Tropical Spastic Paraparesis Research Articles

CXCL-10 in Cerebrospinal Fluid Detects Neuroinflammation in HTLV-1-Associated Myelopathy with High Accuracy

Background and Objectives: HTLV-1-associated myelopathy (HAM) is a chronic progressive inflammatory disease of the spinal cord. This study assesses the diagnostic accuracy of the neuroinflammatory biomarkers neopterin and cysteine-X-cysteine motif chemokine ligand 10 (CXCL-10) in cerebrospinal fluid (CSF) for HAM. Methods: CSF samples from 75 patients with neurological disorders—33 with HAM (Group A), 19 HTLV-1-seronegative with other neuroinflammatory diseases (Group B), and 23 HTLV-1-seronegative with non-neuroinflammatory diseases (Group C)—were retrospectively evaluated. CSF examination included routine analysis, neopterin, and CXCL-10. The diagnostic potential of the biomarkers was evaluated using receiver operating characteristic curves. Results: Higher white cell counts and concentrations of protein, neopterin, and CXCL-10 in CSF were detected in group A (patients with HAM) and group B (p < 0.05). Neopterin showed good accuracy for HAM (A) (cut-off 15 nmol/L, 80% sensitivity, 74% specificity) and other neuroinflammation (group B) (cut-off 20 nmol/L, 79% sensitivity, 83% specificity). CXCL-10 demonstrated the highest accuracy in both groups, with Group A (cut-off 110 pg/mL, 97% sensitivity, 96% specificity) and Group B (cut-off 220 pg/mL, 100% sensitivity, 100% specificity). Conclusions: Neopterin and CXCL-10 in CSF are accurate biomarkers for detecting neuroinflammation, including HAM. CXCL-10, in particular, is the superior biomarker for both chronic and acute neuroinflammatory diseases.

Exploring the Impact of Interferon-Gamma Single Nucleotide Polymorphisms on HTLV-1 Infection: Unraveling Genetic Influences in Viral Pathogenesis.

Human T-lymphotropic virus-1 (HTLV-1) induces neoplastic adult T-cell leukemia/lymphoma (ATLL) and neurological HTLV-1 associated myelopathy (HAM) in approximately 3%-5% of infected individuals. The precise factors that facilitate disease manifestation are still unknown; interaction between the virus and the host's immune response is key. Cytokines regulates physiological activities and their dysregulation may initiate the pathogenesis of various malignant and infectious diseases. Genetic variations, particularly polymorphisms in gene regulatory regions, lead to varying cytokine production patterns. Interferon-gamma (IFN-γ), a key cytokine in HTLV-1 infection, is a signature cytokine for T-helper 1 (Th1) cells that interferes with viral replication and enhances innate and adaptive immune responses during viral infections. The IFNG gene possesses several single nucleotide polymorphisms (SNPs), among which the +874A/T SNP has been widely studied for its functional role in HTLV-1 infection. The purpose of this review was to provide insight into the impact of IFNG SNPs on HTLV-1 Infection.

Performance evaluation of CXCL10 ELISA “cosmic” kit to measure CXCL10 in cerebrospinal fluid of patients with HTLV‐1‐associated myelopathy

AbstractObjectivesThis study aimed to validate the clinical utility of cerebrospinal fluid (CSF) CXCL10 measurements in HTLV‐1‐associated myelopathy (HAM) using a CXCL10 ELISA “Cosmic” kit, a more widely applicable method than cytometric bead array (CBA).MethodsCSF CXCL10 levels were measured in 165 samples from 111 patients with HAM and 18 controls using a CXCL10 ELISA “Cosmic” kit. We assessed the following: (1) CSF CXCL10 concentrations by HAM activity level (high, moderate, and low) versus controls; (2) correlation with CBA; (3) cutoff values, sensitivity, and specificity for differentiating among HAM activity levels; (4) changes in HAM activity after steroid therapy; and (5) relationship between HAM activity and prognosis in patients undergoing steroid therapy. A correlation coefficient of ≥0.9 with CBA was the primary endpoint.ResultsThe median CSF CXCL10 levels in the high, moderate, low, and control groups were 4016.0, 841.0, 112.8, and 102.5 pg/mL, respectively. The ELISA findings were highly correlated with the CBA findings (r = 0.99). Cutoff values were set at 2500 pg/mL (sensitivity, 93.3%; specificity, 100%) to distinguish between high and moderate activity and 180 pg/mL (sensitivity, 81.8%; specificity, 100%) for low to moderate activity comparable to CBA. The new cutoffs enabled the detection of HAM activity changes and prediction of motor disability progression under steroid therapy.ConclusionCXCL10 ELISA “Cosmic” kit findings were strongly correlated with CBA findings, meeting the primary endpoint and demonstrating comparable sensitivity and specificity for distinguishing HAM activity. This product shows a promising ability to determine the therapeutic strategy.

