HTLV-I-associated myelopathy endemic in Texas-born residents and isolation of virus from CSF cells

We report three Texas-born patients with spastic paraparesis and well-documented infection with HTLV-I. CSF examination showed moderate pleocytosis, protein elevation, and elevated IgG index. Oligoclonal bands were present in two patients. On MRI, one patient had frontal lobe lesions that were low intensity on T1- and high intensity on T2-weighted images. HTLV-I immunoblot studies of serum and CSF revealed reactivity to p19, p24, p53, gp46, or gp68 from all three patients. Titration studies of serum and CSF antibodies on ELISA and immunoblot assays indicated an intrathecal virus-specific response. HTLV-I-specific p19 antigen capture assay and polymerase chain reaction (PCR) demonstrated HTLV-I in lymphocyte cultures derived from each patient's peripheral blood mononuclear cells (PBMC) or CSF cells. Using HTLV-I- and HTLV-II-specific pol and gag primers, PCR studies of PBMC cells obtained directly from the patients demonstrated that the patients were infected with HTLV-I and not HTLV-II. These three cases are to our knowledge the only US cases in whom virus isolation from the CSF has been accomplished. Importantly, two patients may be the first US cases of myelopathy arising from endemic infection.     

Diagnosis of HAM/TSP based on CSF proviral HTLV-I DNA and HTLV-I antibody index

The contribution of human T-cell lymphotropic virus (HTLV-I) DNA by PCR in CSF and the intrathecal synthesis of antibodies to HTLV-I by the antibody index (AI) to the diagnosis of HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were evaluated. Cases of spastic paraparesis compatible with HAM/TSP had increased AI for HTLV-I (60/73) and HTLV-I proviral sequences in CSF (25/27). Among 27 patients with other neurologic diseases, three had increased AI and another three had positive HTLV-I DNA in CSF. Thus, the combination of PCR for proviral DNA and AI for HTLV-I in CSF provides consistent criteria for the diagnosis of HAM/TSP.     

Oligoclonal IgG bands in patients with HTLV-I associated myelopathy--detection by agarose isoelectric focusing, transfer to cellulose nitrate and immunoperoxidase staining

The patient with HTLV-I associated myelopathy (HAM) shows a quite uniform clinical picture characterized by slowly progressive spastic paraparesis, slight sensory disturbances and urinary frequency, and the pathogenetic relationship between spastic paraparesis and HTLV-I was established. Since then, the role of the virus in causing myelopathy has drawn increasing attention. However, we have little information about cerebrospinal fluid (CSF) abnormalities in patients with HAM. Analysis of CSF oligoclonal bands (OB) in 22 patients with HAM was reported. All of 22 patients had typical clinical signs and symptoms of HAM with high titers of anti-HTLV-I antibodies in the serum by particle agglutination method. And these antibodies against HTLV-I were confirmed by enzyme-linked immunosorbent assay and western blot. Detection or characterization of CSF OB was done by high resolution agarose gel (HARG) electrophoresis with silver staining and immunofixation method with immunostaining. Other method for detection OB was by agarose isoelectric focusing (IEF), transfer to cellulose nitrate and immunoperoxidase staining (Olsson, 1984). CSF OB was detected in 13 of 22 patients with HAM by the method of immunofixation, using HRAG. All of CSF OB reacted with peroxidase conjugated goat anti-human IgG serum. More than 3 oligoclonal bands were not detected in HRAG electrophoresis. However, CSF OB was detected in all of 22 patients by the method of Olsson (IEF, in agarose, double-antibody peroxidase labelling and avidin-biotin amplification). The majority of patients with HAM had at least 5 or more OB in the region between pH 6.8 and 9.5.(ABSTRACT TRUNCATED AT 250 WORDS)     

An inverse correlation of HTLV-I viral load in CSF and intrathecal synthesis of HTLV-I antibodies in TSP/HAM.

