Individual BOI of TSC is variable given the wide spectrum of disease manifestation in TSC (17). To evaluate the disease burden, in parallel to direct cost analysis, QoL assessment is an important outcome measure, and has increasing attention in recent years (40-42).
Novel findings on HRQoL of TSC patients
This is the first study to establish HRQoL measurements in the general Chinese TSC population, which includes both pediatric and adult subjects. Besides serving as a quantitative reference for future research and resource allocation to improve the QoL of our TSC population, it also provides an array of new perspectives regarding QoL of TSC patients.
Firstly, this is a unique study in making a direct comparison of HRQoL of TSC with DS, the latter being the most common chromosomal disease with well-known impact on HRQoL. Our findings suggested that subjects with TSC had a poorer HRQoL than those with DS. Such comparison is justified because, on a robust sample recruited through TSC patient support group, we applied the same validated health-state classification system (i.e. HUI-Ch) used in the local DS cohort recruited through its patient support group. Previous studies compared QoL of TSC patients with other illnesses such as asthma, cancer, inflammatory bowel disease and diabetes, but this study is the first study comparing QoL of TSC with another multi-organ-involved genetic disease with well-known impact on HRQoL (41).
Secondly, it is worth highlighting that the mental and physical health conditions in TSC correlated with a significantly lower HRQoL. Putting it into clinical context, we recommend physicians to identify these health conditions and take notice of their association with poorer HRQoL, so as to provide better care for these TSC patients. Our study found that physical problems, such as epilepsy and skin problems, were associated with a significantly poorer HRQoL. On the other hand, the mental problems were arguably a bigger issue to attend to. The prevalence of mental problems including ADHD, anxiety, autism, behavioral problems, learning difficulties was high, and the presence of these problems were associated with significantly lower HUI2 and/or HUI3 scores. With reference to the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study, inadequately assessed neuropsychiatric problems of TSC patients were common (43). Development of TAND checklist aimed to address the previous lack of evaluation of these problems (44). However, TAND checklist has not been applied in local clinical settings, and the prevalence of TANDs in local TSC patients was previously unknown. The findings in our study reveals the service gap in evaluating TANDs in our TSC patients and addressing the implication on their HRQoL. On top of that, our study attempts to address a research gap since the potential relationship of TAND with impaired HRQoL has been inadequately investigated in the literature. A number of studies have suggested the association between seizure, intellectual disabilities, ASD, ADHD and other neurobehavioral manifestations (45-48). However, the coexistence of seizure and various mental problems makes it difficult to determine the key factor that can independently predict an impaired HRQoL in TSC patients. The multiple regression model in this study suggested that behavioral problems and ADHD are the significant independent predictors for a deficit in HUI2 and HUI3 scores respectively. We further looked into the score decrements in individual health attributes in patients with these problems. It was found that besides their significant association with impaired cognitive functioning, ADHD was also associated with impaired speech, and having behavioral problems was associated with impaired self-care. In the background of a dearth of research on neuropsychological therapy for TSC patients, our study provides insights for future therapeutic research that might target ADHD and behavioral problems, and the associated functional impairment these problems cause, in order to improve the QoL of TSC patients (17). Local healthcare providers should take particular notes of ADHD and behavioral problems in TSC patients. When therapies are developed for these problems, our study provides essential baseline HRQoL measurement in local TSC patients for outcome evaluation.
Thirdly, we demonstrated that the TSC patients with multiple (in particular, 6 or more) physical and mental health conditions were associated with a lower HRQoL. Similar patterns were observed in the local DS population, in which a gradient relationship was found, with an increasing number of developmental behavioral problems resulting in a lower HRQoL. However, it has not been reported in previous TSC literature. Physicians should pay particular attention to patients’ HRQoL when seeing TSC patients with multiple physical and mental problems. To our knowledge, these patients might visit multiple specialty outpatient clinics locally. Now we know that multiple outpatient clinic visits in these patients raised two issues: first, it contributes to a substantial direct cost in our healthcare system; second, their QoL impairment is related to multiple physical and mental problems, and could not be addressed adequately unless by a multidisciplinary team (1). Overseas research provides guidance on setting up a TSC multidisciplinary team, and we believe such a team would benefit our TSC patients by giving a holistic care plan addressing various physical problems and individual QoL issues (49).
