Human T-lymphotropic virus type 1 (HTLV-1) is estimated to infect at least 5–10 million individuals with a heterogeneous global distribution (1). Its endemic regions include the Southwestern part of Japan, South America, the Caribbean area, and sub-Saharan Africa. This retrovirus causes a neuroinflammatory disease, called HTLV-1-associated myelopathy (HAM), in a small proportion of infected individuals (2, 3). Due to the chronic inflammatory destruction of the spinal cord, HAM results in various symptoms, including motor and sensory disturbance in the legs and neurogenic bladder and bowel dysfunctions (4). In severe cases, patients become wheelchair-bound and require urinary catheters and enemas. Although corticosteroids are most widely administered to slow the disease progression, no curative therapy is currently available (5). Thus, symptomatic treatment is the mainstay of management. Therefore, data regarding the burden of complicated symptoms on health-related quality of life (HRQoL) are necessary to enhance medical care and research for patients with HAM. However, information is extremely limited because of the rarity of the disease.

Among the HRQoL measures, the Short Form-36 (SF-36) and the EuroQoL 5-dimension (EQ-5D) are most widely used to measure generic health status in clinical research (6, 7). The SF-36 assesses physical and mental health status using 36 questions. The Short Form 6-dimension (SF-6D), which is a health state utility index, can be calculated from the SF-36 in some languages (8, 9). The EQ-5D also generates a health state utility index using five questions (10). Regarding HRQoL of patients with HAM, several reports from Brazil have been published. Mainly using the SF-36, they have shown that this patient population had poor HRQoL (11–17). Although the SF-6D has not been reported to date, Rosadas et al. have recently demonstrated that the EQ-5D index in patients with HAM living in Brazil and the United Kingdom was significantly lower than that in the general population and HTLV-1 carriers (18). Moreover, these studies have reported that HAM-related symptoms, such as gait dysfunction, pain, and lower urinary tract symptoms, decreased HRQoL by comparing patients with each symptom with those without each symptom (11–18). However, as HAM simultaneously causes multiple symptoms, strictly estimating the effect of each symptom is impossible using univariate analysis performed in these studies with relatively small sample sizes (<60 subjects).

Therefore, this study analyzed the SF-36 and SF-6D data obtained from more than 500 patients in Japan to reveal the effects of HAM and related symptoms on HRQoL. These patients had worse HRQoL than the general population. Moreover, multivariate analysis demonstrated that not only gait dysfunction but also other symptoms of HAM were significantly associated with poorer HRQoL. To our knowledge, this is the first study that has examined the SF-36 and SF-6D of patients with HAM from Japan.

In this study, we evaluated the HRQoL of Japanese patients with HAM for an average disease duration of 16.5 years. Most patients had not only gait dysfunction but also sensory disturbance, urinary dysfunction, and constipation. In this study, the SF-6D and SF-36 subscale scores were lower than the population standards. Multivariate analyses demonstrated that all these symptoms were significantly associated with worse HRQoL.

To our knowledge, no studies have reported on the SF-6D score in patients with HAM; however, the poor scores found in this study were consistent with those reported in a study conducted in Brazil and the United Kingdom, which used the EQ-5D index as a health-related utility value (18). We considered that the decrease in the SF-6D score was clinically meaningful because it was as large as a minimal important difference of 0.05–0.1 (23). Moreover, all symptoms analyzed were significantly associated with lower SF-6D scores in the multivariate analysis. The coefficients in OMDS 5 or higher (vs. OMDS 0–4) and persistent leg pain (vs. absent) were remarkably large and met the minimal important difference, indicating that the management of motor and sensory dysfunctions in the legs has a strong impact on HRQoL. However, caution is required in interpreting the results of this study. Although the SF-36 comprises questions directly reflecting gait function (PF) and pain (BP), no questions focus on other HAM-related symptoms. Hence, compared to gait function and pain, the SF-36 indirectly evaluates the effects of leg numbness, urinary dysfunction, and constipation on HRQoL, which may lead to an underestimation of their burden. Therefore, recognizing that all major symptoms of HAM can significantly affect HRQoL is important.

