known propensity to present with action tremors of limbs, tremulous speech and head tremors preceding ataxia., The mean ICARS score presented for SCA12 patients by Choudhary et al. was 41.2 + 13.8 suggesting stage 2 (of 3) of ataxia. Higher severity of ataxia in this study could be due to much longer disease duration of 9.24 ± 5.1 years among their SCA12 cohort compared to ours.
In our study, all three SCA types exhibited no/mild depression, with SCA12 patients aggregating significantly lower scores compared to SCA1 and 2. Depression prevails in up to 17-26% of SCA patients (including SCA1, 2, 3, 6) and up to 33% of SCA12 patients. Depression is likely associated with the neurodegenerative process in SCAs. In a previous study, depressive symptoms correlated with severity of ataxia., However, depression may not be singularly attributable to motor dysfunction. Patients with greater ataxia severity (e.g. SCA1) may have lower depression compared to less ataxic types such as SCA3. Additionally, while ataxia severity worsens, depression scores remain static up to two years. Depression has been determined to correlate with poor functional status and QoL in patients with SCA1, 3 and 6 apart from ataxia progression. Lower scores on BDI-II in our SCA12 patients were also consistent with generally lower scores on BARS.
Although our SCA patients exhibited low scores on BDI-II scale with mean scores lying within normal cut-off, we did not compare these with healthy controls. Similar to our study, overall mean scores in minimal to mild range of severity were observed in patients with Friedreich ataxia in whom depression was assessed using Beck Depression Inventory (BDI). However, these mean scores displayed significantly higher values compared to the general population.
Among SCA1 patients, only age at presentation and ataxia severity correlated with few QoL domains. Despite SCA1 patients having lowest mean age at presentation in our cohort, we found that age correlated with QoL. This is likely to be due to the severity of SCA1, which shows faster progression compared to 2, 3 and 6.
Among SCA2 patients, we found that disease duration correlated with several QoL domains which mainly defined the PCS. This is probably due to progressive severity of ataxia among SCA2 patients, also evidenced by their high BARS scores. ADL score impacted mainly MCS components, suggesting that functional dependence influences mental aspects of QoL. Disease duration has been previously reported to correlate with greater disease severity, balance problems, and increased functional dependence among SCA2 patients. Depression affected QoL domains among SCA2 in a broad manner in our study. Although depression severity has not been differentially reported to be higher in SCA2, we found a higher proportion among SCA2 compared to SCA1.,
Interestingly, despite older age at onset among SCA12 patients, this did not impact QoL domains whereas duration of disease did, suggesting that despite later disease onset, its progressive nature does influence QoL. Age less than 34 years is associated with higher scores in vitality and social functioning domains on SF-36 in a previous study among SCA patients. Depression and ataxia severity emerged as significant predictors of QoL domains amongst SCA12 patients despite relatively low mean scores; Hence, even mild depression and ataxia significantly influence QoL.
In our study, Katz ADL score and ataxia severity dominantly accounted for the variance in QoL amongst SCA12 patients. This suggests that functional independence is a dominant contributor towards better QoL in SCA12. Depression, although consistently noted, had lower impact on PCS or MCS scores. BDI contributed strongly to QoL. Hence, patients' perception of QoL is only partially influenced by disease-related physical impairment, but also other factors such as depression, which therefore, must be carefully sought and treated.
There are a few longitudinal and cross-sectional studies among SCA patients which have observed that they perceive poor health as a result of depression, pain and functional impairment, and visual abnormalities.,,,,,, In a large European multicentric study of 526 SCA patients that used Euro-Quality of 5 Dimensions (EQ-5D) to assess QoL, no difference in rating was found between SCA1, 2, 3 and 6 except more frequent pain among SCA3 patients. Unlike the above and other studies, we have employed SF-36 as a tool to measure QoL. SF-36 has been used in one other study amongst SCA patients. In a cross-sectional Spanish study which used the SF-36 in 80 patients with SCA, SF-36 scores correlated with both disease duration and disease severity. In a study from India, among 41 SCA patients of types 1, 2 and 3, mean global score for WHO-QOL (0-100 scale) was 50.3 ± 12.8, although this study did not assess determinants of QoL.
The novelty of our study is that it assesses QoL and its determinants among SCA12 patients in comparison to SCA1 and 2. Our report includes patients who had mild to moderate disease, both in terms of ataxia severity as well as mean disease duration. Despite this, there was significant impairment in QoL although SCA12 patients fared relatively better. We did not evaluate the presence of other movement disorders or non-cerebellar features except depression. A detailed neuropsychiatric profile was not performed including suicidal ideation which is reportedly increased among SCA patients.
We acknowledge that a comparison among different SCAs is limited by inability to select a comparable disease stage since rates of progression differ. As such, a longitudinal study with a larger cohort will be additionally informative, especially as our sample size is small. Since this is a cross-sectional study, it does not explore evolution of QoL with disease progression and whether these predictive determinants continue to play contributory roles. Additionally, poor QoL is not entirely explained by the factors that we have studied, and socio-demographic factors need to be assessed to more comprehensively explain poor QoL in SCA patients.
| Conclusions|| |
Our study reports that patients with SCA12 experienced better QoL compared to SCA1 and SCA2 patients at similar disease duration despite being significantly older. SCA12 patients showed less severe depression and ataxia than SCA1 and 2. The severity of ataxia and depression emerged as significant predictors of QoL amongst all three SCA types. Longitudinal QoL outcomes in these patients, relative to other SCA types, must be determined in future studies to see if this relative QoL advantage amongst SCA12 patients persists, or gets eclipsed with time.
We thank Dana Kopec Administrator, QualityMetric Incorporated, now part of OptumInsight for providing us the license (QualityMetric CT135696) to use SF-36v2 with certified scoring software 4.0™ on our request.
Permission to use Beck Depression Inventory (BDI II) was obtained from Pearson India Education Services Private Limited.
Ethical compliance statement
The study was approved by the Ethics committee, All India Institute of Medical Sciences, New Delhi (IESC/T-209/2010).
Written informed consent was obtained from all study participants.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]