Introduction

HTLV-1, a human retrovirus, is the causative agent of Adult T Leukemia/Lymphoma (ATLL) and HTLV-1-associated myelopathy (HAM/TSP)[1], at least 5–10 million people infected worldwide, almost 5–10% of them in Brazil [2]. However high, such numbers may be an underestimate since only 2/3 of the world has been mapped for HTLV infection [3]. Clinically, HAM/TSP is characterized by muscle weakness, hyperreflexia, spasticity in the lower extremities and urinary disturbances associated with preferential damage to the thoracic spinal cord [4]. HTLV-1 has been shown to be associated not only with HAM/TSP but also with several inflammatory diseases, such as alveolitis, polymyositis, arthritis, infective dermatitis, Sjögren syndrome and uveitis [5–9]. In addition, sensory and gait abnormalities, isolated bladder dysfunction, erectile dysfunction, and sicca syndrome, have all been reported among HTLV-1–infected individuals without HAM/TSP [10].

Several neurological manifestations that are not explained by myelopathy have been described in so-called symptomatic persons, such as peripheral polyneuropathy, myositis, dysautonomia and cognitive alterations, as well as cranial neuropathies, movement disorders and an amyotrophic lateral sclerosis (ALS)-like syndrome [11]. Despite the fact that few patients (<10%) will develop classical syndromes (ATLL and HAM/TSP), preliminary observations indicate that other symptoms and subclinical neurological disturbances can develop in those individuals [12], but they have not been well-defined as new clinical outcomes related to early inflammation process.

In addition, peripheral neuropathy is significantly more frequent in the seropositive group. In a study with 153 HTLV-1-infected carriers, the presence of higher frequency of motor and bladder dysfunctions in HTLV-1 patients as compared with uninfected control subjects was found [13]. Those data suggest that HTLV-1-infected individuals may exhibit a wide variety of neurological manifestations distinct from the classical picture of HAM/TSP [13]. It is unclear whether such manifestations share a common characteristic with the spinal cord disease.

This study aims to demonstrate that some clinical conditions, neurological finds and HTLV-1 proviral load may be associated with further development of full-blown HAM/TSP, in individuals considered free of the disease according to currently used criteria for its diagnosis. To do so we studied patients from a large cohort of asymptomatic HTLV-1 carriers who have been followed for more than twenty years.

Methods

Our cohort has 659 HTLV-1-only infected subjects, with its inception dating back to 1997 [14]. It is an open cohort, with new patients added at a rate of approximately 50 per year. To avoid confounding, patients with HIV and/or HCV co-infections were excluded from this research, as well as other 90 patients who did not have a regular follow-up. For this study, 175 cases with confirmed HTLV-1 infection and without a HAM/TSP diagnosis were included and blindedly assessed during their regular follow-up at the HTLV outpatient clinic of the Institute of Infectious Diseases “Emilio Ribas”, Sao Paulo city, Brazil.

Results

We enrolled 175 HTLV-1 patients on this study and classified them as having or not criteria for the diagnosis of the intermediate syndrome. Based on a thorough neurological examination, 42 patients met the criteria for making the diagnosis of the intermediate syndrome, whereas 133 did not and were called “asymptomatic” (not having the intermediate syndrome). All of them had intermediate symptoms that were classified as probable HAM/TSP at entry, primarily neurogenic bladder confirmed by urodynamic study. Table 1 shows the univariate analyses of socio demographic variables and proviral load of all volunteers; mean age of the enrolled subjects (n = 175) was 46.3 years and 130 (74.3%) were females. Most of the patients were white (56.5%), and the PVL from the IS cases was six times that from patients without IS (p<0.001). Clinical classificafion on Table 2 shows that neurologic symptoms/signals (p<0.001), visual disorders (p = 0.001), oral manifestations (p = 0.001), skin lesions (p<0.001), bladder disorders (p<0.001), and rheumatologic symptoms (p = 0.001), were strongly associated to IS, except for disautonomy (p = 0.21).

