Retrospective clinic and urodynamic study in the neurogenic bladder dysfunction caused by human T cell lymphotrophic virus type 1 associated myelopathy/tropical spastic paraparesis (HAM/TSP)

HTLV‐I associated tropical spastic paraparesis (TSP) and HTLV‐I associated myelopathy (HAM) is an endemic disease in Caribbean Island. Bladder‐sphincter dysfunctions are almost present. The objectives of the study are to describe clinic and urodynamic characteristics of voiding disorders in Martiniquan population, evaluate if there is a relationship between motor and urinary handicap, and evaluate prognosis factors of urologic complications.


INTRODUCTION
HTLV-I associated tropical spastic paraparesis (TSP) and HTLV-I associated myelopathy (HAM) was described in 1988. 1 Definite HAM/TSP criteria to diagnose the disease date from 2006: (i) non-remitting progressing spastic paraparesis with sufficiently impaired gait to be perceived by the patient himself, with or without sensory symptoms or signs, when present, remain subtle and without a clear-cut sensory level. Sphincter signs or symptoms may or may not be present; (ii) presence of HTLV-I antibodies in serum and/or cerebrospinal fluid (CSF) confirmed by Western blot and/or HTLV-I PCR positive in the blood; (iii) exclusion of other disorders that can mimic HAM/TSP. A new parameter should be included for the diagnosis of HAM/TSP that is the HTLV-1 proviral load ratio CSF/serum. This ratio is always >1 in HAM/TSP patients and <1 in asymptomatic subjects. Only 2-3% of infected individuals develop HAM/TSP by mechanism incompletely understood. 2 The infection is estimated to affect 10-20 millions people. In 1999, the seroprevalence in Martinique was estimated to 2.2% among global population. Incidence of HAM/TSP is 1.7/100,000 per year. There are large endemic foci in the Caribbean. The mean age at onset ranges from 40 to 50 years. There is a female to male preponderance ranging from 3.5:1 in Martinique. The dominant modes of transmission of HTLV-I are mainly blood borne from packed red blood cells or platelets, from mother to child in breast milk and sexual transmission in adults. 3 Concerning the prognosis, the more often, there is a stability occurring after initial deterioration. The neurological disability occurs mainly during the first year of the disease and becomes relatively stable thereafter. High age of onset constitutes a poor clinical prognosis factor either for motor and urinary disability progression. Immunodeficiency is among a factor that facilitates HAM/TSP development.
Palliative treatment for HAM/TSP includes steroids to decrease spinal cord inflammation. Therapeutic trials aimed at reduction in HTLV-I proviral load in peripheral blood mononucleated cells seem to be very promise. 4 Bowel and bladder disturbances are reported in about 80% of patients, and are heterogeneous. 5,6 The purpose of the study is to describe clinic and urodynamic characteristics of voiding disorders in Caribbean population, evaluate if there is a relationship between motor and urinary handicap, and thirdly determine clinic and urodynamic severity parameters in HAM/TSP population predictive of urologic complications.