The authors measured human T-cell lymphotrophic virus type I (HTLV-I) proviral load and intrathecal synthesis of antibodies to HTLV-I in CSF of 13 Brazilian patients with tropical spastic paraparesis/ HTLV-I-associated myelopathy (HAM). The authors also measured HTLV-I proviral load in peripheral blood mononuclear cells of five of these patients and found that it was 10- to 100-fold higher than that in CSF cells. The combination of HTLV-I proviral load and intrathecal synthesis of antibodies to HTLV-I appears to be a useful marker of disease progression. Patients with high viral load and no intrathecal synthesis of antibodies to HTLV-I had more rapidly progressing, serious clinical disease.     

Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases

Tropical spastic paraparesis (TSP) is a common myeloneuropathy with primary and predominant involvement of the pyramidal tract and minimal sensory loss. The epidemic form of TSP is related to toxic nutritional factors, but the endemic form occurs in clusters in tropical areas, especially in India, Africa, the Seychelles, Colombia, and areas of the Caribbean. We describe the clinical and epidemiological features of 25 TSP patients from Martinique (French West Indies) with serum antibodies to human T-lymphotropic virus type I (HTLV-I). Furthermore, all 11 patients who were seropositive for HTLV-I had specific HTLV-I antibodies in their CSF. All were women. The age of onset varied from 25 to 60 years (mean, 45 years). The main clinical features are spastic paraparesis or paraplegia with spasticity of the upper limbs, minimal sensory loss, and bladder dysfunction. Minimal estimated incidence and prevalence are 1 per 100,000 inhabitants per year and 8 per 100,000, respectively. Seventeen percent of the relatives of patients with HTLV-I-associated TSP have HTLV-I antibodies (1 husband and 7 children). In Martinique, the prevalence of HTLV-I antibodies in the general population is about 2% and reaches 10% for neurological disorders other than TSP. Since our initial report, the association between spastic paraparesis and HTLV-I has been confirmed in Jamaica, Colombia, and Japan, suggesting the neurotropism of this lymphotropic human retrovirus.     

HTLV-I infection and neurological disease in Rio de Janeiro.

Fifty patients with chronic neurological diseases attending a clinic in Rio de Janeiro, Brazil, were examined for evidence of HTLV-I infection. Fifteen of 27 with progressive paraparesis of obscure origin had antibodies to HTLV-I in high titre in their serum samples, and 10 of 13 studied had antibodies in their cerebrospinal fluid. The clinical features of the antibody positive patients were similar to those of patients with HTLV-I associated myelopathy from other countries except that half of the Brazilian patients were white. Seven patients had multiple sclerosis and one of these had antibodies to HTLV-I in the serum. None of the eight patients with motor neuron disease and four with polymyositis had HTLV-I antibodies in their serum samples.     

Increased reactivity to HTLV-I in inflammatory nervous system diseases

The presence of IgG antibodies reacting with purified and disrupted human T-lymphotropic virus type I (HTLV-I) was examined by an indirect enzyme-linked immunosorbent assay (ELISA) in sera from 49 patients with multiple sclerosis (MS), 21 patients with aseptic meningoencephalitis (AM), 12 patients with Guillain-Barré syndrome (GB), and 30 patients with tension headache (TH). This was also assessed in the concentrated cerebrospinal fluid (CSF) of most of these patients, as well as in sera of 60 blood donors (BD). Standardized amounts of serum IgG and CSF IgG were used in ELISA. For sera, higher reactivity with HTLV-I was found in all four patient groups compared with the BD group, but no significant differences were observed among the four groups. There was higher reactivity with HTLV-I in the CSF of patients with MS, AM, and GB compared to findings in patients with TH. Ten serum (2 MS, 3 GB, 3 TH, 2 BD) and 3 CSF (1 MS, 1 GB, 1 TH) specimens considered positive by ELISA for HTLV-I were found negative on confirmatory Western blot analysis. We extended this study to analyze the in vitro production of anti-HTLV-I-IgG antibodies by the 24-hour cultivation of unstimulated lymphocytes from peripheral blood and CSF of 6 additional patients with MS directly in HTLV-I antigen-coated wells of microtiter plates. This was followed by determination of specific antibodies by ELISA in the same wells. No antibody production was measurable. Our data do not favor the hypothesis of an HTLV-I-related human retrovirus in the etiology of MS.     

