Neurological Manifestations in Human T-Cell Lymphotropic Virus Type 1 (HTLV-1)-Infected Individuals Without HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Longitudinal Cohort Study.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) is the agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), observed in up to 5% of infected individuals. Despite low prevalence, many HTLV-1-infected patients who do not fulfill criteria for HAM/TSP present with neurological complaints related to sensory, motor, urinary, or autonomic manifestations. The aim of this study was to determine the incidence of neurologic manifestations and risk factors associated with these outcomes. METHODS: The incidence of HAM/TSP and new signs and neurologic symptoms were computed in a group of patients enrolled in a cohort study. RESULTS: Of 414 subjects, 76 had definite HAM/TSP, 87 had possible or probable HAM/TSP, and 251 subjects had no neurologic manifestation and were selected for analysis. Definite HAM/TSP developed in 5 (1.47%) patients. Follow-up of at least 3 years was achieved in 51% of patients. The incidence rate was computed in 1000 person-years (206 for hand numbness, 187 for feet numbness, 130 for nocturia, and 127 for urgency). Average incidence rate in neurological exam was 76 for leg hyperreflexia, 53 for leg weakness, and 37 for Babinski sign. In the applied Expanded Disability Status Scale, the incidence rate of worsening 1 point was 134 per 1000 person-years. Kaplan-Meier curves stratified by sex and proviral load showed that females and patients with proviral load >50,000 copies/10(6) peripheral blood mononuclear cells had a higher risk of progression. CONCLUSIONS: Development of neurological symptoms or signs occurred in up to 30% of asymptomatic subjects during 8 years of follow-up.

Soluble IL-2 receptor and beta-2 microglobulin as possible serologic markers of neurologic disease in HTLV-1 infection.

The human T-cell leukemia virus (HTLV-1) is the causative agent of a variety of neurologic diseases, including HTLV-1 Associated Myelopathy (HAM/TSP) and overactive bladder. Investigation of immune markers such as soluble interleukin-2 receptor (sIL-2R) and beta-2 microglobulin (B2M) has shown some promising results in distinguishing patients with neurologic disease from those with carrier status. The objective of the present study was to determine if plasma levels of sIL-2R and B2M are markers of neurologic disease in individuals infected with HTLV-1. The present study was divided into two parts. A cross-sectional study and a nested case control study. In the cross-sectional study, HAM/TSP patients had higher plasma levels of B2M and sIL-2R than patients with overactive bladder and HTLV-1 carriers (P < 0.01 for all comparisons). For the nested case control study, the sIL-2 receptor test was able to distinguish patients with HAM/TSP from patients in the combined group of carriers and patients with overactive bladder with a sensitivity of 75.8% and false positive rate of 25.4%. Plasma levels of these markers did not change with the development of HAM/TSP and overactive bladder in HTLV-1 carrier patients. The present study has shown the importance of sIL-2 receptor in helping identifying HAM/TSP. However, the levels of these makers did not change significantly with the development of neurologic disease.

Onabotulinumtoxin type A improves lower urinary tract symptoms and quality of life in patients with human T cell lymphotropic virus type 1 associated overactive bladder.

AIM: To evaluate the efficacy of the onabotulinum toxin type A in the treatment of HTLV-1 associated overactive bladder and its impact on quality of life (QoL). METHODS: Case series with 10 patients with overactive bladder refractory to conservative treatment with anticholinergic or physical therapy. They received 200Ui of onabotulinumtoxin type A intravesically and were evaluated by overactive bladder symptoms score (OABSS) and King's Health Questionnaire. RESULTS: The mean (SD) of the age was 52+14.5 years and 60% were female. All of them had confirmed detrusor overactivity on urodynamic study. Seven patients had HAM/TSP. The median and range of the OABSS was 13 (12-15) before therapy and decreased to 1.0 (0-12) on day 30 and to 03 (0-14) on day 90 (p<0.0001). There was a significant improvement in 8 of the 9 domains of the King's Health Questionnaire after the intervention. Hematuria, urinary retention and urinary infection were the complications observed in 3 out of 10 patients. The mean time to request retreatment was 465 days. CONCLUSION: Onabotulinum toxin type A intravesically reduced the OABSS with last long effect and improved the quality of life of HTLV-1 infected patients with severe overactive bladder.

Clinical manifestations associated with HTLV type I infection: a cross-sectional study.