New insight into the molecular etiopathogenesis of konzo: Cyanate could be a plausible neurotoxin contributing to konzo, contrary to thiocyanate

IntroductionChronic cassava-derived cyanide poisoning is associated with the appearance of konzo, a tropical spastic paraparesis due to selective upper motor neuron damage. Whether the disease is caused by a direct action of cyanide or its metabolites is still an open question. This preliminary study assessed the neurotoxic effects of thiocyanate (SCN) and cyanate (OCN), two cyanide metabolites hypothesized to be plausible toxic agents in konzo. MethodsCultured mouse neuroblastoma (Neuro-2A) and human neuroblastoma (SH-SY5Y) cell lines were incubated (24, 48, and 72hours) in sodium OCN or sodium SCN in a disease-relevant concentration range. Cell viability, caspase (3, 8, and 9) activities, and reactive oxygen species (ROS) generation were evaluated using appropriate assay kits. Additionally, electrophysiological responses induced by OCN and SCN in primary spinal cord neurons (from Sprague Dawley rats) were assessed by whole-cell patch-clamp techniques. ResultsBoth OCN and SCN were toxic in a dose-dependent way, even if SCN toxicity appeared at very high concentrations (30mM, corresponding to more than 100-fold higher than normal plasmatic levels), contrary to OCN (0.3-3mM). OCN was markedly more toxic in a poor culture medium (MEM; IC50 = 3.2mM) compared to a glucose- and amino acid-rich medium (DMEM; IC50=7.6mM). OCN treatment increased the ROS generation by 8.9 folds, as well as the Caspase-3, Caspase-8, and Caspase-9 activities by 3.2, 2.5, and 2.6 folds, respectively. Finally, OCN (and SCN to a lesser extent) induced depolarizing currents in primary spinal cord neurons, through an activation of ionotropic glutamate receptors. ConclusionOur results suggest OCN as the most plausible neurotoxic agent involved in konzo, while SCN toxicity could be questioned at such high concentrations. Also, they support apoptosis, oxidative stress, and excitotoxicity as probable mechanisms of OCN neurotoxicity.

Correlation Between TWEAK Serum Level and HTLV-1 Proviral Load in HAM/TSP.

Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the main neurological manifestation of HTLV-I, is a chronic inflammatory disease. Viral-host interaction and host genetics are two important contributors to the development of the HAM/TSP. This study was conducted to measure the serum level of tumor necrosis factor-alpha-like weak inducer of apoptosis (TWEAK) by ELISA method in three groups of participants including 34 HAM/TSP patients (HAM/TSP), 35 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). Also, the titer of the proviral load in two groups of HAM/TSP and ACs was assessed by the real-time polymerase chain reaction (PCR). The statistical results showed that, there is no significant difference between the three groups in TWEAK cytokine level (p = 0.667). Also, there was no significant difference in proviral load titer between groups of HAM/TSP and ACs (p = 0.08). Furthermore, no significant difference was observed between proviral load and TWEAK cytokine concentration between groups of HAM/TSP and ACs. Our findings showed that despite the inflammatory nature of HAM/TSP disease, the expression level of TWEAK in HAM/TSP patients is not significantly different from the groups of ACs and HCs. Therefore, the involvement of other factors in causing HAM/TSP is not unexpected.

