Impact of Spinal Muscular Atrophy on Caregivers’ Daily Activities and Health-related Quality of Life

Background Spinal muscular atrophy (SMA) is a genetic debilitating disease affecting approximately 10,000 individuals in the United States. Individuals with SMA frequently require caregiver support and care. Through a partnership with a large patient organization, we surveyed caregivers of individuals with SMA below 18 years of age to understand the impact of SMA on caregivers with respect to their daily activities and health-related quality of life (HRQoL). In addition to structured questions, a standardized HRQoL instrument, the EQ-5D-5L and visual analogue scale, were administered. Results The caregiver sample consisted of 45 unpaid caregivers of individuals with SMA. Of them, 22% reported that they were sole caregivers that received no additional caregiving support and 98% were parents of an affected individual. The majority of caregivers cared for individuals with type 2 (58%), followed by type 1 (38%) and type 3 (4%) SMA. Sixty-four percent of the individuals with SMA were able to sit without support or better, while 31% had some motor function and 5% reported no motor function. On average, caregivers reported spending 136 hours/month managing the overall treatment, care, and support for the affected individual. Most of the individuals (91%) were reported to have received nusinersen; caregivers reported spending 29 hours managing treatment in a typical month. Caregiver time investment correlated directly with disease severity measured by both SMA type and patient motor function level. On average, caregivers rated their overall health as 76 on a scale of 0-100 using the EQ-5D-5L HRQoL visual analogue scale. Specifically, 42% of caregivers reported any inability to do their usual activities and 73% reported any anxiety or depression.


Introduction 3
Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder that results in progressive muscle weakness and atrophy [1,2]. The disorder manifests due to a defect and/or deletion in the survival motor neuron 1 (SMN1) gene, resulting in low levels of the survival motor neuron (SMN) protein [1]. A second paralogous gene, SMN2, also produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the mRNA transcript. The number of copies of the SMN2 gene is inversely correlated with SMA severity in most cases [5]. As such, SMA has been a leading genetic cause of morbidity in infants and young children, with an estimated incidence of approximately as 9.4 in 100,000 live births in the US [6].
There are multiple subtypes of SMA which are categorized as types 0-4 based on clinical criteria such as age of symptom onset and achievement (or failure) of motor milestones [3,7]. Type 0 SMA is rare.
It is characterized by a decrease in fetal movement during pregnancy and severe weakness and hypotonia at birth. Patients born with type 0 SMA usually could not survive beyond the age of 6 months. Type 1 SMA is the most common and severe subtype, which has an onset between 0-6 months. Based on natural history, these patients have severe hypotonia, cannot control their head movements, and will never sit independently [1]. Patients with type 1 SMA have severe impairment of swallowing, respiratory function and survival. Patients with type 2 or type 3 SMA experience disease onset before and after the age of 18 months, respectively. Those with type 2 SMA are unable to stand or walk without support, whereas patients with type 3 SMA are able to stand and walk until the disease progresses [1]. Patients with type 4 SMA are diagnosed in adulthood and have milder muscle weakness. As SMA progresses there is general loss of motor and respiratory function resulting in increased dependence on the caregiver. Fear of disease progression and respiratory complications could also lead to profound, emotional, and psychosocial consequences on caregivers and their families [8]. More generally, parents of children with SMA have been shown to exhibit higher levels of stress than parents of otherwise healthy children [9].
Historically, SMA management was limited only to supportive care. The landscape changed in December 2016 when the United States (US) Food and Drug Administration (FDA) approved Spinraza® (nusinersen), an SMN2 targeting anti-sense oligonucleotide, as a disease-modifying therapy (DMT) for SMA. Nusinersen is administered intrathecally, with four loading doses followed by maintenance doses every 4 months [10]. Additionally, a gene therapy, Zolgensma® (onasemnogene abeparvovec-xioi ), which replaces the SMN1 gene received FDA approval in May 2019 for the treatment patients with SMA less than 2 years of age [11].
Since the advent of novel DMTs for a previously untreatable condition, the impact of the disease and disease management on caregivers may also change. Given the severity of SMA, it has previously been demonstrated there is a significant impact of caregivers' lives [12]. Studies have assessed the health-related quality of life (HRQoL) in SMA showing there is deterioration of HRQoL in SMA patients as well as their caregivers compared with the overall population [13,14]. Qian et al. surveyed the impact of SMA on patients (n = 21) and their parents (n = 64) [12]. This study found there is a considerable impact SMA has on social-emotional aspects of parents' daily living such as loss of sleep or stress from the idea of premature death.
However, to our knowledge, there is limited published data on the impact of SMA on a caregiver's HRQoL and the social implications of the disease in the US before and after the introduction of the disease modifying therapies. The aim of this study was to understand the impact of SMA on a caregiver's daily activities and HRQoL. This study provides valuable insight into caregivers' reports of overall HRQoL and potential challenges they face.