Is myelopathy of unknown origin related with tropical spastic paraparesis and myelopathy associated with human T cell lymphotropic virus type I?

Paired cerebrospinal fluid (CSF) and serum samples from 52 Italian patients affected by myelopathy of unknown origin (MUO) were tested for the presence of antibodies to human T cell lymphotrophic virus type I (HTLV-I) by an enzyme-linked immunosorbent assay, in an attempt to demonstrate a common retroviral origin of MUO, tropical spastic paraparesis (TSP) and HTLV-I-associated myelopathy (HAM). All the patients complained of weakness to the legs, while weakness to the arms, mild sensory disturbances, impaired bladder and bowel functions, and impotence were present in different percentages. All CSF and serum samples were devoid of HTLV-I antibodies. The possible relations between MUO, TSP and HAM are discussed.     

Epitope analysis of the cerebrospinal fluid IgG in HTLV-I associated myelopathy patients using phage display method

We, for the first time, analyzed the binding motifs of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF) of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with a phage library displaying 12-mer random peptides. As a result, the sequences highly homologous to HTLV-I gp46 192-199, 237-243 and 255-261 were the common linear epitopes of high affinity- IgG exclusively detected in both CSF and sera of the patients. These IgG responses were confirmed with corresponding HTLV-I peptides and serum antibody titers significantly correlated with disease severity or duration. Gp46 237-243 has not been detected in previous enzyme-linked immunosorbent assay (ELISA) studies using bound longer peptides, suggesting the usefulness of the phage display method.     

Search for HTLV-I and LAV/HTLV-III antibodies in serum and CSF of multiple sclerosis patients

In order to confirm the findings on the presence of antibodies against human T-lymphotropic retroviruses in subjects affected by multiple sclerosis we studied paired serum and CSF samples from 32 MS patients. Both ELISA and Western blot procedures were employed to detect antibodies against HTLV-I and LAV/HTLV-III antigens. Negative results were obtained in all samples examined, except one which was reactive to HTLV-I in ELISA but not in Western blot.     

Multiple sclerosis and human T-cell lymphotropic retroviruses: negative serological results in 135 German patients

Summary A total of 135 sera and 18 cerebrospinal fluid (CSF) samples from patients with multiple sclerosis (MS) were screened for antibodies to human T-cell lymphotropic virus type I(HTLV-I) and human immunodeficiency virus (HIV) by ELISA tests. None of the sera or CSF reacted with HIV antigens. Only 3 out of 135 MS sera but no MS CSF showed increased reactions in the ELISA test for HTLV-I. However, these positive reactions were classified as non-specific by immunoprecipitation. Thus no serological evidence for infection with HIV, HTLV-I, or a related retrovirus was found in the MS patients.     

Absence of antibodies to HTLV-I and HIV in serum and cerebrospinal fluid of Italian patients with multiple sclerosis

Because of the undecided question whether HTLV-related virus antibodies are present in multiple sclerosis (MS), we tested cerebrospinal fluid (CSF) and serum from 52 MS patients and 32 patients affected with other neurological diseases. ELISA procedure was used to detect antibodies against HTLV-I and HIV. Negative results were obtained in all samples examined.     

Human T-lymphotropic virus type I antibodies in the serum of patients with tropical spastic paraparesis in the Seychelles

Tropical spastic paraparesis (TSP), a chronic myelopathy of unknown etiology, was studied in the Seychelles. Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus antibodies were determined using an enzyme-linked immunosorbent assay and confirmed with an indirect fluorescent antibody test in serum samples of 20 patients with TSP and 16 controls. Test results indicated that 17 patients (85%) and two controls (transverse myelopathy and clinically probable multiple sclerosis) were positive for HTLV-I. Serum samples of nine healthy controls and five with other neurologic diseases were negative for HTLV-I. No serum samples were positive for human immunodeficiency virus. Estimated relative risk for TSP in those subjects whose serum is positive for HTLV-I antibodies is 40. This result is highly statistically significant. Although primarily associated with adult T-cell leukemia and non-Hodgkin's lymphoma, HTLV-I could also be an etiologic agent of TSP.     

