Interferon-beta treatment in patients with childhood-onset multiple sclerosis.

We present a report of the use of interferon-beta before 18 years of age in 16 patients with childhood-onset multiple sclerosis. This study demonstrated that the treatment is safe and well tolerated.

Cell surface phenotype and human T lymphotropic virus type 1 antigen expression in 12 T cell lines derived from peripheral blood and cerebrospinal fluid of West Indian, Guyanese and African patients with tropical spastic paraparesis.

Twelve long-term cell lines were established from peripheral blood mononuclear cells (PBMC) or cerebrospinal fluid cells of patients with human T lymphotropic virus type I (HTLV-1) seropositive tropical spastic paraparesis (TSP) originating from the French West Indies, French Guyana or the Central African Republic. Most of these long-term interleukin-2-dependent cell lines exhibited a pattern characteristic of CD4(+)-activated T cells with high expression of CD2, CD3 and CD4 antigens, associated with a strong density of TAC and DR molecules. Nevertheless, in five cases CD8 expression was present at a significant level. HTLV-I antigens were never detected in uncultured PBMC, but they were expressed in a few cells after short-term culture and after 4 months the majority of the cells were HTLV-I positive, as demonstrated by indirect immunofluorescence (IF) using polyclonal or monoclonal anti-p19 and anti-p24 antibodies. Low and variable levels of reverse transcriptase activity were detected in supernatant fluids of these cell lines only after 4 months of culture, when at least 50% of the cells exhibited HTLV-I antigens by IF. However, numerous type C HTLV-I-like viral particles were detected, mostly in the extracellular spaces, with rare budding particles. Similar findings were found in three T cell lines derived from West Indian and African patients with adult T-cell leukaemia/lymphoma (ATLL). Differences in high Mr polypeptides were detected by Western blot in cell lysates when comparing TSP- or ATLL-derived T cell lines. Thus a signal of 62K was easily detectable in all the TSP lines, but not in the ATLL lines. In all cell lines bands corresponding to p53, p24 and p19 viral core polypeptides were present, as was the env gene-coded protein p46.

High human T-cell lymphotropic virus type I proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese, and African patients with tropical spastic paraparesis.

Human T-cell lymphotropic virus type I (HTLV-I) proviral integration status was examined by Southern blot analysis in peripheral blood mononuclear cell (PBMC) DNA from patients presenting a tropical spastic paraparesis (TSP) and serological evidence of HTLV-I infection. Surface phenotype and morphological aspects of PBMC were also studied. A polyclonal HTLV-I proviral integration was found in the PBMC of the 10 patients studied irrespective of their geographical origin (French West Indies, French Guiana, and Africa), the duration of their clinical illness, or the HTLV-I antibody titer. Furthermore, by dilution experiments and hypothesizing that only one copy of HTLV-I proviral DNA is present in one cell, we estimated that this HTLV-I integration is present in 3% to 15% of their PBMC. All 10 TSP/HTLV-I patients studied had an average of 10% of their lymphocytes abnormal, presenting either a misshapen nucleus or an adult T-cell leukemia/lymphoma (ATL)-like feature. Moreover, an elevated CD4/CD8 ratio associated with the presence of activated T cells with a high level of DR expression was observed in most patients. The significant frequency of viral-positive PBMC and the important load of HTLV-I proviral DNA that we observed in TSP/HTLV-I patients might play an important role in the pathogenesis of this recently identified clinico-virological entity.

Characterization of HTLV-I isolates and T lymphoid cell lines derived from French West Indian patients with tropical spastic paraparesis.