CX3CR1+/UCHL1+ microglial extracellular vesicles in blood: a potential biomarker for multiple sclerosis

In neuroinflammation, distinguishing microglia from macrophages and identifying microglial-specific biomarkers in peripheral blood pose significant challenges. This study comprehensively profiled the extracellular vesicles (EVs) of microglia and macrophages, respectively, revealing co-expressed EVs with UCHL1 and CX3CR1 as EVs derived specifically from microglia in human blood. After extensive validation, using optimized nano flow cytometry, we evaluated plasma CX3CR1+/UCHL1+ EVs across clinical cohorts [multiple sclerosis (MS), HTLV-1 associated myelopathy (HAM), Alzheimer’s disease (AD), and Parkinson’s disease (PD)], along with established neurodegenerative markers (NMDAR2A and NFL). The findings discovered a notable rise in CX3CR1+/UCHL1+ EVs in MS, particularly heightened in HAM, in contrast to controls. Conversely, AD and PD exhibited unaltered or diminished levels of microglial EVs. An integrated model of CX3CR1+/UCHL1+, NMDAR2A+, and NFL+ EVs demonstrated promising diagnostic potential for distinguishing MS from controls and HAM. As to the disease duration, CX3CR1+/UCHL1+ EVs increased in the initial five years of MS, stabilizing thereafter, whereas NMDAR2A+ and NFL+ EVs remained stable initially but increased significantly in the subsequent five years, suggesting their correlation with disease duration. This study uncovers unique blood microglial EVs with potential as biomarkers for MS diagnosis, differentiation from HAM, and correlation with disease duration.

Rapidly Progressive HTLV-1 Associated Myelopathy after Immune Checkpoint Inhibitor Therapy

Rapidly Progressive HTLV-1 Associated Myelopathy after Immune Checkpoint Inhibitor Therapy

Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics.

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with age of onset varying sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ABCD1 ortholog Abcd1 (CG2316). Knockdown or deficiency of Abcd1 leads to VLCFA accumulation, salivary gland defects, locomotor impairment and retinal lipid abnormalities. Interestingly, there is also evidence of reduced peroxisomal numbers. Flies overexpressing the human cDNA for ABCD1 display a wing crumpling phenotype characteristic of the pex2 loss-of-function. Surprisingly, overexpression of human ABCD1 appears to inhibit or overwhelm peroxisomal biogenesis to levels similar to null mutations in fly pex2, pex16 and pex3. Drosophila Abcd1 is therefore implicated in peroxisomal number, and overexpression of the human ABCD1 gene acts a potent inhibitor of peroxisomal biogenesis in flies.

Plasma vitamin D levels are correlated with the pathogenesis of human T-cell leukemia virus type 1-associated diseases.

The active form of vitamin D (VD) exerts hormonal effects by regulating the expression of genes involved in T-cell activity, cell differentiation, and proliferation. Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of life-threatening diseases, adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy (HAM). Among ATL patients, hypercalcemia is one of the most serious complications due to bone resorption. In this study, wild-type mice administered UV-irradiated HTLV-1-infected cells showed up to 47% decrease of plasma VD level compared with untreated mice. To clarify the effect of HTLV-1 on plasma VD level, 315 samples registered in nationwide cohort study on ATL onset were measured. The VD level in HAM (14.98 ± 8.5 ng/mL) was significantly lower than those in asymptomatic carriers and ATL (p < 0.05). Upon comparing the VD levels in ATL stratified by disease subtypes, acute ATL showed a lower level (15.81 ± 12.0 ng/mL) than chronic and smoldering types (p < 0.05). In the longitudinal observation, VD levels were significantly higher in untreated spontaneous remission cases than in ATL progression cases, in which the VD levels decreased approximately 40% after onset. In cases of relapse after transplantation, the plasma VD level dropped to 38.7% of the pre-relapse level, while in cases of complete remission, the VD level increased with improvement of the performance status. Taken together, these results suggest that plasma VD level is a potential indicator for the onset and relapse of HTLV-1-associated diseases.

