Analysis on Health-related Quality of Life of 180 Chinese Patients with Sporadic Creutzfeldt-Jakob Disease

Aims Sporadic Creutzfeldt-Jakob disease (sCJD) heavily affects the patient’s motor, cognitive, and psychological functions with 100% fatality rate. Yet, there are few studies focusing on the impact of sCJD on the health-related quality of life (HRQoL) of the patients with validated instrument. We examined physical and mental conditions of those sCJD patients in China for the rst time. Methods With EQ-5D-3L instrument, a telephone-based cross-sectional study was conducted in order to obtain health statuses of 180 probable Chinese sCJD cases diagnosed in the National Center for CJD surveillance from January 2017 to July 2018. Besides, a visual analogue score (VAS) was performed to evaluate the health status of the sCJD patients from the family members and relatives who nursing the patients. Results Nearly all of 180 sCJD patients showed the apparent problems in the demission of mobility, usual activities and self-care. More than 1/3 of patients (38.33%) recalled the moderate and severe problems in the demission of pain/uncomfortable. 47.78% of them had the problems in the demission of anxiety/depression. The health utility of sCJD patients was low, with the median of 0.206. Meanwhile, the EQ-VAS score of those sCJD patients was also extremely low, with the median of 0. Conclusion Compared with the published data of several other diseases, the quality of life of Chinese sCJD patients was extremely poor as demonstrated by the results of the generic EQ-5D-3L. More social attentions need to be paid to reduce the healthy and economic burdens for sCJD patients and their families.


Introduction
Human prion diseases include Creutzfeldt-Jakob disease (CJD), Kuru, fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker syndrome (GSS) [1,2] . The incidence of CJD is around 1 to 2 cases per million of population annually. Among all CJD subtypes, sporadic CJD (sCJD) accounts for nearly 85-95%, while 5-15% of CJD cases are familial or genetic CJD (fCJD or gCJD). Less than 1% CJD cases are acquired that are related with a de nite medical history and termed as iatrogenic CJD [3] . A new type of CJD termed as variant CJD (vCJD) has emerged since 1996, which attributes to the outbreak of bovine spongiform encephalopathy (BSE). The clinical manifestations of CJD may vary largely. A couple of neuropsychological symptoms are frequently observed in CJD patients, particularly in sCJD cases, mainly encompassing progressive dementia, myoclonus, visual or cerebella disturbance, pyramidal or extrapyramidal dysfunction and akinetic mutism, which are used in the diagnostic criteria for CJD. With serious conditions of health and rapid progression, CJD patients eventually develop to disability and death.
The World Health Organization (WHO) de nes health as "not only the absence of physical defects and diseases, but also a complete physical, mental status and good social adaptation" in 1989. The traditional indicators, such as incidence rate and prevalence rate, do not meet the demand of evaluating health status completely. Thereby the concept and de nition of health-related quality of life (HRQoL) have been proposed and widely accepted. European Quality of Life-5 Dimensions instrument (EQ-5D) is a measurement for health status, which allows comparisons of preference-based health-related quality of life across diverse populations. As a multi-dimensional measurement, EQ-5D instrument is easy to understand and has a high reliability and validity [4,5] . This scale is suitable for the general population [6] and the population with diseases [7,8] , as well as the patients with cognitive impairment [9,10] . A study has even [11] suggested that the EQ-5D might have advantages over other dementia-speci c measures and can be used routinely as a stand-alone measure of quality of life in dementia research. Actually, the quality of life of many neurodegeneration diseases has been evaluated with the methodology of EQ-5D instrument [12][13][14] . However, the relevant data for human prion diseases are less described.
In this study we recruited 180 probable-diagnosed Chinese sCJD cases referred to the National Center for CJD surveillance from 2017 to 2018. The quality of life of those patients was assessed with multi-dimensional EQ-5D-3L questionnaire. We found signi cant impediment in the dimensions of mobility, self-care and usual activities. The utility scores and the visual analogue scale (VAS) of sCJD patients were very low.

Study population
Totally 180 probable sCJD cases diagnosed by the Center for CJD surveillance China from January 2017 to July 2018 were enrolled into this study. Patients were diagnosed and subtyped according to the diagnostic criteria [3] issued by WHO and the CJD diagnostic criteria issued by China CDC. An expert board consisting of neurologists, neuropathologists, epidemiologists and laboratory staff made the nal diagnosis after evaluating the data.