Note
Nusinersen was the only FDA approved treatment at the time this study was conducted, and as such, any treatment results described herein reflect experiences with nusinersen.

Data Source
De-identified data was directly collected from a survey with unpaid caregivers, of patients with SMA < 18 years old, who were routinely involved in the management of a patient's disease. The survey was administered electronically through an online platform and was fielded in February 2019.

Survey Design
Through partnership with a large patient organization, a survey was administered to 101 respondents 5 (56 adult patients and 45 unpaid caregivers of a patient < 18 years of age). Any patients diagnosed with type 1-4 SMA who were ≥ 18 years and unpaid (non-professional) adult caregivers who were routinely involved in the care and management of a patient with SMA (< 18 years of age) were eligible for the study. This paper summarizes the findings reported exclusively by caregivers of patients < 18 years of age as related to their HRQoL and their daily activities. Other findings from this study are reported elsewhere.
To recruit participants, a survey e-link was distributed through an email listserv and posted on the patient organization's website between January to February 2019. The survey contained 45 structured questions, divided into multiple sections collating patient and caregiver demographics, patient health history, treatment and care, and their experience with treatment. A section was dedicated to collecting information on caregiver time to infer the impact of the disease and disease management on caregivers' daily activities. Attributes such as treatment, the amount of the time that came from paid work, unpaid work, and social activities (e.g., household chores, childcare, hobbies, or lifestyle activities) was included to understand the proportion of time spent on disease management.
In addition, the EQ-5D-5L (EuroQoL-5 Dimension-5 Level) and visual analogue scale (VAS) were administered to caregivers [15]. The EQ-5D, a simple validated instrument developed by a multidisciplinary group of researchers, is commonly used to assess HRQoL in both the general population and a population with a disease [16]. The EQ-5D assesses five dimensions of health: mobility, selfcare, usual activities (e.g., work, study, housework, or leisure activities), pain/discomfort, and anxiety/depression. It is also a common tool used in health economic evaluations to calculate utility values, which capture the change of a patient or caregivers' HRQoL, as related to a treatment. In the EQ-5D-5L, each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems [17]. The respondent results are scored ranging from 0 to 1, where 0 corresponds to death and 1 corresponds to perfect health (negative value may be possible in certain instances). In addition, an EQ VAS records the patient's self-rated health on a vertical scale, with the ends labelled 'The best health you can imagine' and 'The worst health you can imagine'. The EQ VAS can be used as a quantitative measure of health outcomes that reflects the respondent's own 6 judgement. A central Institutional Review Board reviewed and approved the study.

Quality Assurance and Data Analysis
The data quality assurance and quality control included multiple steps. From a programing standpoint, skip logic was implemented to ensure caregivers were only asked relevant questions.
Similarly, range checks were included to minimize erroneous responses which were outside the valid range (e.g., an age of "136" instead of "36") and were inconsistent with previous responses. The survey was tested by multiple researchers using test links to ensure an accurate program. Further, a preliminary check of the program was conducted after approximately 10% of the sample had been recruited to ensure accuracy.
The caregiver sample was described with respect to demographics, and other characteristics of caregivers, as well as the demographics and clinical characterizes of the SMA patients less than 18 years old for whom they care. Descriptive statistics were used to characterize the study data.
Frequencies and percentages were reported for categorical variables as well as means, medians, and standard deviations for continuous variables. The number of subgroup analyses performed was minimized due to the limited sample size. The two main sub-analyses performed were by type, (type 1 vs. type 2/3), and by current motor function status (minimal motor function, sitting, and standing/walking). All analyses remain descriptive; there was no attempt to conduct a statistical testing on these data. All results were reported for the total sample. The analysis was conducted in SAS version 9.3 and R version 3.3.