RNAseq-differentiated gene expression profile of people living with HTLV-1 in the Brazilian Amazon region: a pilot study

In this study, we aimed investigated the differential gene expression profiles of samples from uninfected individuals (control group) and study groups of asymptomatic human T-lymphotropic virus 1 (HTLV-1) carriers and patients with HTLV-1-associated myelopathy (HAM) by exploratory RNA sequencing (RNA-Seq) analysis. The gene expression profiles of individuals in the asymptomatic group were represented by 3 genes, most associated with cell cycle regulation. The gene expression profiles of individuals in the HAM group were represented by 12 genes, the majority of which are associated with the immune response. The HLA-A gene and the non-coding RNA LINC02470 were upregulated in the asymptomatic and HAM groups. The HLA-DQB1 and HLA-C genes were downregulated in the asymptomatic and HAM groups. In this pilot study, although limited in terms of methodological rigor, we showed differential gene expression profiles in different clinical groups of HTLV-1 infection. However, further studies are needed to confirm these findings.

Imbalanced IL10/TGF-β production by regulatory T-lymphocytes in patients with HTLV-1-associated myelopathy/ tropical spastic paraparesis

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-β. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines.MethodsAsymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-β-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells.ResultsTotal frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group.ConclusionsA higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-β may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.

IL-10 predicts incident neuroinflammatory disease and proviral load dynamics in a large Brazilian cohort of people living with human T-lymphotropic virus type 1.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

HTLV-1-Associated Myelopathy (HAM) Incidence in Asymptomatic Carriers and Intermediate Syndrome (IS) Patients.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

Cannabinoid receptors as new targets for HTLV-1 associated myelopathy (HAM/TSP) treatment

Background/AimThe roles of endocannabinoids are described in immune modulation and neuroprotection. HTLV-1-associated myelopathy (HAM/TSP) is an inflammatory neurodegenerative disease. Therefore, in this study, the interactions of HTLV-1 regulatory factors and host cannabinoid receptors (CBRs) were evaluated in HAM/TSP. MethodsNineteen HAM/TSPs, 22 asymptomatic carriers (ACs), and 18 healthy controls (HCs) were enrolled. RNA was extracted from PBMCs and then reverse-transcribed to cDNA. The gene expression of CB1R and CB2R, as well as HTLV-1 proviral load (PVL), Tax and HTLV-1 basic leucine zipper factor (HBZ) were assessed by RT-qPCR. ResultsThe mean expression of CB1R in ACs (8.51 ± 2.76) was significantly higher than HAMTSPs (1.593 ± 0.74, p = 0.05) and also HCs (0.10 ± 0.039, p = 0.001). The CB2R gene expression level in ACs (2.62±0.44) was significantly higher than HAM/TSPs (0.59 ± 0.15, p = 0.001) and HCs (1.00 ± 0.2, p = 0.006). Meanwhile there was a strong correlation between CB1R and CB2R gene expression levels in the HCs and HAM/TSPs (p = 0.001). HTLV-1-Tax expression in HAM/TSPs (386 ± 104) was higher than ACs (75 ± 32) and statistically significant (p = 0.003). While HTLV-1-HBZ was only expressed in three AC subjects and five HAM/TSPs, thus it cannot be analyzed. ConclusionThe up-regulation of CB2R has immunomodulatory effects in inflammatory reactions. While CB1R as a neuroprotective agent may suppress inflammatory reactions in ACs, preventing HAM/TSP. It seems that, like multiple sclerosis (MS), cannabinoid medications are beneficial in HAM/TSP.

HTLV: un nou subiect pentru screeningul prenatal?

Human T-cell leukemia virus-1 (HTLV-1) is the first infectious agent proven to cause cancer, and it is considered among the most potent carcinogens for humans. HTLV-1 is esti­ma­ted to have infected 5-10 million individuals, with only about 5% of people that contract the virus expected to de­velop any associated disease. Within Europe, Romania ap­pears to be the only region endemic to HTLV-1. There are two primary diseases associated with HTLV-1, T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM), or tropical spastic paraparesis (TSP). Each is linked to a dis­tinct mode of transmission: ATL with breastfeeding, and HAM/TSP with blood transfusion. The main ways of viral trans­mis­sion are from mother to child by breastfeeding, via blood transfusions, or through sexual intercourse. Vertical in­fec­tion rate has been found to be 14.2%. In Romania, HTLV is included in the screening for blood donors, but not in prenatal screenings. Vertically transmitted infections can be reduced with up to 87% by avoiding breastfeeding. New re­search supports the effectiveness of prenatal screening fol­lowed by avoiding breastfeeding in reducing new cases of HTLV in endemic areas, and such measures must be taken in Romania as well.

