Clinical course of neurogenic bladder dysfunction in human T-cell leukemia virus type-1-associated myelopathy/tropical spastic paraparesis: a nationwide registry study in Japan

Data from HAM-net were analyzed (UMIN000028400) [19]. The Additional file 1: Methods section presents details of HAM-net. Briefly, HAM-net prospectively collects patient data, including demographic information and medical conditions, such as symptoms, comorbidities, and medications, through annual telephone interviews with patients conducted by trained nurses and coordinators. Owing to the fact that HAM-net does not have any recommendations or protocols for examination and treatment, patients are treated at the discretion of doctors.

Of the 558 patients enrolled in HAM-net between April 1, 2012, and December 31, 2018, 547 patients had HAM-BDSG data at enrollment (Set A of Fig. 1). We extracted information of patients who had responded consecutively to annual interviews over six years (Set B). Specific patient information was extracted from Set B for further analyses: those who did not use urinary catheters throughout the 6-year follow-up (Set C) and those who had never received mirabegron, a β3-adrenergic agonist for overactive bladder symptoms, by the 3rd-year interview (Set D). The St. Marianna University School of Medicine Bioethics Committee approved this study (Approval ID No. 2044), and all participants provided written informed consent.

Demographic information, including age and sex, was extracted. To evaluate lower limb motor function, we extracted Osame Motor Disability Score (OMDS; Additional file 1: Table S2) [19], a scale specific to HAM/TSP that ranges from 0 to 13, with higher scores indicating greater walking disability. To assess urinary dysfunction and symptoms, we extracted information regarding the use of urinary catheters and medications for urinary dysfunction and scores of the following internationally validated urinary symptom measures: I-PSS [13], OABSS [14], and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) [21]. Missing data for urinary symptom scores were 1.7%, and those for other valuables were < 1.0%; missing data were not imputed.

We assessed urinary dysfunction severity using the HAM-BDSS (Additional file 1: Table S1) and HAM-BDSG (Additional file 1: Figure S1) [18]. These measures were recently developed to assess urinary dysfunction in patients with HAM/TSP. HAM-BDSS is composed of eight items derived from I-PSS and OABSS, with scores ranging from 0 to 40 points, where higher scores indicate greater symptom severity. Thus, HAM-BDSS can be calculated from I-PSS and OABSS data. The questions of the HAM-BDSS are subdivided into those related to storage and voiding symptoms (four questions each).

HAM-BDSG comprises four grades (grades 0–III) based on the presence or absence of urinary symptoms or medications and dependency on urinary catheters.

Of note, HAM-BDSS of patients with HAM-BDSG 0 is not always zero because judging the presence or absence of urinary symptoms depends on patients’ sense and recognition.

The outcomes of interest were: 1) prevalence and characteristics of urinary dysfunction in patients with HAM/TSP; 2) associations between urinary and gait dysfunction severity; 3) urinary dysfunction progression; and 4) treatment effects on urinary symptoms.

Table 1 summarizes the 547 patient characteristics (Set A). At enrollment, 503 patients (92.0%) had urinary symptoms or were taking medications (HAM-BDSG ≥ I). Mean (SD) age was 61.9 (10.7) years, and 74.6% of patients were female. The mean age of disease onset was 45.3 (14.8) years, higher in patients with HAM-BDSG III than patients with other grades. Mean disease duration was 16.6 (11.6) years, which increased with HAM-BDSG up to grade II; however, that of patients with HAM-BDSG III was shorter than that of patients with HAM-BDSG II. Similar to a previous report [18], HAM-BDSS of patients with HAM-BDSG II was lower than that of patients with HAM-BDSG I (median [IQR], 8.5 [2–17.8] vs. 19.0 [13.0–26.0]), which suggested that urinary catheterization improved urinary symptoms. Medications for urinary symptoms were administered to 34.0% of patients, of which α1 adrenergic agonists (12.4%) and anticholinergics (11.3%) were the most frequently prescribed medications.

