The human T cell lymphotropic virus type 1 is the causal agent of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). About 10 million people are infected by HTLV-1 worldwide.1 HAM/TSP is characterized by back pain, hyperreflexia, spastic paraparesis, and Babinski sign.2 Manifestations of the genitourinary system such as erectile dysfunction, increased urinary frequency and urgency, with or without incontinence, and nocturia are documented in virtually all patients with HAM/TSP.3–5 Moreover, these manifestations may be detected in a large percentage of HTLV-1 subjects who do not fulfill criteria for HAM/TSP.5 The urinary complaints are responsible for serious impairment of quality of life, development of depression, and increased risk for upper urinary tract infection and kidney dysfunction due to increased intravesical pressure and residual urine volume.6–8 The main urodynamic findings in patients with urinary dysfunction associated with HTLV-1 are overactivity of the detrusor, sphincter-detrusor dyssynergia, and impaired bladder contractility.8,9 As only few studies have addressed the treatment of such events in this population, it remains undefined if the therapeutic interventions used in individuals not infected with HTLV-1 have the same response in those infected by the virus. The onabotulinumtoxin type A has been used with success to improve urinary symptoms in patients with overactive bladder symptoms due to multiple sclerosis or spinal cord injury.10,11 We had previously shown in a limited number of patients with urologic dysfunctions the short-term results of the use of onabotulinumtoxin.12 Here we extend this observation to a large number of patients, besides evaluating the long-term therapeutic response to onabotulinumtoxin type A in HTLV-1 infected patients with overactive bladder refractory to conservative treatment with anticholinergic drugs or physical therapy.

The aim of this study was to determine the effect of onabotulinumtoxin type A in controlling symptoms of lower urinary tract in patients infected with HTLV-1 refractory to conservative treatment with anticholinergic and pelvic floor physical therapy associated with parasacral or intracavitary neuromodulation (vaginal or anal).

Table 1 summarizes demographic and clinical features of patients undergoing treatment with onabotulinumtoxin type A. All of them had already used at least two anticholinergic drugs (oxybutynin and propantheline bromide), given orally in full tolerated dosage. Of the 10 participants of the study, three had received in addition to oral, intravesical oxybutynin, but remained with urge incontinence. Two cases also had physical therapy with sacral, vaginal or trans-anal electrical stimulation with no improvement. The majority of the patients had illness duration for a long period. Detrusor overactivity was observed in all patients before therapy. Bladder empty dysfunction was detected in seven patients. Five of them had acontractile detrusor documented and six performed self-intermittent catheterization. The majority of these patients (n=04) had HAM/TSP, but in three cases urinary dysfunctions were the main neurologic symptoms. The impact of treatment on urological symptoms and OABSS after 30 days and 90 days of the therapeutic intervention is shown in Table 2. After application of onabotulinumtoxin type A, there was a significant reduction in the frequency (p=0.008), urgency (p=0.007) and nocturia (p=0.008). In addition, there was a significant reduction of OABSS measured 30, 90 and 365 days after the application of onabotulinumtoxin (p<0.005). No surgical complication was observed during the intraoperative period. Three out of 10 patients presented complications detected after therapy characterized by urinary tract infection and hematuria. Urinary retention were observed in two of these patients who were able to void spontaneously before treatment that persisted for 31 and 65 days after therapy. In all three cases, the infection was in the lower urinary tract and the patients responded promptly to ciprofloxacin. In patients who presented hematuria the symptoms disappeared within two days. Those patients who developed urinary retention needed to use self-intermittent catheterization. Despite being able to void spontaneously before therapy, these patients had high void residual volume.

Table 3 shows the impact of the treatment on QoL. Of the nine domains comprised in the King's Health Questionnaire, a statistically significant reduction was demonstrated in eight of them. Regarding the general health perception, the statistical significance was not achieved but the p-value was 0.05.

The duration of the treatment effect was assessed by survival analysis and expressed in a Kaplan–Meier curve (Fig. 1). The average time for requiring retreatment or returning to the previous treatment OABSS was 465.7 ± 66.3 days (Fig. 1).