Determination of molecular epidemiologic pattern of human T-lymphotropic virus type 1 (HTLV-1) in Alborz province, Iran.

Human T-cell lymphotropic virus type 1 (HTLV-1) is linked to two debilitating diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy tropical spastic paraparesis (HAM/TSP), which are prevalent in various parts of the world, including the Alborz province in Iran. Understanding the prevalence and evolutionary relationships of HTLV-1 infections in these endemic areas is of utmost importance. In the realm of phylogenetic studies, long terminal repeat (LTR) region of HTLV-1 stands out as highly conserved, yet more variable compared to other gene segments. Consequently, it is the primary focus for phylogenetic analyses. Additionally, trans-activator of transcription (Tax), an oncoprotein, holds a pivotal role in the regulation of gene expression. This cross-sectional study delved into the phylogenetic analysis of HTLV-1 among individuals in Alborz province of Iran. To confirm infection, we amplified partial sequence LTR (PLTR) and HTLV-1 bZIP factor (PHBZ). For phylogenetic analysis, we sequenced the full sequence LTR (FLTR) andfull Tax sequence (FTax). The FLTR and FTax sequences underwent analysis using BioEdit, and phylogenetic trees were constructed using MEGA-X software. Out of the roughly 15,000 annual blood donors in Alborz, 19 samples tested positive for HTLV-1, indicating a 0.13% HTLV-1 positivity rate among blood donors. Furthermore, the HTLV-1 virus prevalent in the Alborz province belongs to subtype A (cosmopolitan) subgroup A. The findings revealed that while mutations were observed in both the LTR and Tax genes, they were not significant enough to bring about fundamental alterations. Despite positive selection detected in three Alborz isolates, it has not led to mutations affecting Tax function and virulence.

How do socioeconomic determinants of health affect the likelihood of living with HTLV-1 globally? A systematic review with meta-analysis.

Human T Lymphotropic Virus type 1 (HTLV-1) is a neglected retrovirus associated with many clinical disorders, most notably Adult T-cell Leukemia/Lymphoma and HTLV-1-Associated Myelopathy (HAM). Found in endemic clusters across the world, high prevalence has been reported in minoritized groups who suffer from health inequities. This study investigates the association between HTLV-1 prevalence and the following socioeconomic determinants of health: education, income, and employment, which are markers of health inequity. A systematic review was conducted by searching the following databases: Ovid/Medline, Embase, Global Health Database, Web of Science, LILACS and SciELO. Primary studies in English, Spanish and Portuguese mentioning HTLV-1 and one of education, income and/or employment were included. A random-effects meta-analysis was performed, and odds ratios (OR) were calculated to determine the association between these socioeconomic determinants of health and HTLV-1 prevalence. 42 studies were included. The likelihood of having HTLV-1 was higher in individuals with less than completed primary education compared to those who completed primary education (OR 1.86 [95% CI 1.34-2.57]; p < 0.01). This may be because individuals with low education have reduced access to and understanding of health information, thus increasing the prevalence of risk factors associated with HTLV-1 infection. No other determinants were found to be statistically significant. Fewer years of schooling are associated with increased likelihood of contracting HTLV-1. Therefore, health promotion materials and public health policies regarding HTLV-1 must consider those with lower educational levels to effectively reduce disease transmission. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=335004, identifier (CRD42022335004).

Mycophenolate mofetil for the long-term treatment of HTLV-1 associated myelopathy: A case report

Human T-cell leukemia virus type 1 (HTLV-1) can cause HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Current treatment options for HAM/TSP are limited. We present a woman with rapidly-progressive HAM/TSP with significant, sustained clinical improvement following initiation of mycophenolate mofetil (MMA). Peripheral blood mononuclear cells from the patient, her asymptomatic carrier husband and eight healthy controls were isolated. Frequencies of T-cell populations upon exposure to low and high MMA concentrations and differences in proliferation were analyzed using flow cytometry and a CSFE-proliferation assay. Characterization of T-cell function and proliferation showed higher levels of GranzymeB in HTLV-1+ donors. The improvement and stability of symptoms in this patient with HAM/TSP following MMA initiation requires further study as a potential treatment for HAM/TSP.

