Impact of Nusinersen on the Health-Related Quality of Life and Caregiver Burden in Patients with Spinal Muscular Atrophy with Symptom Onset before the Age of 6 Months

Article information

Ann Child Neurol. 2025;33(2):39-47

Publication date (electronic) : 2025 March 14

doi : https://doi.org/10.26815/acn.2024.00668

Yun Jeong Lee, MD¹, Hyunwoo Bae, MD², Young Kyu Shim, MD³, Jae So Cho, MSc⁴, Jong Hee Chae, MD^,5,6, Soonhak Kwon, MD^,2

¹Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

²Department of Pediatrics, Kyungpook National University Children’s Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

³Department of Pediatrics, Korea University Ansan Hospital, Seoul, Korea

⁴Department of Pediatrics, Seoul National University Bundang Hospital, Seoul, Korea

⁵Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea

⁶Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea

Corresponding authors: Soonhak Kwon, MD Department of Pediatrics, Kyungpook National University Children’s Hospital, School of Medicine, Kyungpook National University, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea Tel: +82-53-200-5704, Fax: +82-53-425-6683, E-mail: shkwon@knu.ac.kr

Jong Hee Chae, MD Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-3622, Fax: +82-2-743-3455, E-mail: chaeped1@snu.ac.kr

Received 2024 July 13; Revised 2024 November 30; Accepted 2024 December 21.

Abstract

Introduction

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord [1]. It is most commonly caused by a homozygous deletion in the survival motor neuron 1 (SMN1) gene on chromosome 5q13, which results in reduced levels of survival motor neuron (SMN) protein [1]. Humans have a similar gene, SMN2, that also produces the SMN protein. However, due to alternative splicing that excludes exon 7, the SMN2 gene generates a less functional version of the SMN protein. The number of SMN2 copies is strongly correlated with the severity of SMA; more copies can partially compensate for the loss of functional SMN protein, thus influencing the clinical manifestations of the disease [2].

The most common symptoms of SMA are bilateral symmetrical weakness and progressive muscle atrophy, predominantly affecting the lower limbs. SMA is classified into four clinical subtypes based on the age at onset and the severity of symptoms. These range from the most severe, type 1 (infantile-onset), to the least severe, type 4 (adult-onset) [1]. Approximately 50% of infants with SMA present with type 1, characterized by symptom onset at or before 6 months of age and a median life expectancy of less than 2 years without respiratory support [3].

Living with SMA poses significant challenges for patients, their families, and caregivers, stemming from restricted motor, bulbar, and respiratory functions. This condition leads to a reduced quality of life (QoL) for both patients and their caregivers [4,5]. Additionally, parents caring for children with SMA experience considerable burdens related to time, finances, and psychosocial activities [5,6].

Recent advances in SMA treatment, including antisense oligonucleotides [7,8], small molecules [9], and gene therapy [10], have paved the way for changes in the disease trajectory. Nusinersen, an antisense oligonucleotide, modifies the splicing of the SMN2 gene to increase the expression of the full-length SMN protein. This has led to improved motor function and increased survival in SMA patients across various levels of disease severity [7-9]. However, there is a lack of studies focusing on the perspectives of children and caregivers regarding the impact of disease-modifying therapies for SMA on their daily lives [10-15]. Changes in health-related quality of life (HRQoL), activities of daily living, levels of independence, and caregiver burden in response to these interventions need to be addressed. Additionally, the number of validated patient-reported outcome measures for the SMA population is limited [16]. Furthermore, measuring QoL in very young infants with SMA is particularly challenging, as they cannot directly complete an HRQoL instrument. In such cases, proxy reports by parents are necessary.

This study aimed to evaluate the impact of nusinersen treatment on HRQoL and functional performance in patients with infantile-onset SMA and the caregiver burdens reported by their caregivers over time.

Materials and Methods

Results

1. Motor function

This study included eight patients with SMA and their caregivers. The median age at symptom onset was 2.5 months (range, 0.25 to 6.00), and the median age at the initiation of nusinersen treatment was 4.6 months (range, 1.1 to 15.1). The median baseline scores for CHOP INTEND and HINE-2 were 12 (range, 4 to 31) and 1.0 (range, 0 to 6), respectively. Patients received a median of eight nusinersen doses (range, 6 to 15). Seven patients completed the third maintenance dosing assessment. Prior to treatment initiation, ventilator and tube feeding support was necessary for three patients. Detailed baseline characteristics of each patient are presented in Table 1. Notably, both CHOP INTEND and HINE-2 scores showed significant increases from baseline at the time of the third maintenance dosing in all eight patients with SMA type 1. The CHOP INTEND score increased to 26.81±3.97 (mean±standard deviation; P<0.001), and the HINE-2 score improved to 8.82±1.33 (P<0.001) (Fig. 1). During treatment, no additional ventilator or tube feeding support was required by any of the patients.

Table 1.

Baseline characteristics of patients with SMA type 1

Fig. 1.