Strength of this study
Our study provides a robust account of HRQoL of Chinese TSC patients. HUI-Ch has been chosen because it is a validated system and allows reliable comparison between HRQoL of normal population and populations with various diseases. Informant report is shown to give more complete information than merely self-reported for TSC, as there is a wide variation in intellectual disability in TSC patients which affects their ability to self-report (21, 50, 51). Validation process was completed with direct oversight by HUI developers, and the HUI-Ch received final approval from the developers of HUI(23). Therefore, the use of HUI-Ch allows healthcare professionals to make reliable interpretations on the HRQoL of the local TSC population and comparison across various disease entities with their HUI3 scores previously reported. As exemplified in Table 6, when subgroups of our TSC cohort with certain conditions (epilepsy, autism, anxiety problems, CKD) were compared with the general population with these conditions, the HUI3 scores of individuals with TSC were generally lower. This quantitative comparison has broad implications in terms of policy making, as well as communicating and counselling with parents about the outcome of TSC. As part of our TSC patient registry, this study reflects patients’ QoL, which complements our previous TSC study that focused on the direct cost incurred by TSC patients on the healthcare system (1). Together they provide direction for better local healthcare planning towards a tailored management for local TSC patients.
Comparison with other studies on QoL of TSC population
While previous TSC QoL studies mainly focused on its correlation with drug trials, epileptic status or surgery outcome, there is a paucity of study on the QoL of TSC patients as a whole (3, 52-54). We are aware of one study in the published literature that reported on HRQoL of TSC patients using HUI scores (42). Of the 214 patients in their study, the mean HUI3 score was 0.43, which was quite similar to our findings (0.49). While their study involved TSC patients from the Netherlands only, independent findings from our results on a group of Chinese TSC patients support the generalizability of the finding that TSC patients have poorer HRQoL. Our study provides additional analysis of the overall and single-attribute HUI2 scores, besides the HUI3 scores used in their study. Since HUI2 and HUI3 systems have their own advantages, findings on HUI2 scores can provide complementary information regarding the HRQoL of TSC patients (28). Considering the health conditions correlating with a lower HUI score, our study concurs with them that the presence of CKD did not associate with a significantly lower HRQoL. In their study, TSC-associated epilepsy and the refractory status were found to correlate with HRQoL score. Our finding is in line with theirs, as the presence of epilepsy was associated with significantly lower HUI3 scores from two-sample t-test. On the other hand, their study did not take into account the mental problems in TSC patients. Our study takes another step by considering a number of mental problems TSC patients have and finding the significant indicators for HUI score decrements by multiple regression. Epilepsy and TAND are closely interrelated in pathogenesis and treatment perspective as reported in various recently developed models (45, 46, 55). While epilepsy and TAND coexist in many TSC patients, our study gives insights that ADHD and behavioral problems are the independent predictors for impairment in HRQoL. Further research is needed to look into the cause-and-effect between seizure and different neurobehavioral problems in TSC patients.
There are two recent studies conducted in Asia assessing the QoL of TSC patients in Malaysia and mainland China respectively (29, 30). We compared these two studies with our study and identified 3 distinctive differences.
First of all, both of these studies assessed TSC children aged 2 to 18 years using PedsQL. Their results may provide useful reference for managing TSC children. Whereas in our study, we included both pediatric and adult populations and this patient group is representative of all surviving TSC patients in our public healthcare system as shown in our previous study (1). Since TSC has a changing clinical course throughout lifetime, patients may experience extra HRQoL impairment as they grow into adulthood (17). Adult TSC patients had inadequate surveillance rates as reported in Chopra M. et al. This might be accounted by the difficulties they faced during transition from multidisciplinary pediatric care to the fragmented adult healthcare sectors (17, 56). They also experienced impaired work productivity, and significantly higher out-of-pocket direct cost than that of TSC incurred in pediatric patients (57). Therefore, our study would provide a more holistic view of the general TSC population and may be useful in healthcare policy making.
Secondly, different QoL assessment tools were used. PedsQL 4.0 and HUI have different psychometric properties. Existing evidence showed various strengths and limitations in these QoL tools respectively (58). The HUI2 and HUI3 measurements provided in our study can serve as an additional reference in evaluating the QoL in the TSC population.