Human T-lymphotropic virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia in a small percentage of infected individuals. HTLV-I infection is increasingly associated with clinical manifestations. To determine the prevalence of clinical manifestations in HTLV-I infected individuals, we conducted a cross-sectional study of 115 HTLV-I-infected blood donors without myelopathy and 115 age- and sex-matched seronegative controls. Subjects answered a standardized questionnaire and underwent physical examination. Compared with controls, HTLV-I-infected subjects were more likely to report arm or leg weakness (OR = 3.8, 95% CI: 1.4-10.2; OR = 4.0, 95% CI: 1.6-9.8, respectively), hand or foot numbness (OR = 2.1, 95% CI: 1.1-3.9; OR = 4.8, 95% CI: 2.0-11.7, respectively), arthralgia (OR = 3.3, 95% CI: 1.7-6.4), nocturia (OR = 2.7, 95% CI: 1.04-6.8), erectile dysfunction (OR = 4.0, 95% CI: 1.6-9.8), and to have gingivitis (OR = 3.8, 95% CI: 1.8-7.9), periodontitis (OR = 10.0, 95% CI: 2.3-42.8), and dry oral mucosa (OR = 7.5, 95% CI: 1.7-32.8). HTLV-I infection is associated with a variety of clinical manifestations, which may occur in patients who have not developed myelopathy.

Brain magnetic resonance imaging white matter lesions are frequent in HTLV-I carriers and do not discriminate from HAM/TSP.

Human T lymphotropic virus (HTLV)-I is known to cause HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other pronounced disease in less than 4% of those infected. However, evidence is accumulating that a proportion of HTLV-I carriers have neurological and urological symptoms without fulfilling criteria for HAM/TSP. Brain white matter (WM) lesions on magnetic resonance imaging (MRI) are frequently seen in HAM/TSP. HTLV-I carriers with MRI scans for other neurological diagnoses have WM lesions more frequently than expected. We studied 10 patients with HAM/TSP and 20 HTLV-I carriers without overt neurological disease and evaluated clinical characteristics, viral load, total, small, large, confluent WM lesion number, and lesion volume on MRI. Cerebral WM lesions were found in of 85% of HTLV-I carriers and 80% of HAM/TSP patients. Lesion number, size or location was no different between carriers and HAM/TSP. Cognitive function was lower in HAM/TSP (p = 0.045) but did not correlate with WM lesion number. Viral load and peripheral blood mononuclear cell interferon production correlated positively (p = 0.001) but did not correlate with lesion number or volume. Conventional brain MRI frequently shows WM lesions in HTLV-I-infected individuals suggesting potential early central nervous system inflammation with rare development of progressive disease.

Psychiatric Disorders in HTLV-1-Infected Individuals with Bladder Symptoms.

BACKGROUND: Previous studies have reported high rates of depression and anxiety in HTLV-1 infected individuals with the neurological disease and in the asymptomatic phase. No study has investigated the rates in individuals that already show bladder symptoms without severe neurological changes; that is, during the oligosymptomatic phase. The present study investigated patients in this intermediate form on the spectrum of the infection. METHODOLOGY/PRINCIPAL FINDINGS: Participants answered a sociodemographic questionnaire, the Mini International Neuropsychiatric Interview Brazilian Version 5.0.0 (MINI PLUS) and the Hospital Anxiety and Depression Scale (HADS). Data analysis was performed in STATA statistical software (version 12.0). Depressive disorder was the most frequent comorbidity. Current depressive disorder was higher in the group of overactive bladder subjects (11.9%), and lifelong depression was more frequent in the HAM/TSP group (35%). The three groups had similar frequencies of anxiety disorders. Increased frequency and severity of anxiety and depression symptoms were observed in the overactive bladder group. CONCLUSION/SIGNIFICANCE: The results suggest that individuals with overactive bladders need a more thorough assessment from the mental health perspective. These patients remain an understudied group regarding psychiatric comorbidities.

Characterization of the immune response to Leishmania infantum recombinant antigens.

Leishmaniases have a high prevalence in tropical countries. In order to improve existing diagnostic systems based on total Leishmania proteins, and to identify antigen candidates for vaccine development, an intensive search for the identification of antigens was performed using molecular biology techniques. In this study, the immune response to three L. infantum recombinant antigens was evaluated. Upon stimulation with KMP11, mononuclear cells from leishmaniasis patients produced high levels of IL-10, while a predominant IFN-gamma production could be observed in cultures stimulated with H2A and soluble Leishmania antigen. All the recombinant antigens induced very little IL-5. KMP11 decreased IFN-gamma production by 48% in cultures of peripheral blood mononuclear cells from cutaneous leishmaniasis patients who had been stimulated with soluble Leishmania antigen. Furthermore, antibodies to KMP11 were detected in the sera from all patients with visceral leishmaniasis and in the majority of the sera from patients with cutaneous leishmaniasis or individuals with asymptomatic L. chagasi infection. Thus, KMP11 is recognized by cells and sera of patients with different clinical forms of leishmaniasis, and KMP11, through IL-10 production, proved to be a potent antigen in modulating type 1 immune response.

Treatment of strongyloidiasis in HTLV-1 and Strongyloides stercoralis coinfected patients is associated with increased TNFα and decreased soluble IL2 receptor levels.

BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) infection has been associated with recurrent and disseminated strongyloidiasis and adult T cell leukemia/lymphoma (ATLL). METHODS: We compared immunological aspects and markers for ATLL in HTLV-1 patients with or without strongyloidiasis, and evaluated the influence of Strongyloides stercoralis treatment on the immune response and clinical outcomes of HTLV-1 infection. RESULTS: Levels of TNFα and IFNγ were lower in patients coinfected with HTLV-1 and S. stercoralis than in patients with HTLV-1 only (p < 0.05), and there was an increase in TNFα levels after anthelmintic treatment. Levels of sIL-2R were higher in patients with HTLV-1 coinfected with S. stercoralis and anthelmintic treatment decreased sIL-2R levels (p < 0.05). The one patient who developed ATLL was coinfected with S. stercoralis. CONCLUSION: These data show that helminthic infection has a modulatory role in HTLV-1 infection and that S. stercoralis may be a cofactor in the development of ATLL.

Onabotulinumtoxin type A improves lower urinary tract symptoms and quality of life in patients with human T cell lymphotropic virus type 1 associated overactive bladder

ABSTRACT Aim: To evaluate the efficacy of the onabotulinum toxin type A in the treatment of HTLV-1 associated overactive bladder and its impact on quality of life (QoL). Methods: Case series with 10 patients with overactive bladder refractory to conservative treatment with anticholinergic or physical therapy. They received 200Ui of onabotulinumtoxin type A intravesically and were evaluated by overactive bladder symptoms score (OABSS) and King's Health Questionnaire. Results: The mean (SD) of the age was 52 + 14.5 years and 60% were female. All of them had confirmed detrusor overactivity on urodynamic study. Seven patients had HAM/TSP. The median and range of the OABSS was 13 (12-15) before therapy and decreased to 1.0 (0-12) on day 30 and to 03 (0-14) on day 90 (p < 0.0001). There was a significant improvement in 8 of the 9 domains of the King's Health Questionnaire after the intervention. Hematuria, urinary retention and urinary infection were the complications observed in 3 out of 10 patients. The mean time to request retreatment was 465 days. Conclusion: Onabotulinum toxin type A intravesically reduced the OABSS with last long effect and improved the quality of life of HTLV-1 infected patients with severe overactive bladder.

Helminthic infection and the risk of neurologic disease progression in HTLV-1.

BACKGROUND: Infection with the human T-cell lymphotropic virus, type 1 (HTLV-1) has been associated with an increased Th1 response. Interestingly, a higher prevalence of helminthic coinfection has been observed among infected individuals, and subsequent modulation of the immune response typically associated with helminths may influence clinical outcomes among HTLV-1 coinfected individuals. OBJECTIVE: This study was conducted to elucidate the association between helminthic coinfection and the development of clinically characterized neurologic disease that occurs in HTLV-1 infection. STUDY DESIGN: In a cohort analysis, incidence of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was recorded. Incidence of clinical outcomes and disease-free survival of several neurologic outcomes associated with HTLV-1 were estimated using the Kaplan-Meier method with log-rank tests. The relationships between helminthic infection and risk of HTLV-1 neurologic outcomes were assessed by Cox proportional hazard modeling. RESULTS: Seventy-four coinfected and 79 non-coinfected patients were followed, with 92 helminthic infections observed in the coinfected group. One patient per group developed HAM/TSP and the risk of progression to neurologic disease outcomes did not differ among those with and without helminthic coinfection (p>0.45). A significant difference was noted in the prevalence of neurologic disease outcomes among all patients at the conclusion of the study (p<0.01). CONCLUSIONS: These data suggest that treated helminthic infection does not affect risk of development of neurologic disease in HTLV-1 infection, and reinforce that treatment of helminths does not adversely affect patients with HTLV-1. Importantly, among all patients, an overall progression of neurologic disease was observed.

Immune responses to an inactive vaccine against American cutaneous leishmaniasis together with granulocyte-macrophage colony-stimulating factor.

The immunological response in healthy subjects to a crude leishmania antigen vaccine (Leishvacin) plus rhGM-CSF without prior Montenegro (DTH) skin testing was evaluated. Fifty-six healthy volunteers received vaccine plus either placebo or rhGM-CSF at day 0, followed by either a vaccine booster or placebo at day 21. IFN-gamma and IL-5 levels were significantly enhanced by day 21. The adjuvant group had a higher percentage of individuals with a significant response to vaccination than the corresponding placebo group. Eighty-six percent of all volunteers were DTH-positive by day 42. Leishvacin is capable of sensitizing lymphocytes from individuals not previously exposed to leishmania antigen. Use of rhGM-CSF enhanced the immune response, indicating that it may improve immunological response to the vaccine.