Changes in (A) Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and (B) Hammersmith Infant Neuromuscular Examination section 2 motor milestones (HINE-2) scores over time. SMA, spinal muscular atrophy.

2. PedsQL Infant Scales and PEDI-CAT analyses

Since the PedsQL Infant Scale is only applicable to patients under 24 months of age, we excluded one patient who began treatment at 15.1 months and was evaluated at 3 years of age from the PedsQL Infant Scale analysis. For the remaining seven caregivers, the mean baseline PedsQL Infant Scale scores were as follows: 61.91±5.19 for physical functioning, 72.30±1.66 for physical symptoms, 73.07±5.68 for emotional functioning, 100.46±1.60 for social functioning, and 67.89±8.89 for cognitive functioning subscales, with an average total score of 73.13±3.43. We observed a significant decline over time in all scales of the PedsQL Infant Scale, including the total scores (Fig. 2). The PEDI-CAT was assessed by eight caregivers, with baseline mean scores of 32.02±0.70 for daily activity, 33.7±0.91 for social-cognitive, and 28.23±1.11 for mobility domains. All domains demonstrated significant improvement over time (P<0.001 for all domains) (Fig. 3).

Fig. 2.

Changes in Pediatric Quality of Life Inventory (PedsQL) Infant Scales over time. (A) Physical functioning, (B) physical symptoms, (C) total score, (D) emotional functioning, (E) social functioning, and (F) cognitive functioning. L, loading dose; M, maintenance dose.

Fig. 3.

Changes in Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) over time. (A) Daily activity, (B) social-cognitive, and (C) mobility. L, loading dose; M, maintenance dose.

3. Caregiver burden

ACEND assessments conducted with the eight caregivers generally revealed low mean scores across all seven domains, with the lowest scores observed in the transfer domain. During the treatment, there was a statistically significant reduction in the burden associated with feeding, grooming, dressing, sitting, play, transfers, mobility, emotional aspects, and finances (P<0.001 for all domains). However, the burden related to time did not change from baseline, as demonstrated in Fig. 4 (P=0.731).

Fig. 4.

Changes in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) over time. (A) Feeding/grooming/dressing, (B) sitting/play, (C) transfer, (D) mobility, (E) time, (F) emotion, and (G) finance. L, loading dose; M, maintenance dose.

4. Correlation between motor function and PEDI-CAT and ACEND scores

In the context of PEDI-CAT results, CHOP INTEND scores showed moderate positive correlations with daily activities (r=0.545, P=0.003) and social-cognitive domains (r=0.692, P<0.001) and a strong positive correlation with the mobility domain (r=0.767, P<0.001) (Table 2). Additionally, daily activities (r=0.787, P<0.001), mobility (r=0.857, P<0.001), and social-cognitive domains (r=0.799, P<0.001) displayed strong positive correlations with HINE-2 scores. CHOP INTEND scores were moderately associated with a reduced burden in sitting/play (r=0.612, P<0.001) and transfer (r=0.610, P<0.001) in the correlation analysis with ACEND. Similarly, HINE-2 scores showed a moderate positive correlation with a reduced burden in sitting/play (r=0.612, P<0.001) and mobility (r=0.588, P<0.001) and a strong correlation with a reduced burden in feeding/grooming/dressing (r=0.750, P<0.001) and transfer (r=0.798, P<0.001).

Table 2.

Correlations between PEDI-CAT, ACEND, and motor function assessments

Discussion

Our study evaluated HRQoL, functional performance, and caregiver burden in infants with SMA, utilizing a variety of patient-reported outcome measures to track changes in these areas during nusinersen treatment. Our findings indicate that the baseline total scores and subscores on the PedsQL Infant Scale, except for the social functioning score, were lower than those reported for healthy controls in previous studies, which ranged between 76.6 and 89.6 [22]. Despite significant improvements in motor outcomes, there was a decline in both the total score and all subscores of the PedsQL Infant Scale during treatment. The PedsQL Infant Scales have been employed in numerous studies to assess HRQoL in chronically ill infants with conditions such as kaposiform hemangioendothelioma, chronic liver disease, and Kawasaki disease [22-25]. Unlike prior studies that compared the HRQoL of ill infants with that of healthy controls, our research focused on the impact of treatment intervention on patients with SMA, specifically examining changes in PedsQL Infant Scale scores. The reasons for the apparent lack of a positive impact of nusinersen on HRQoL in infants with SMA remain uncertain. Our findings suggest that considerable caregiver anxiety, despite improvements in motor function, and potential bias in proxy responses may contribute to this discrepancy. Caregivers often struggle to objectively evaluate their child’s HRQoL, possibly conflating their perceptions with personal emotions [26]. Additionally, our results may have been influenced by parents’ elevated expectations regarding the new treatment’s potential to enhance motor functions to levels comparable to those in healthy infants. This may lead to their dissatisfaction or disappointment with the therapy, which in turn could affect their perceptions of the patients’ HRQoL.