Fig. 1.

Kaplan–Meier curve. Survival analysis in HTLV-1 infected patients with refractory overactive bladder submitted to intravesical application of onabotulinumtoxin A. Time to request retreatment or to return to previous treatment OABSS.

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Urinary tract dysfunction (UD) plays an important role in the morbidity related to HTLV-1 infection.5,8,21,22 Initially, it was thought that urinary symptoms were caused by urinary tract infection, but one study failed to prove this hypothesis, and OAB symptoms are in fact due to neurological disease.8,23,24 Although several studies have investigated the physiopathology of UD, there are few studies assessing the efficacy of therapeutic strategies in HTLV-1 infected subjects. In this open label clinical study, we assessed the long-term therapeutic response of HTLV-1 infected subjects to onabotulinumtoxin type A. This drug was able to control the OAB symptoms, mainly urgency and incontinence for a long period (mean of 466 days) and improved QoL of the patients.

The cases enrolled in this study have experienced conservative treatment for a mean period of six years and had not achieved total control of the symptoms. In addition to the use of more than one drug orally, intravesical therapy had been applied in two patients. Although seven patients had impairment of detrusor contractility, we preferred to use a standard dose of the onabotulinum toxin type A in all patients (200UI), as recommended by Cruz et al.10

In the present study, OABSS was used to measure the OAB severity. This score evaluates the main symptoms of OAB giving different weights for each question related to the symptoms. Therefore, urgency and incontinence translate into more points in the score than frequency and nocturia. This score was also applied in a randomized controlled trial evaluating onabotulinumtoxin A in patients with multiple sclerosis.10 Our data show a significant decrease of OABSS in all periods of evaluation after the application of onabotulinumtoxin type A, which persisted for a long time (Fig. 1). The time for retreatment of the patients was higher than previously documented25 and several factors may explain this finding. It is known that the response to intravesical injections of onabotulinumtoxin type A is quite variable and dependent on the neurological disease related to urinary dysfunction.26 Moreover, we only offered retreatment when the patients requested it or when they presented the same or higher OABSS compared to the score observed before therapy.

UTI, hematuria and urinary retention were the most common complications, but their frequencies were similar to rates reported for patients with other neurologic diseases.10,27,28 As previous reported, UTI may occur after therapy.12,29 This fact may be explained by urine colonization in patients using self-intermittent catheterization due to high void residual volume or by endoscopic treatment. Anyway UTI is frequently documented in HTLV-1 infected patients. Regarding urinary retention, this complication was more frequent than the rate observed in other series.30 However, this was a predictable event, as all patients who presented urinary retention were not voiding normally, as they empty the bladder by involuntary contraction. In such cases, patients should be informed that urinary retention may be observed after therapy.

Gotoh et al. founded a direct relationship between OAB severity and impairment on quality of life (QoL). They also found that the symptoms with the highest bother score was frequency and urgency among patients under 50 years, urgency in the age range of 50–70 year, and incontinence in those over 80 years.31 In our study, incontinence was the symptom with the highest impact on QoL, but we did not investigate by age groups.

The limitations of the present study include the small sample size, the absence of a control group, and lack of continuity of care and the impossibility to apply all therapeutic armamentarium, such as posterior tibial stimulation and sacral neuromoduation. Also, we did not perform urodynamic study in the post-treatment evaluation for ethical reasons. First, there was no doubt about the clinical improvement and second the conduction of an urodynamic study by minimally invasive technique was not available in our service.

We recently showed that endocavitary (vaginal and anal) electrical stimulation combined with pelvic physiotherapy is an effective treatment of HTLV-1 associated urinary dysfunction.32 Here we found that onabotulinumtoxin type A promoted improvement in urinary symptoms and on QoL with acceptable rates of complications and may be used in patients infected with HTLV-1 with urinary incontinence.

Onabotulinumtoxin type A should be considered in the treatment of overactive bladder associated to HTLV-1 refractory to anticholinergic drugs and physical therapy.

The authors declare no conflicts of interest.