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Table 1. Univariate analyses of socio demographic variables and their association with the intermediate syndrome.

https://doi.org/10.1371/journal.pntd.0006967.t001

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Table 2. Conditions associated with HTLV-1 seropositivity among patients with and without the intermediate syndrome.

https://doi.org/10.1371/journal.pntd.0006967.t002

On a multivariate model analysis, including gender, age, and PVL and several clinical conditions, such as oral conditions, bladder disorders and rheumatological symptoms were independently associated with SI outcome. In this same model, all these variables and age were also significantly associated with the outcome, when included as continuous variables (Table 3).

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Table 3. Logistic regression of variables associated with intermediate syndrome.

https://doi.org/10.1371/journal.pntd.0006967.t003

Table 4 shows that the presence of more than three or more signs and/or symptoms was significantly associated with the intermediate syndrome (p = 0.006), therefore the the cut-off point for that diagnosis was set at this point.

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Table 4. Association of the neurologic symptoms with HTLV-1 DNA proviral load.

https://doi.org/10.1371/journal.pntd.0006967.t004

Discussion

This study aimed to define the early neurological disorders that can be present in HTLV-1-infected subjects. We found 24% of HTLV-1-infected patients from our outpatient service who were initially considered asymptomatic to have enough signs and symptoms putting them on a novel category, called intermediate syndrome. The correlation between some of their symptoms and the proviral load also reinforces the importance of such mild forms, which may constitute either an independent clinical intermediate syndrome or markers for an early diagnosis of HAM/TSP. A significantly PVL was also present in patients presenting three or more symptoms or signs.

HAM/TSP is a chronic progressive myelopathy characterized by bilateral pyramidal tract involvement with sphincter disturbances. Why only a small proportion of HTLV-1-infected individuals develops classical HAM/TSP is not known [11]. The main neurological symptoms of the disease are progressive and lead to deterioration in the quality of life, but minor neurological symptoms can also be found among HTLV-1 carriers [11]. In a study with 153 HTLV-1-infected carriers and 388 HTLV-2-infected subjects, the presence of neurological abnormalities was prospectively ascertained, with a higher frequency of motor and bladder dysfunctions in HTLV-1 as compared with uninfected control subjects [10]. All those data suggest that HTLV-1-infected individuals can exhibit a wide variety of neurological manifestations distinct from the classical picture of HAM/TSP [11]. It is unclear whether those manifestations share a common characteristic with this diagnosis.

We and others have shown a correlation between proviral load and Tax gene expression with the presence of HAM/TSP [14,19,20]. We hypothesize that the burden of HTLV-1 was correlated with neurological disturbances that fall short of HAM/TSP, and with cognitive dysfunction. Demonstration of that hypothesis might provide a link between HTLV-1 burden and early neurological dysfunctions, providing impetus to the development of methods aiming to reduce the proviral load in infected subjects.

Perhaps the explanation for the observed neurological findings lies in the white matter. The white matter present in the CNS has the important function of transporting neural signals from subcortical regions to the cortex and from the cortex to the subcortical regions. In the CNS, ischemic and traumatic injuries often result in significant functional deficit, most of which can be attributed to white matter dysfunction [21–23]. In the case of HTLV-1, there is participation of components of the inflammatory response on the mechanisms underlying the demyelination process characteristic of this disease [20].

We found that HTLV-1 infection is associated with a variety of clinical manifestations occurring in patients who either do not have or who did not have developed full HAM/TSP yet. The correlation between some of their symptoms and the proviral load also reinforces the importance of such milder forms, which may constitute either an independent clinical SI or markers for an early diagnosis of HAM/TSP. A significantly higher proviral load was present in patients presenting more than three symptoms/signs, a cut-off point that can constitute a surrogate marker for clinical progression.

In conclusion, this preliminary report identified the presence of some clinical and neurological symptoms, in subjects classified originally as "asymptomatic," which may be promising markers for early HAM/TSP progression. This knowledge may contribute for a stricter clinical vigilance of the so-called asymptomatic HTLV-1 positive patients, prompting the introduction of a treatment for the infection, if and when it becomes available in the future.

Supporting information

Acknowledgments

Maira Pedreschi for performing the HTLV-1 proviral load quantification; and all the volunteers in this study for accepting participating.