METHODS
We conducted a retrospective study in Martiniquan population from the registry of University Hospital of Martinique † Deceased. Prof. Christopher Chapple led the peer-review process as the Associate Editor responsible for the paper. Potential conflicts of interest: Nothing to disclose. defining HAM/TSP with the criteria from 2006. All the patients of the island diagnosed by the neurologists complained about urologic symptoms were assessed in urodynamic study. Demographic data (age, gender), comorbidities (diabetes, lumbar and cervical stenosis, chronic alcoholism, stroke, pelvic surgeries) were reported. Urinary symptoms were divided in two groups: storage (increased daytime frequency, urgency, nocturia, urge urinary incontinence) and voiding (slow stream, feeling of incomplete emptying symptoms, intermittent stream). Perineal examination was divided in three groups: central (decreased sensitivity and motricity, high reflexes, anal hypertonia), peripheral (decreased sensitivity and motricity, low reflexes, anal hypotonia), and mixed (decreased sensitivity and motricity, increased reflexes, anal hypertonia). Evolution of the pathology was divided in three groups: <5 years, 5-10 years, and >10 years. Urologic complications were reported: infectious disorders (repetitive urinary infection, pyelonephritis, and prostatitis) and morphologic complications (bladder with increased compliance (>100 ml/cm H20), vesicoureteral reflux, hydronephritis, and ureteral dilatation). Disability evaluation was performed by the Urinary Symptom Profile (USP) questionnaire, 7 Osame score. 8 Urethral pressure profilometry (standard equal to 120 minor age), cystometry with bladder filling 20 ml/s, 50 ml/s or cold ice water if detrusor overactivity was suspected, compliance (standard >30 ml/cm H20), uroflowmetry with post-void residual volume after catheterization (significant >30% urine volume), electromyography were performed. All the curves of urodynamic studies were systematically reviewed by two specialized doctors.
For qualitative variables, the distribution of the frequencies associated is calculated. For quantitative variables, means are calculated. Statistic study used was x 2 to compare percentages, means comparison test to compare qualitative and quantitative data. The level of statistical significance for the P-value was set at less than 0.05.

RESULTS
Ninety eight patients were enrolled. Thirty eight patients were excluded because urodynamic studies were not available. The base-line characteristics of the patients are given in Table I.

Concerning Clinical Data
Storage symptoms were reported for 75% of the patients, whose increased daytime frequency in 60% of cases, urgency in 48% of the cases, nocturia in 36% of cases, stress urinary incontinence in 18% of cases; urge urinary incontinence in 40% of cases.
Forty percent of the patients reported voiding symptoms: slow stream in 70% of the cases, feeling of incomplete emptying symptoms in 28% of the cases, intermittent stream in 50% of the cases.
There was no correlation between USP score and Osame score (P ¼ 0.07). USP score was not more significantly severe for the patients with a long evolution of the disease (P ¼ 0.87). There was no significant correlation between Osame score and evolution duration of the disease (P ¼ 0.475).
Perineal examination was reported: 18.3% had central dysfunction, 11.7% peripheral dysfunction, 10% mixed dysfunction, 25% normal function, and 35% of patients had not perineal examination data available. There was no significant correlation between perineal examination and disease duration evolution (P ¼ 0.540).
Bladder pressure during voiding was high (>40 cm H2O) in 37.3% of the case. The correlation between disease duration evolution and bladder pressure during voiding was not significant (P ¼ 0.712).
Urethral activity was normal in 32.2%, increased in 47.5%, decreased in 20.3% of the patients.
There was no correlation between urethral activity and evolution of the disease (P ¼ 0.274). Urethral sphincter electromyography showed 78% detrusor sphincter dysynergia. Eighteen percent of the patients had not electromyography. There was no significant correlation between evolution duration of HAM/TSP and detrusor sphincter dysynergia (P ¼ 0.625).
Significant post-void residual volume (>30%) was found in 58% of the patients. There was no significant relationship between post-void residual volume and detrusor sphincter dysynergia (P ¼ 0.515), detrusor underactivity (P ¼ 0.132), and long duration evolution of the disease (P ¼ 0.817).

Urologic Complications
Sixty five percent of the patients presented at least one urologic complication (Fig. 1).
Mean Osame score was 6.31 for patient with urologic complication versus 5.5 for patient without urologic complication. There was no significant correlation between Osame score and urologic complication (P ¼ 0.3097). Urologic complications were not more frequent for patients with long evolution duration of HAM/TSP (P ¼ 0.348). About 51.6% of the patients presented morphologic complications (36.7 % had hypertonic bladder, 10% had hydronephrosis, 3.3% had vesicoureteral reflux, and 1.6% had ureteral dilatation).
Morphologic complications frequency did not increase with evolution duration of the disease (P ¼ 0.741).
About 41.7% of the patients presented infectious complications (31.7% had repetitive cystitis, 10% pyelonephritis). Evolution duration of the disease did not influence infectious complications frequency (P ¼ 0.156).
There was no significant statistical correlation between detrusor activity registered in cystometry and urinary complications (P ¼ 0.432 for detrusor overactivity and P ¼ 0.107 for detrusor underactivity).