In this study, the SF-36 subscale scores other than the MH score were below the national average, and the subscales related to physical health were lower than those related to mental health. PF was worst of all the subscales. These findings are consistent with those reported in a Brazilian study (15), suggesting that poor physical health is a characteristic feature of HAM. Regarding the association between OMDS and the subscale scores, PF is naturally and strongly correlated with OMDS because PF mainly reflects mobility. Moreover, OMDS 5 or higher was significantly associated with a decrease in RP, GH, and SF scores; however, the differences in the coefficients between OMDS 5, 6, and 7–13 were relatively small, indicating that there is a large gap in HRQoL between OMDS 0–4 and 5. As a result, maintaining gait function better than OMDS 5 may be important for better HRQoL and can be a therapeutic goal for patients with HAM. In general, gait dysfunction caused by HAM progresses slowly, requiring 5–10 years on average to reach OMDS 5 (19, 24). However, some patients with high inflammatory activity in the spinal cord experience faster deterioration, with OMDS 5 or higher within 2 years after the disease onset (25). Thus, early diagnosis is important for preventing loss of treatment opportunities. Although there is no curative treatment for HAM, evidence suggests that corticosteroid therapy is effective in maintaining gait function (26). The international guideline for HAM recommends the use of corticosteroids based on the rate of disease progression (5). Early diagnosis, evaluation of progression, and treatment initiation at the appropriate time are all essential in the treatment of HAM.

In addition, we found that sensory disturbance and urinary dysfunction affect HRQoL in patients with HAM. First, persistent leg pain and numbness were associated with lower RP scores, indicating that not only gait dysfunction but also sensory disturbance hamper daily activity in patients with HAM. Second, although the OMDS had no significant influence on MH, persistent leg pain and numbness as well as the use of intermittent catheters (HAM-BDSG II) were significantly associated with lower MH scores. These findings are consistent with those reported in recent HRQoL studies in patients with multiple sclerosis and neuromyelitis optica, both of which are neuroinflammatory diseases causing symptoms similar to those in HAM. They reported that not gait dysfunction but chronic pain, including numbness, was associated with depression and mental health satisfaction (27, 28). Third, leg pain, numbness, and urinary dysfunction were also associated with lower GH and VT scores. Intermittent catheterization had the greatest impact on GH and VT of all the symptoms analyzed. In an HRQoL study involving patients who developed neurogenic bladder dysfunction after radical hysterectomy, GH, VT, and MH scores were lower in patients on intermittent catheterization than those in patients with spontaneous voiding, despite similar clinical backgrounds other than the use of intermittent catheters (29). The negative effects of urinary dysfunction on GH, VT, and MH observed in the present study are supported by this report. Collectively, sensory and urinary dysfunctions in patients with HAM should be carefully managed to maintain better HRQoL both physically and mentally.

In this study, the use of indwelling catheters or manual extraction or enemas was not associated with the SF-36 subscale scores despite being the most severe form of bladder and bowel dysfunction. Although the reason is unclear, “response shift” may be one of the reasons. Response shift is a psychological process occurring in individuals with deteriorating health, in which internal standards and values change to adapt to a new situation (30, 31). Longitudinal studies are required to understand the changes in HRQoL over time in patients with HAM.

This study has several limitations. First, HRQoL is influenced by several factors not included in our analysis, such as education, employment status, and comorbidities (23). Moreover, we did not evaluate the intensity of the symptoms; HAM causes many other symptoms, including low back pain and spasticity (4). Therefore, we could not completely adjust symptom severity and potential confounders. Second, the coefficients only indicate associations, and therefore, may not necessarily mean the impact of the symptoms. Third, all symptoms were assessed using information collected through telephone interviews. Although telephone interviews were conducted uniformly by trained nurses and coordinators to collect reliable information, the accuracy of these assessments may be lower than that of a physical examination. In addition, because leg pain, numbness, lower urinary tract symptoms, and constipation are common even in the general population, we could not conclude that these symptoms were caused by HAM. Finally, because we only included Japanese patients, generalizability to other populations may be limited.

We demonstrated that HRQoL of patients with HAM was poorer than that in the general population and was associated with various symptoms, including motor, sensory, and bladder and bowel dysfunctions. Therefore, these patients should be comprehensively monitored and managed to achieve better HRQoL.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Bioethics Committee of St. Marianna University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

MK, JY, TS, NY, NA, SA, KT, AT, and YY contributed to the conception and design of the study. MK, JY, and KT conducted the statistical analysis. MK, JY, TS, NY, NA, SA, KT, EH, TW, AC-R, MN, YA, KK, TK, SS, HM, AK, SI, AT, and YY analyzed and interpreted the results and critically revised the manuscript. MK, JY, and YY drafted the manuscript. All authors read and approved the final version of the manuscript to be submitted.

SA was employed by the LSI Medience Co., Tokyo, Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.