HTLV-1 antibodies in serum and cerebrospinal fluid in tropical spastic paraparesis in Brazil

HTLV-1 antibodies were investigated in serum and in CSF of 150 patients with neurologic disorders mainly myelopathies. The patients were considered into three groups according to the possible relationship of their disease to the presence of HTLV-1 antibodies: no relationship risk (control group), occasional risk group, and possible risk group. In this latter are 56 patients with crural spastic paraparesis or paraplegia of unknown etiology (SP). HTLV-1 antibodies were tested by the passive particle-agglutination method for anti-ATLA antibody detection. The search was negative in all patients of the control group, and positive (serum and/or CSF) in 16.5% of the patients from the second group and in 55.4% of the SP patients group. Clinical patterns in SP cases with HTLV-1 antibodies were those of tropical spastic paraparesis (TSP). CSF patterns considered (cytology, protein content and gamma-globulins rate) were different between TSP group with HTLV-1 antibodies in CSF and SP group with no HTLV-1 antibodies detection either in serum or in CSF. The difference was significant. Results of this investigation confirm the high incidence of TSP in Brazil, and bring additional indication for searching HTLV-1 antibodies in the CSF.     

Antibody titers to HTLV-I-p40tax protein and gag-env hybrid protein in HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with increased HTLV-I proviral DNA load.

We studied the relationship between antibody titers to recombinant HTLV-I p40tax protein and gag-env hybrid protein in serum (by an enzyme-linked immunosorbent assay) and HTLV-I proviral DNA load in peripheral blood mononuclear cells (by a quantitative polymerase chain reaction method) in 18 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 17 HTLV-I carriers without HAM/TSP and 16 HTLV-I uninfected controls. The IgG and IgA antibody titers to either of the proteins correlated significantly with the HTLV-I pX (coding p40tax protein) and pol DNA amounts in HTLV-I infected subjects. HAM/TSP patients had significantly higher titers of IgG and IgA antibodies to the HTLV-I proteins than did the HTLV-I carriers without HAM/TSP. While the IgM antibodies to the HTLV-I proteins were found in only 6% of HTLV-I carriers without HAM/TSP, they were found in 40% of HAM/TSP patients, especially those having both a high HTLV-I proviral DNA load and high titers of the IgG and IgA antibodies. HAM/TSP patients with the IgM antibodies had a tendency to deteriorate more frequently on the Kurtzke's disability status scale and magnetic resonance imaging of the brain (leukoencephalopathy) than did those without in the two-year follow-up. Thus, the presence of IgM antibody and high titers of IgG and IgA antibodies to the HTLV-I proteins, together with the increased HTLV-I proviral DNA load, appears to distinguish HAM/TSP patients from HTLV-I carriers without HAM/TSP.     

Chronic progressive myelopathy associated with HTLV-I: oligoclonal IgG and anti-HTLV-I IgG antibodies in cerebrospinal fluid and serum

Among 22 patients with human T-lymphotropic virus type I (HTLV-I)-associated chronic progressive myelopathy, agarose isoelectric focusing (AIF) revealed oligoclonal IgG bands in 21: in 3 in CSF only; in 11 in CSF and to some extent in serum; and in 7, identical patterns in CSF and serum. By immunoblot after AIF of CSF and serum, we observed bands of anti-HTLV-I IgG antibodies in 19 patients: in 5 in CSF only; in 9 in CSF and partly in serum; and in 5, identical in CSF and serum. Oligoclonal anti-HTLV-I IgG antibody bands could only partly be traced to oligoclonal IgG bands. If, prior to AIF, serum and CSF were absorbed with HTLV-I antigen, practically all oligoclonal HTLV-I-specific IgG antibody activity was abolished, while the oligoclonal pattern of total IgG was affected only to a minor extent. Alongside with HTLV-I-specific oligoclonal B cell response, HTLV-I myelopathy is regularly accompanied by production of oligoclonal IgG of unknown antibody specificities.     

Evidence of preferential female prevalence of HTLV-I associated tropical spastic paraparesis in Bahia-Brazil.