DISCUSSION
Firstly, our study found female to male preponderance ranging from 3.6:1 in Martinique, in agreement with other studies. The mean age was above 55 years, which cause problem of the comorbidities (voiding syndrome for men, urinary incontinence for women) and drugs interfering with neurologic bladder. 9,10 Secondly, HAM/TSP urinary symptoms are sometimes isolated for a long time and urinary handicap seems to evolve independently, which can cause a delay in the diagnosis that can be harmful. 11 As in multiple sclerosis: there is not relationship between functional status and walking ability, type and severity of urinary disorders. 12 Then, concerning urinary symptoms, we found more storage symptoms, whatever duration of HAM/TSP, as in other study. 13 Urinary symptoms were not predictive of urodynamic study. Concerning perinea examination, there is not a type of predominant disorder and it does not seem to have evolution during duration of the disease. Not other study speaks about perinea study.
Moreover, in our study, cystometry reported detrusor overactivity in more of the cases, as reported in literature. 6,[13][14][15] Other studies found more detrusor underactivity. 16,17 This detrusor overactivity can be associated to a bladder contractility dysfunction (under or acontractility) in 30% of the cases, resulting dysuria. As in multiple sclerosis, there was no significant correlation between the type of detrusor activity and urologic complications. 12 Furthermore, more third of the patients had bladder pressure >40 cm H20, during voiding. High bladder pressure is a prognosis severity factor of renal integrity in neurological diseases (as multiple sclerosis and spina bifida). 12,18 Low compliance was found in 25% of the patients, which is found in other studies. Urethral activity was increased in most of the patients. Just one study speaks about urethral activity and it was found normal in more of the patients but the population was younger. 16 There is no relationship between urethral activity and disease evolution duration; it was shown that the urethral pressures do not give diagnostic, physiopathologic, or prognostic elements in multiple sclerosis. 12 What is fundamental is detrusor sphincter dysynergia in 78% of the patients. Other studies find it from 25% to 88% of the cases. 14,16 There was no significative statistical relationship between detrusor sphincter dysynergia and evolution of the disease, neither urologic complication, instead of a study on multiple sclerosis that showed 50% of urologic complications in patients with detrusor sphincter dysynergia versus none in patients without detrusor sphincter dysynergia. 19 More than half of the patients had post-void residual volume >30%. Other studies found more patients with post-void residual volume (75-100%). 15,20 In our study, there is no relationship between urologic complication and post-void residual volume. However, post-void residual volume is known as a risk factor of kidney complications. 21 A study found that it is the only urodynamic parameter correlated to motor disability. 22 Likewise, urologic complications are present for 65% of the patients. It is more than in multiple sclerosis (40%). 12 Few studies reported urologic complications in HAM/TSP: morphologic complications between 19.2% and 70.8%, hydronephrosis from 3,8% to 8%, vesicoureteral reflux in 11.5% of the cases, urinary infections in 36% of patients. 6,16 There was no relationship between morphologic urologic alteration and evolution duration of the disease in our study. But detrusor overactivity, detrusor sphincter dysynergia, and urethral overactivity were found in more of the patients with morphologic urologic complication, which are risk factors of vesicoureteral reflux. The number of infectious urologic complications was the same than in other studies. 6 More of the patients with pyelonephritis had detrusor overactivity, urethral overactivity, detrusor sphincter dysynergia, post-void residual volume in our study.
The limits of the study are the small population which did not permit to evaluate all the parameters. The other limitation is the fact that the study is retrospective because some datas are missing and the evolution of the disease cannot be analyzed.

CONCLUSION
Urologic symptoms are similar to the literature and are not always in relationship with urodynamic study: so a systematic urodynamic study is necessary to evaluate HAM/TSP neurogenic bladder. There is no relationship between urologic and motor handicap. No clinic or urodynamic criteria are predictive of urologic complications. These patients need a closer and regular follow up throughout life by a multidisciplinary team.