Thirdly, the healthcare system and policy are different in all 3 studies’ settings. Notably, in our locality, mTOR inhibitors were only prescribed to a restricted proportion of patients (16.5%) (1), whilst in mainland China, mTOR inhibitors (Sirolimus) are widely available to children with TSC. mTOR inhibitors alter the disease progression in TSC by inhibiting the mTOR pathway (59), hence may bring about changes to the QoL in TSC patients. The variation in prescription patterns of mTOR inhibitors may reflect a different QoL profile. Our study provides HRQoL data in a distinct healthcare system and contributes to the diversification of QoL database of the TSC population.
Of note, epilepsy was found to be an independent predictor for poorer HRQoL in Ding Y et al’s study, which targeted children with TSC (30), but not in our study which targeted adult and pediatric TSC patients. This may be related to the proxy-reported nature of questionnaires used in evaluating QoL of children. As caregivers are easily burdened by taking care of patients with severe forms of epilepsy and the correlating neurological and psychiatric manifestations (60, 61), the perceived HRQoL of a child with epilepsy in various attributes may be lower in a parent-reported questionnaire. Previous psychometric studies in PedsQL showed disparity between child- and parent-reported QoL scores in children with neurodisability (58). Whilst caregivers for pediatric TSC patients reported seizure as one of the most bothersome concerns in Rentz AM et. al’s study (62), it is worthwhile for future studies to evaluate whether psychosocial support and referral to patient advocacy groups would be an effective solution (17). Moreover, the effect of caregiver perception on proxy-reported QoL evaluation of pediatric TSC patients remains to be further explored.
The recent publication by TOSCA Consortium Investigators reported BOI on 143 individuals from 7 European countries, ranging from 3 to 58 patients from each country, using both self- and caregiver-reported questionnaires (40). Their study evaluated BOI in a comprehensive approach, in terms of impact on education, employment status, satisfaction of medical care, QoL etc. Considering QoL measures alone, both our study and the TOSCA study demonstrated a large impact of TSC on the QoL of TSC individuals and their families. However, direct comparison cannot be made as different QoL tools were used. One of the limitations mentioned in the TOSCA study is the potential overestimation of the overall QoL of the TSC population, because their patient sample consisted of a smaller proportion of epileptic TSC patients as compared to the overall TSC cohort. Although epilepsy was not shown to be an independent predictor of poorer QoL in our study, patients with epilepsy are known to have poorer QoL from our two-sample t-test results and from the literature (42). On the contrary, the proportion of patients with seizure reported in our study was 77.8%.
The study by Sam Amin et al. also reported impaired overall QoL in TSC adult and pediatric patients (41). They suggested that QoL of TSC patients remains poor after adjusting for epilepsy and learning disability, which may be related to other comorbidities impacting their QoL and requires further study. This concurs with our suggestion that epilepsy is not an independent predictor of poorer QoL in TSC patients. Rather, ADHD and behavioral problems, which coexist in many but not all TSC patients with a history of epilepsy, are the independent predictors of poorer QoL found in our study. Another point to note is that their study compared the QoL of TSC patients evaluated on the PedsQL scale with children who suffered from asthma, diabetes, cancer and inflammatory bowel disease. However, the impact of TSC does not confine to childhood and may even worsen with age, as elaborated above. Our study does not limit to pediatric age groups, and provides additional insight by comparing the QoL of TSC patients with DS patients. This comparison is of high clinical relevance, as DS is similar to TSC – both are multisystem-involved genetic diseases requiring long-term multidisciplinary surveillance and with well-recognized long-term impact on HRQoL (23, 63).
Limitations
While interpreting the results of this study, certain caveats need to be taken into account. HUI questionnaires were distributed with the help of TSCAHK, so selection bias may exist. The selected population may be of higher activity of daily living, resulting in overestimation of HRQoL of the whole cohort. To ensure the reliability of the data collected, we compared this cohort with the cohort of all surviving TSC patients in Hong Kong as retrieved from our previous study (1). There was no statistically significant difference in terms of age, sex and epileptic status. With the use of proxy-assessed questionnaires, there was intrinsic limitation in the accuracy of HRQoL assessed, especially on the subjective domains. Nevertheless, it was shown that reliability and agreement of proxy responses to the index patients tended to be the best for close relatives (64). In our study, all proxy respondents were the close relatives of the respective index patients. Lastly, this study was observational in nature. There were limitations regarding establishing the causal relationship between the presence of Child Health Questionnaire and HRQoL.