Lymphoid cell lines derived from the peripheral blood of French West Indian patients with HTLV-I sero-positive Tropical Spastic Paraparesis and HTLV-I isolates were characterized. While patients' peripheral blood lymphocytes did not express detectable HTLV-I antigens when uncultured, they did so after short-term culture. Established cell lines were of T-cell lineage: CD2+, CD3+, CD4+, CD7+, WT31+ with activated T-cell markers CD25+, DR+ and a clonal rearrangement of the beta and gamma genes of the T-cell receptor. HTLV-I antigens were detected in cell lines by indirect immunofluorescence, Western blot and radio-immunoprecipitation assays. After 4 months in culture, low levels of Mg2+ dependent reverse transcriptase activity were detected and electron microscopy revealed numerous type-C retroviral particles similar to HTLV-I virions. Western blot and radio-immunoprecipitation analysis of purified viruses revealed gp46, p24, p19 and Pr53gag proteins similar to those detected in HUT 102 and MT2 cell lines. Deep analysis of env-coded precursor of one TSP versus ATL isolates revealed minor differences in their molecular weights. Southern blot analysis using 32P HTLV-I env gene as a probe showed the presence of HTLV-I proviral fragments clonally integrated into the genome of the cell lines. Our data suggest that HTLV-I isolated from Tropical Spastic Paraparesis does not differ significantly from the leukemogenic prototypes. Does HTLV-I induce either acute lymphoproliferative diseases or chronic neuromyelopathies depending upon as yet unknown co-factors? This question remains to be determined.

Intrathecal synthesis of antibodies to human T lymphotropic virus type I and the presence of IgG oligoclonal bands in the cerebrospinal fluid of patients with endemic tropical spastic paraparesis.

Tropical spastic paraparesis (TSP), a neuromyelopathy predominantly involving the pyramidal tract and commonly observed in tropical and equatorial areas, was recently found to be associated with human T lymphotropic virus type I (HTLV-I). We investigated sera and cerebrospinal fluid (CSF) from 19 patients with TSP who were from the Caribbean area, French Guiana, and Africa. Our results showed an elevated intra-blood-brain barrier IgG synthesis rate and an elevated IgG index, with an increased HTLV-I antibody-to-albumin ratio and the presence of CSF oligoclonal bands in the majority of the patients. These data, in association with similar HTLV-I antibody patterns between patients with TSP who were from these three regions, strengthen the probable etiologic role of HTLV-I in the pathogenesis of such chronic neuromyelopathies.

HTLV-I-associated tropical spastic paraparesis in Martinique: a reappraisal.

Human T-lymphotropic virus type I (HTLV-I)-associated tropical spastic paraparesis in Martinique has been identified in 54 patients, 49 women and 5 men. This myelopathy represents an endemic problem on this island and the earliest documented case dates from 1952. A blood transfusion history was obtained in 7 of the 54 patients (13%). There was a preponderance of cases from the northern Atlantic coast of Martinique, the most humid region on the island. The prevalence in this region reached 49.5 per 100,000, compared with the global prevalence of 11.9 cases per 100,000 for the island. An immune-mediated mechanism may be important in the pathogenesis of HTLV-I-associated tropical spastic paraparesis.

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.

[Tropical spastic paraparesis in Martinique. High prevalence of anti-HTLV-I antibodies]. / Paraparésies spastiques tropicales en Martinique. Haute prévalence d'anticorps HTLV-I.

Owing to the frequent occurrence in tropical countries of subacute spinal cord diseases of unknown origin, a nosological entity called tropical spastic paraparesis has been individualized. Twenty-two cases have been observed in Martinique. The presence in the serum of antibodies directed against human T-cell leukaemia/lymphoma virus (HTLV-I) in 15 of these 22 patients suggests that this lymphotropic virus or a related one might also be neurovirulent.

Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis.

10 out of 17 (59%) patients with tropical spastic paraparesis (TSP) had antibodies to human T-lymphotropic virus-I (HTLV-I), as did 5 out of 5 TSP patients with systemic symptoms. Only 13 out of 303 (4%) controls, made up of blood donors, medical personnel, and other neurological patients, had such antibodies. These findings suggest either that HTLV-I is neurotropic or that the virus or a related one contributes to the pathogenesis of TSP.