Demographics of Caregivers and Patients
A total of 45 unpaid, primary caregivers with a mean age of 37 years (range 23-52) completed the survey. The caregivers were predominantly female (82%), non-Hispanic white (86.7%), and parents of children with SMA (98%) [ Table 1]. Of the respondents, 22.1% reported that they were sole caregivers that received no additional caregiving support and 77.8% reported they received additional caregiving support that was paid (46.7%) or unpaid (31.1%). The patients with SMA under the care of caregivers ranged from under 1 year to 17 years old and 51% were female. These caregivers and 7 patients were dispersed across the US.

Patient Health History
A majority of caregivers cared for patients diagnosed with type 2 (57.8%), followed by type 1 (37.8%), and type 3 (4.4%) SMA. The SMA diagnosis was established in 33.3% of patients before 6 months of age, 55.6%% of patients between 6-18 months of age, and 11.1% of patients after they were 18 months old. Of the patients with type 1 SMA, 14 (82.4%) were diagnosed before the age of 6 months and of the 26 patients with type 2, 21 (80.8%) were diagnosed between 6-18 months of age. Sixty-four percent of patients achieved sitting without support or better; 31.1% were reported to have some motor function but were unable to sit, and 4.4% reported having no motor function. reported by 56% of caregivers. Overall, treatment for type 1 SMA required a higher monthly time investment for treatment. Caregivers also reported that 14.6% (SD 25.7) of the time was taken from paid work and remaining 85.4% came from unpaid work and social activities.

SMA Impact on Caregiver's HRQoL
Caregivers also reported a mean perceived health status of 76.1 out of 100 (SD 16.97) using the EQ-5D VAS. Of the 45 respondents, 35 caregivers (77.7%) noted they did not have any concerns with mobility or self-care on the EQ-5D-5L [ Figure 2]. Seventy-three percent and 53.3% of caregivers expressed they had some level of anxiety/depression and pain/discomfort, respectively. Moreover, while 57.8% of respondents did not identify any problems with performing their usual activities, the remaining caregivers (42.2%) noted varying levels of problems with completing usual activities.