Nonpharmacological interventions and outcomes in the management of complications of human T-cell lymphotropic virus type 1-related myelopathy/tropical spastic paraparesis: A systematic review.

Human T-cell lymph tropic virus type 1 (HTLV-I)-related myelopathy/tropical spastic paraparesis (TSP) is a progressive inflammatory process affecting the spinal cord that occurs as a result of HTLV 1. The use of nonpharmacological approaches has always been one of the treatment strategies in these patients, but disagreement about these interventions and their results has led to their limited use. Therefore, this study aimed to identify nonpharmacological interventions and their consequences in these patients. We followed the Cochrane Handbook for systematic reviews of interventions. The present report is organized according to the preferred reporting items for systematic reviews and meta-analyses. This study was conducted at PubMed, Cochrane Library, Web of Science, and Scopus, among all published studies by December 30, 2021. Keywords were: HTLV-1, Human T-lymph tropic virus 1, HTLV-I-associated myelopathy, HAM/TSP, tropical spastic paraparesis, nonpharmacological intervention, nonpharmacological treatment, massage, physiotherapy, acupuncture, acupressure, and exercise. The quality of the studies was assessed using JADAD. Of 288 articles, 11 were eligible for data extraction published between 2014 and 2021. 90/9% of studies were randomized clinical trials. 81/8% of articles were of high quality. The total sample size was 253 people, of which 137 (54/15%) were women. Approaches such as exercise and motion therapy, electrotherapy, behavioral therapy, and virtual reality can be used for these patients. With these interventions, results such as improved mobility and balance, physical condition, pain, quality of life, muscle spasticity, maximum inspiratory pressure, and urinary symptoms can be achieved. The most common physical therapy method used in studies was active and passive body movements, which are associated with positive results for patients. Due to the small sample size in this group of studies, it is necessary to conduct more clinical trials for more accurate conclusions. Furthermore, due to the limited number of studies that have used electrical stimulation or combined intervention packages, it is not possible to say with certainty what effect these methods have on patients. It is necessary to conduct more clinical trials.

HTLV-1-associated myelopathy in Spain

BackgroundHTLV-1 infection is a neglected disease. Over 10 million people are infected worldwide, with hot spots of high endemicity across all continents. Roughly 5% of HTLV-1 carriers develop HTLV-1-associated myelopathy (HAM), a progressive subacute neurological disabling disease. MethodsWe report the main features of patients diagnosed with HAM up to date in Spain, a non-endemic country with a relatively high migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. ResultsA total of 451 cases of HTLV-1 had been recorded in Spain until the end of year 2022. HAM had been diagnosed in 58 (12.9%). The current incidence is of 2-3 new cases per year. Women represent 76%. Mean age at diagnosis is 49 years-old. Nearly 60% are Latin Americans. Although sexual transmission is the most likely route of HTLV-1 acquisition, up to 6 individuals had been infected following solid organ transplantation. Rapid onset myelopathy developed in all but one of these transplant recipients from three HTLV-1-positive donors. HTLV-1 subtype 1a transcontinental was the only variant recognized in HAM patients. HTLV-1 proviral load was significantly greater in HAM patients than in asymptomatic HTLV-1 carriers (677 vs 104 HTLV-1 DNA copies/104 PBMC; p=0.012). Symptom relief medications and physiotherapy have been the only treatment providing some benefit to HAM patients. Neither significant clinical nor virological efficacy was noticed using antiretrovirals in at least 9 HAM patients. Two thirds of HAM patients ended up in a wheelchair and with urinary/fecal sphincter incontinence. ConclusionHAM is the most frequent clinical manifestation of HTLV-1 infection in Spain, a non-endemic country. Middle aged women migrants from Latin America are the most frequently affected. Two thirds end up in a wheelchair despite using antiretroviral therapy.