Data collection
Information related to the disease, such as the epidemiological data, the main clinical manifestations, the foremost symptoms, the special abnormalities on MRI brain scan, periodic sharp wave complexes (PSWC) on EEG and test results of protein 14-3-3 in cerebrospinal uid (CSF) were collected with a designed questionnaire through the monitoring network. A retrospective investigation then was conducted through telephone inquiring by the staff of Center for CJD surveillance with EQ-5D-3L and EQ-VAS questionnaire. During the telephone follow-up, patients were excluded because of wrong number or refusal to answer for at least three times. As the rapid progression of disease, the close relatives who knew patients well, including parents, spouses or offspring, were inquired.

EQ-5D-3L
EQ-5D-3L instrument provides evaluation for a total of 243 unique health states described, using a system comprising ve dimensions as mobility (MO), self-care (SC), usual activities (UA), pain/discomfort (PD) and anxiety/depression (AD) at three levels (1=no problems, 2=some/moderate problems and 3=extreme problems) for each dimension. The questionnaire also includes a 20-cm visual analogue scale (VAS) for self-assessment of general health status, with 100 representing the best imagine health status and zero representing the worst health status.
Since the utility of EQ-5D-3L health states can be also in uenced by social elements, e.g., culture, social economic, etc [15,16] . Several countries, such as UK, USA and Japan, have already developed their national EQ-5D-3L value sets. Several years ago, a Chinese population (social preference) value set for EQ-5D-3L was proposed using a time-trade off (TTO) approach [17] . The formula is concluded as U = 1 (C + 0.099 × MO2 + 0.246 × MO3 + 0.105 × SC2 + 0.208 × SC3 + 0.074 × UA2 +0.193 × UA3 + 0.092 × PD2 + 0.236 × PD3 + 0.086 × AD2 + 0.205 × AD3 + 0.022 × N3) . MO2, SC2, UA2, PD2 and AD2 mean the patients are at level 2 of respective dimensions and MO3, SC3, UA3, PD3, AD3 indicate at level 3. C means a constant of 0.039 and N3 represents at least one dimension of 3 level else N3 equals 0. Utility scores can vary between -0.149 (worst health) and 1.00 (perfect health) with the meaning of 0 is death. A negative value represents a health condition worse than being dead. Quality control and statistical approach All investigators were trained by a supervisor before the survey. A database was built by Epidata 3.1 for data logging and double checking. Sociological and disease-related characteristics of sCJD patients were analyzed with SPSS version 22.0 for Windows (SPSS Inc., Chicago, IL, USA). Health-related utilities were calculated with Chinese value sets.

General information of the sCJD patients
A total of 180 probable sCJD cases from 29 different provinces, municipalities and autonomous regions were investigated with the questionnaire. Based on the permanent addresses, Shandong, Henan and Beijing were the top three provinces the patients came from. In geography, 88 (48.89%) cases were from eastern regions, 58 were from the middle region and 34 were from the western. 100 (55.56%) patients lived in rural areas. The number of male patients (95) was slightly more than that of female patients (85) with a ratio of 1.12∶1. The average onset age of the patients was 63.16 years old, ranging from 34 years old to 91 years old. Majority of them were in the groups of 56 to 75 years old. In terms of occupation, more than 1/3 of the patients were farmers (40.56%). Retired seniors and housework accounts for 21.11% and 12.22%, respectively.  The quality of life of the sCJD patients Using the instrument of EQ-5D-3L, the quality of life of 180 Chinese probable sCJD patients were evaluated. As shown in Table 2, all patients recalled the problems in the dimensions of mobility (100.00%) and usual activities (100.00%), while 99.44% of the patients had problems in the dimension of self-care with only one patient did not report problem in self-care. In terms of the dimension of pain/discomfort, more than one third of the patients (38.33%) had problems. For the emotional dimension, nearly half (47.78%) of the patients experienced anxiety and depression. Further analysis the dead patients and the still alive ones did not identi ed statistical difference in the dimensions of pain/discomfort (c2=0.174, P= 0.676) and anxiety/depression c2= 0.851, P= 0.356 .  Fig 1A). Only 8 cases had the scores larger than 0.3.
The values of EQ-VAS of 180 sCJD patients were also evaluated, ranging from zero to 70, with the average data of 4.81 and the median of zero. Analysis of the data distribution of those cases showed that the VAS scores of 63.33% patients were zero and 12.22% cases were less than 10, while only a small potion (5.00%) of the patients revealed the VAS score larger than 20 (Fig 1B).
The health utilities of those 180 sCJD patients were also calculated by the value sets from other countries in order to see the possible difference and to compare with the data of other diseases reported from different countries. As shown in Fig 2, the utility obtained from Chinese value sets was the highest with a median of 0.206, whereas the utility using UK value set was the lowest with a median of -0.043. The utilities using Japan value set (median: 0.132) and Thailand one (median: 0.037) were at middle level, respectively.