Discussion
The findings of this survey suggest that SMA has a substantial impact on caregivers' daily activities as well as their HRQoL. The vast majority of the caregivers reported their patients were receiving treatment with nusinersen. In the primary study of this survey (results reported elsewhere) the majority of these caregivers reported they were either 'very' or 'extremely satisfied' with the current DMT [18]. While caregivers valued the advancement in the treatment landscape, there continues to be a large time expenditure required in managing the treatment and care for their SMA patients. On average, caregivers reported spending nearly 17 working days, defined as 8 hours/day, each month managing the care and supporting their patient with SMA. The substantial time investment, on 10 average 29 hours per month on SMA treatment remains high. The time burden may be attributed to the time caregivers spent working with insurance providers and managing treatment related details such as driving to a treatment center and administration of the available treatment.
Importantly, this study suggests that a more severe disease status, as measured by SMA type or patient motor function, was also associated with more time spent managing patient care and lower overall HRQoL for the caregivers. Caregivers of patients with type 1 SMA spent on average 13 additional hours per month managing the care of their patients compared with caregivers of patients with type 2/3 SMA. Similarly, caregivers of patients with minimal function reported spending an average of 63 additional hours every month caregiving compared with caregivers of SMA patients who could stand or walk. Our study shows a directional trend with regard to caregiver HRQoL, patient phenotype, and motor function ability. The HRQoL score reported for caregivers of type 1 SMA patients was approximately 15 points lower than for those with type 2/3 SMA patients. The corresponding difference by motor function was 16 points and 8 points lower for caregivers of patients who had minimal/no function compared with patients who could stand and sit, respectively.
Moreover, while the overall HRQoL score for SMA caregivers was similar to the US population average, the percentage of caregivers reporting anxiety or depression was three times as high as the US population and the percentage of caregivers reporting any problem with their usual activities was more than two times the US population [19]. Furthermore, the percentage of caregivers reporting any problem with self-care was 5.5 times higher than the US population [ Figure 4] [19]. While it is difficult to establish a rationale for 8 caregivers reporting an inability to walk or perform activities of daily living, it is plausible that caregivers may have potentially misinterpreted the question or these caregivers may have a milder type of SMA themselves or that the caregiving burden prevents them from caring for themselves. The EQ-5D-5L methodology employed in this study has been utilized in other studies assessing caregiver outcomes in SMA [13]. López-Bastida et al. similarly noted a reduced HRQoL in caregivers of SMA patients from a Spanish population. A Dutch study utilizing the Caregiver Strain Index (CSI) also assessed perceived caregiver burden by mothers of SMA patients [20]. The study found 76% of mothers had a high caregiver burden, yet 77% also maintained paid employment.
It is also worth noting that a majority of respondents reported utilizing additional caregiving; this support was likely from another family member (unpaid) or a professional (paid). The need for additional support suggests our study may underestimate the impact of the disease on the family and the society. A recent health technology assessment for an SMA treatment acknowledged more than one caregiver may be involved in the care of patients, however as the HRQoL impact remains difficult to quantify for each caregiver, the final assessment only included one caregiver [21]. More research is needed in this area to better understand how the disease may affect multiple caregivers. For example, in our study only 40% of the respondents reported being employed full time, which suggests SMA may have a negative impact on caregiver productivity.
Furthermore, this study showed that despite reaching a higher educational threshold than the national average, as 56% of caregivers held an undergraduate and/or graduate degree compared with the national average of 31% in 2017 (US Census), only 40% were employed full-time [22]. Employed caregivers also reported about 15% of the time they spent caring for their patients was time spent away from paid work. Given the vast majority of caregivers in the survey were parents, the monthly time investment of 17 working days for the management and treatment of SMA may be seen as prohibitive to maintaining full time employment.
The results of this study indicate there is plausible rationale for lost productivity and absenteeism that are not formally assessed at present when therapies are evaluated for cost-effectiveness. The findings of this study are in line with other studies that have assessed caregiver burden and stress prior to the introduction of the disease modifying therapies [12, 13,20].

Limitations
This survey was distributed by an email listserv from a patient advocacy group that may limit the generalizability of these results. The survey participants may have been more engaged with the advocacy group and therefore potentially more likely to take time to inform the study with their responses. As part of the survey design, caregivers of older patients (≥ 18 years old) were not recruited for this study. Additionally, the sample size was limited to 45 caregivers and the sample may not be representative of all SMA caregivers. Furthermore, the survey was limited to how respondents felt at a single point in time. Lastly, while most of SMA patients were receiving treatment with nusinersen, due to the small sample size and relatively short duration of treatment, it is premature to assess the impact of treatment on caregiver outcomes within this study. Future longitudinal studies are needed to further understand how the impact of the disease may change as the treatment landscape evolves and patient outcome continue to improve over time.

Conclusion
This study indicates that SMA has a significant impact on caregivers' daily activities and HRQoL, leading to substantial productivity loss and indirect cost. The overall time required to care for a patient with SMA and the support for current treatment are evidence of the disease impact on families. Family spillover effects should therefore be considered as part of economic assessments for SMA treatments.  Figure 1 Average number of caregiver hours per month spent on managing care by SMA type and current motor function status, n=45

Figures
18 Figure 2 Caregiver EQ-5D-5L responses 19 Figure 3 Average Caregiver HRQoL score by SMA type and motor function status