In order to evaluate the prevalence of HTLV-I infection and its association with tropical spastic paraparesis (TSP) in Bahia, a Northeastern State of Brazil, CSF and sera from TSP patients and CSF and/or sera from some selected groups of individuals were studied. The results seem to indicate a higher prevalence of HTLV-I infection in women than men with TSP and among individuals of HIV risk groups. Some alterations of routine analysis of CSF can suggest HTLV-I infection in TSP patients.     

Possible association of HTLV-I infection and dementia

We report a Swedish patient with progressive dementia possibly associated with human T cell-lymphotropic virus type I (HTLV-I) infection. The clinical investigation revealed no typical sings of other neurological disorders. The patient was probably infected in East-Asia 35 years before onset of the disease. High titers of specific HTLV-I antibodies were detectable with solid-phase peptide ELISA in serum (1:1.600) and cerebrospinal fluid (CSF) (1:20), and the CSF/serum anti-HTLV-I antibody ratio indicated intrathecal HTLV-I antibody synthesis. Western blot for HTLV-I and polymerase chain reaction with primers selected for the HTLV-I pol gene were positive in both peripheral blood and cerebrospinal fluid. HTLV-I antigen was also demonstrated after in vitro co-cultivation of mononuclear cells from peripheral blood. Thus, our findings indicate that HTLV-I infection also may be associated with dementia. In addition, this case report calls attention upon HTLV-I as a possible etiologic agent to neurological diseases in countries previously spared from the infection.     

Spastic paraparesis associated with human T-lymphotropic virus type I: A clinical,serological, and genomic study in Iranian-born Mashhadi Jews

The Mashhadi-Jewish community originating in Iran is a closed and ethnically segregated population with a unique history and a high rate of intrafamilial marriage among its members. A high risk of infection by human T-lymphotropic virus type I (HTLV-I) and of adult T-cell leukemia associated with such infection was found in this population. HTLV-I is also associated with a syndrome of progressive spastic paraparesis. We therefore evaluated the occurrence of HTLV-I infection and spastic paraparesis in Mashhadi-born Iranian Jews who immigrated to Israel. We examined 83 Mashhadi-born subjects (52 women, 31 men; mean age, 61 ± 15.5 years) and 73 age-matched non-Mashhadi Iranian-born Jews. Blood samples were tested for HTLV-I antibodies by particle agglutination test. The polymerase chain reaction (PCR) was used to detect HTLV-I proviral DNA sequences from peripheral blood mononuclear cells. Fifteen Mashhadi-born Jews (18%) were both seropositive and PCR-positive for HTLV-I. Four HTLV-I-seronegative subjects were found to be positive for HTLV-I proviral DNA by PCR. Of the 19 HTLV-I–infected subjects (11 women, 8 men; mean age, 59 ± 16 years), 13 (68%) had spastic paraparesis of varying severity. There were no signs of myelopathy in the Mashhadi-born subjects who were negative for HTLV-I proviral DNA by PCR. None of the non-Mashhadi Iranian Jews was seropositive or PCR-positive for HTLV-I proviral DNA, or had clinical signs of spastic paraparesis. Our study indicates a high incidence of HTLV-I infection and spastic paraparesis in Mashhadi-born Iranian Jews. Possible transmission mechanisms may be related to a high rate of infection in this closed community, or to a genetically transmitted virus in a susceptible high-inbred population.     

A case of HTLV-I associated myelopathy with abnormal patchy MRI lesions in the spinal cord]

We report a case of HTLV-I associated myelopathy (HAM) with a spinal cord MRI showing abnormal multifocal and patchy lesions. A 50-year-old woman suffering from progressive paraparesis was admitted to our hospital. HTLV-I antibodies in the serum and CSF were positive, and a diagnosis of HAM was made. Her T2 weighted spinal cord MRI showed scattered areas of high signal intensity from the cervical to the thoracic cord. The lesions were enhanced with gadolinium-DTPA on T1 weighted imaging. Atrophy of the thoracic cord has been reported in many patients with HAM. In rare cases, T2 weighed thoracic cord MRI showed diffuse high signal intensity. The pattern of high signal intensity in our case, however, was multifocal and patchy, thus differing from the findings of previous reports. And we believe this is the first such report. This case suggests that the MRI of HAM patient may show multifocal and scattered lesions in the spinal cord.