Some studies have suggested a lack of correlation between QoL and functional status in children or adolescents with SMA [27,28]. Despite the deterioration of motor function in SMA types 2 and 3, PedsQL scores have remained stable [27]. Another study indicated that self-reported QoL was higher among patients with SMA type 2 than among those with SMA type 3, even though motor function assessment scores were higher in the SMA type 3 group [28].

The PedsQL Generic Core Scale or Neuromuscular Module, which is commonly used in research on SMA, has demonstrated reliability and validity in pediatric patients with SMA [29,30]. However, there has been limited research on HRQoL using the PedsQL in patients with SMA who are undergoing nusinersen treatment. Notably, a trial involving presymptomatic SMA patients found their PedsQL scores to be comparable to those of healthy controls [15], and children with later-onset SMA who were treated with nusinersen showed a lesser decline in scores on both the PedsQL Generic Core Scale and Neuromuscular Module at 15 months compared to sham controls [10].

The PedsQL Infant Scales are a multidimensional instrument designed to maintain construct consistency across various ages, including items that correspond to the PedsQL Generic Core Scales for ages 2 to 18 years. This tool measures physical, emotional, social, and school/cognitive functioning, allowing for the tracking of generic HRQoL from age 1 month to 18 years across different age groups. However, there is a lack of studies validating the consistency of item measurement in the PedsQL Infant Scale, especially in patients with SMA under 2 years old. SMA manifests at various ages and can vary in type and severity. Although the PedsQL is commonly used in SMA patients, it may not be sensitive enough to fully capture the impact of SMA on QoL. This observation is supported by our previous study, which showed no improvement in the physical health score of the PedsQL Generic Core Scale or in the ‘About My Neuromuscular Disease’ score of the PedsQL Neuromuscular Module for later-onset SMA, despite improvements in motor function assessments [31]. In contrast, for infant-onset SMA, the emotional, social, and school functioning scores on the proxy-reported PedsQL Generic Core Scale showed improvement in the later-onset SMA population [31]. Future research should focus on the ability of PedsQL to detect treatment-related changes or disease progression in SMA, as well as on developing SMA-specific measurement tools [32].

Regarding functional performance, as evaluated using the PEDI-CAT, nusinersen treatment has shown positive impacts across various domains, including daily activities, social-cognitive functions, and mobility. The PEDI-CAT has been validated in SMA groups and has identified differences in functional skills across various types and age groups. However, the mobility and daily activity domains exhibited a floor effect in type I SMA groups [19,33]. The PEDI-CAT offers the potential advantage of a large item bank that encompasses a wide range of ages and abilities. This feature may enhance its ability to detect subtle changes in functional abilities compared to the physical functioning scales used in the PedsQL Infant Scales. This could account for the differing results observed between the PedsQL Infant Scale and the PEDI-CAT.

In contrast to the positive impact observed in the mobility and daily activity domains for patients with infantile-onset SMA, our previous study evaluating PEDI-CAT outcomes in later-onset SMA patients receiving nusinersen treatment did not show meaningful improvements in these areas [31]. These findings suggest that nusinersen treatment has a more pronounced effect on daily activities and mobility in patients with infantile-onset SMA than in those with later-onset SMA. This conclusion is supported by the significant positive correlations between CHOP INTEND and HINE-2 scores and the PEDI-CAT scores in type 1 SMA patients.

Our study observed a significant reduction in caregiver burden across all aspects except for time burden during nusinersen treatment, consistent with previous research that reported a decreased physical impact burden in presymptomatic SMA patients following nusinersen treatment [15]. Additionally, our results showed that reductions in physical impact burden, particularly in activities like sitting/play and transfers, were positively correlated with improvements in motor function, as measured by CHOP INTEND and HINE-2 scores. Therefore, nusinersen treatment can lead to motor function improvements, which in turn, decrease caregiver burden. However, the time burden remained unchanged, as caregivers still had to allocate time for intrathecal injection appointments every 4 months. This finding aligns with another study where caregivers of pediatric patients expressed dissatisfaction due to the time demands associated with treatment and medication administration [34].

This study has several limitations. First, it was conducted with a relatively small sample size, which hindered the performance of subgroup analyses based on patient characteristics such as SMN2 copy number, ventilator support, and orthopedic complications. Second, the inability to measure patient-reported outcomes prior to treatment in some caregivers may limit the generalizability of our findings. Lastly, we were unable to examine baseline demographic factors, such as socioeconomic status, presence of siblings, and place of residence, which could potentially influence HRQoL and caregiver burden.

In conclusion, nusinersen positively affects the functional performance of infants with SMA and reduces the burden on their caregivers. However, the HRQoL as perceived by the caregivers declined over time. The improvement in motor function due to nusinersen primarily reflects changes in functional performance and caregiver burden rather than overall QoL measures. With the emergence of new phenotypes resulting from novel disease-modifying therapies, it is crucial to develop an SMA-specific HRQoL tool that encompasses a wide age range. Such tools would more accurately capture therapeutic responses that are not reflected by traditional motor functional assessments.

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