Discussion
In this study, we have evaluated the health-related quality of Chinese sCJD patients. As a universal scale of quality of life, EQ-5D instrument has been widely used in many studies focusing on the quality of life of various general population and the patients with different diseases. However, there is still lacking of the relevant study on the quality of life in the eld of human prion disease. To our knowledge, this is the rst study that elicits a complete spectrum of utility scores of Chinese sCJD patients by applying the Chinese scoring algorithm. The generation of the EQ-5D-3L scale and its Chinese utility value sets were years early than that of EQ-5D-5L, which leads to the limitation of the wide application of the EQ-5D-5L. Moreover, EQ-5D-3L instrument has been used in the National Health Services Survey (NHSS) 2008 in China. Therefore, we took EQ-5D-3L scale in this study.
CJD is a fatal illness because of its irreversible progression, characterized with long incubation time and rapid disease progression. The duration of sCJD patient are usually shorter than two years, most of them die in half year after onset [18] . Besides of rapid progressive dementia that is the most frequent symptom, many other neuropsychiatry symptoms and signs are also noticed in sCJD patients clinically, which involves in human motor, sensory and mental systems. In line with the clinical features, both the EQ-5D utility scores and the VAS scores of the sCJD patients are extremely low. In Table 3, we have summarized some published data calculated by EQ-5D-3L instrument with the values sets from UK, Japan and Thailand, respectively [19][20][21][22][23][24][25][26] . If we use the data with the value set from UK, the general health utility value of Chinese sCJD patients is the lowest (median -0.043), much lower than that of AD, PD, and even lower than that of stroke on the rst day. If we use the data obtained with the value set of Japan, the utility score of Chinese sCJD cases is also lower that that Japanese children with cerebral palsy (median: 0.44), which is the lowest health utility value among the different diseases evaluated with EQ-5D-3L instrument in the review of Zhou [27] . Apparently, sCJD seriously affects the health status and quality of life of the patients with a high disability rate. We have noticed that among the ve dimensions, mobility, self-care and usual activities are the mostly affected problems for the sCJD patients. High percentage of the investigated cases has recalled to be severely affected, even in the group of the survival patients who appeared clinical manifestations less than 6 months. Our data here have also revealed that only about 1/3 of sCJD patients had problems in pain/discomfort and nearly half had anxiety/depression. Furthermore, we do not see signi cant difference in those two dimensions between dead and survival cases. Pain and discomfort re ect subjective feelings. Anxiety and depression are psychological activities or mental problems, which usually need to be determined or judged by professionals.
sCJD patients usually loss their recognition capacities and language competences rapidly after onset, which may hinder the accurate descriptions of subjective feeling and psychological abnormalities. Particularly at relatively late stage, patients frequently display akinetic mutism. It is reasonable to assume that the problems of the dimensions of pain/discomfort and anxiety/depression in the sCJD patients are underestimated during the survey. In addition, the questionnaires in this study are rated largely by the family members of the patients or the persons who are nursing the patients, which may also decline the correctness to address the subjective and sensory problems.
Although EQ-5D instrument has been considered to be a valid and reliable tool to evaluate the quality of life in institutionalized patients with different types of dementia, there is still inevitable difference in collection of information directly from the patients themselves or from their family members and relatives. The use of a proxy rater de nitely bene ts the feasibility of EQ-5D instrument in the patients with dementia, particularly at advanced stage [28] , but it will also in uence the accuracy of the information collection for the issues regarding to subjective feelings.
sCJD causes more serious outcomes on both sides of patients and their families than many other diseases.   The utilities of Chinese sCJD patients calculated with four different value sets. Graphical data are expressed as median and range