First, we evaluated the association between OMDS and HAM-BDSG using enrollment data (Set A). The proportion of patients with higher HAM-BDSG increased significantly with worsening OMDS (p < 0.001; Fig. 2). Next, we assessed the association between OMDS and HAM-BDSS in patients with HAM-BDSG ≤ I (i.e., those not using urinary catheters). HAM-BDSS and sub-scores were also worse in patients with higher OMDS (p < 0.001; Fig. 3). Collectively, urinary dysfunction in HAM/TSP tended to progress with worsening gait function. However, results also showed that urinary symptom scores were widely distributed even among patients with similar motor dysfunction levels.

We assessed the change in HAM-BDSG from enrollment to the sixth year using data of those followed for six years (Set B). Although there was only one patient with HAM-BDSG III, baseline characteristics of patients with HAM-BDSG 0–II (Additional file 1: Table S3) were similar to those of Set A. Among the 18 patients with HAM-BDSG 0 at enrollment, 12 patients (66.7%) developed new urinary symptoms (HAM-BDSG I), and one patient (5.6%) initiated intermittent catheterization (HAM-BDSG II; Fig. 4). Of the 149 patients with HAM-BDSG I, 11 (7.4%) and five (3.4%) patients became dependent on intermittent and indwelling catheters (HAM-BDSG III), respectively. Seven patients (9.7%) with HAM-BDSG II progressed to HAM-BDSG III.

Because enrollment data suggested that intermittent catheters effectively relieve urinary symptoms, we examined changes in HAM-BDSS in those who initiated catheterization during follow-up. Total, storage, and voiding symptom scores significantly improved after initiating catheterization (mean [SD] change in total score: − 8.93 [10.78], p < 0.001; storage: − 3.78 [4.98], p = 0.001; voiding: − 5.15 [7.76], p = 0.002; Fig. 5).

Because urinary catheterization significantly influenced HAM-BDSS, we assessed the 6-year changes in HAM-BDSS in only those who remained at HAM-BDSG 0 or I (Set C). Although HAM-BDSS was stable or slightly worsened up to the third year, the score significantly improved in the fourth year (Fig. 6). We speculated that changes in medication might have influenced HAM-BDSS and found that mirabegron was newly prescribed to seven patients in the fourth year. In contrast, other medications were largely unchanged (Additional file 1: Table S4). Therefore, we extracted information on 122 patients who had not received mirabegron by the third year to evaluate mirabegron’s effect on the fourth-year HAM-BDSS (Set D). Patient characteristics were similar between those with and without a new prescription of mirabegron (Additional file 1: Table S5). The fourth-year HAM-BDSS significantly improved in patients prescribed mirabegron, although change in voiding symptom score was not significant (mean [SD] change of the total score: − 7.57 [7.30], p = 0.034; storage: − 4.14 [4.34], p = 0.045; voiding: − 3.43 [4.89], p = 0.113; Fig. 7). Changes in HAM-BDSS in those not taking mirabegron were also significant, presumably because of the large sample size. However, these changes were small and were not considered clinically meaningful (mean [SD] change of the total score: − 1.55 [4.20], p < 0.001; storage: − 0.82 [3.04], p = 0.005; voiding: − 0.73 [2.42], p = 0.002). Finally, we performed multivariable linear regression to analyze the effect of mirabegron, adjusted by the third-year HAM-BDSS (Table 2). Results showed that initiation of mirabegron was significantly associated with better scores for all three measures, even after adjustment of the potential confounders of age, sex, and other medications for urinary symptoms (coefficient [95% confidence interval] of the total score: − 5.82 [− 9.13 to − 2.51], p = 0.001; storage: − 2.72 [− 5.02 to − 0.42], p = 0.021; voiding: − 2.81 [− 4.80 to − 0.82], p = 0.006).