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PubMed2006

Proviral load and immune markers associated with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Peru.

Human T-lymphotropic virus type 1 (HTLV-1) is the aetiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective of this study is to identify which ex vivo and in vivo markers are associated independently with HAM/TSP in a Peruvian population. Eighty-one subjects (33 men/48 women) were enrolled: 35 presented with HAM/TSP, 33 were asymptomatic HTLV-1 carriers (ACs) and 13 were HTLV-1-seronegative controls (SCs). Ex vivo markers included T cell proliferation and Th1 [interferon (IFN)-gamma], Th2 [interleukin (IL)-4, IL-5], proinflammatory [tumour necrosis factor (TNF)-alpha] and anti-inflammatory (IL-10) cytokine production in non-stimulated peripheral blood mononuclear cell (PBMC) cultures. In vivo CD4(+) T cell count, markers of Th1 [interferon-inducible protein (IP)-10] and Th2 (sCD30) activity in plasma and HTLV-1 proviral load in PBMCs were also evaluated. In univariate analysis, several markers, including T cell proliferation, IFN-gamma, IP-10, sCD30 and proviral load were associated with HAM/TSP, but in a multiple logistic regression analysis only the proviral load remained associated significantly with disease manifestation [adjusted OR 9.10 (1.24-66.91)]. Our findings suggest that HAM/TSP is associated primarily with proviral load, whereas the observed association with some immune markers seems secondary.

Adult↗
PubMedDate not supplied

Guillain-Barré syndrome in a patient with hereditary spastic paraparesis. A case report.

OBJECTIVE: To report the unusual occurrence of Guillain-Barre syndrome (GBS) in a case of hereditary spastic paraparesis (HSP) and describe its effect on the preexisting clinical picture as well as the importance of early recognition and treatment. CLINICAL PRESENTATION AND INTERVENTION: A 41-year-old man known to have HSP developed an acute and rapid deterioration of muscle power associated with paresthesia in both upper and lower limbs. Clinical examination revealed flaccid quadriparesis with areflexia. Nerve conduction studies were suggestive of demyelinating polyneuropathy and CSF analysis showed increased protein but no cells. The diagnosis of GBS was made in addition to HSP. The patient received intravenous immunoglobulins 20 mg/kg body weight/day for 5 days. He responded very well to the treatment clinically and neurophysiologically and thereafter, he reverted to the preexisting spastic picture of HSP. CONCLUSION: The peripheral demyelination with GBS was severe enough to obscure the preexisting clinical picture, but fortunately it responded very well to treatment. The clinical associations with HSP are widely variable, therefore it is very important to recognize acquired treatable causes of weakness in such patients in order to prevent an increase in disability.

Adult↗
PubMed1992

Tissue expression pattern directed in transgenic mice by the LTR of an HTLV-I provirus isolated from a case of tropical spastic paraparesis.

Human T lymphotropic virus type I (HTLV-I) causes adult T cell leukemia/lymphoma and a chronic neurological disease called either tropical spastic paraparesis (TSP) or HTLV-I-associated myelopathy. The different outcomes of this infection could be due to both host and viral factors and it has been proposed that genetic differences could make some HTLV-I strains neurotropic. In this paper, we examined the pattern of tissue-specific expression determined by a long terminal repeat (LTR) obtained from a case of TSP. We constructed transgenic mice in which this LTR controlled the expression of the nlslacZ reporter gene. We observed that in three independent lines of transgenic mice, the reporter gene was expressed predominantly in the central nervous system (CNS), in choroid plexus, and in cells of the hippocampus and cerebellum. Our observations indicate the existence of CNS cells permissive for the expression of HTLV-I and which may be of importance in the pathogenesis of TSP.

Animals↗
PubMed2006

Brain volume measurements in patients with human T-cell lymphotropic virus-1-associated tropical spastic paraparesis.

Human T-cell lymphotropic virus (HTLV)-1 is associated with a chronic progressive neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) that affects 0.2% to 3% of HTLV-1-infected people. The authors aimed at exploring, in vivo, whether brain volume reduction occurs in patients with HAM/TSP through the use of magnetic resonance imaging (MRI). T1 pre/postcontrast spin echo-weighted images (WIs) and T2WIs of the brain were obtained in 19 HAM/TSP patients and 14 age-and sex-matched healthy volunteers. Both patients and healthy individuals were imaged at a 1.5-Tesla magnet by employing a conventional head coil. Focal T1 and T2 abnormalities were calculated and two measurements of brain parenchyma fraction (BPF) were obtained by using SIENAx (Structural Image Evaluation,using Normalisation, of Atrophy; University of Oxford, Oxford, UK) and MIPAV (Medical Image Processing, Analysis, and Visualization; National Institutes of Health, Bethesda, USA) from T1WIs. No significant differences in BPF were found between patients and healthy subjects when using either SIENAx or MIPAV. Analysis of individual patients detected that BPF was lower by 1 standard deviation (SD) relative to patients' average BPF in one patient. The authors conclude that reductions in BPF do not occur frequently in patients with HAM/TSP. However, the authors believe that one individual case of significant brain atrophy raises the question as to whether atrophy selectively targets the spinal cord of HAM/TSP patients or may involve the brain as well. A larger patient population analyzing regional brain volume changes could be helpful in determining whether brain atrophy is a marker of disease in patients with HAM/TSP.

Adult↗
PubMed1995

IgA antiphospholipid antibodies in HTLV-1-associated tropical spastic paraparesis.

A retrovirus, human T cell lymphotropic virus type 1 (HTLV-1), is an essential but not a sufficient aetiologic factor for tropical spastic paraparesis (TSP). Because some TSP patients have biological false positive tests for treponemal infections (BFP-STS), we used ELISA to study BFP-STS and anticardiolipin antibodies in 42 Jamaican TSP patients. The data indicate that in TSP anticardiolipin antibodies occur in about 26% of patients, are associated with biological false positive treponemal serology, are relatively restricted to the IgA isotype and may be induced by HTLV-1 or other nontreponemal infections.

Adult↗
PubMed1997

[HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)].

Human T lymphotropic virus type I(HTLV-I) is associated with the nonfatal neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Many clinical signs of involvement outside the central nervous system (CNS) have been described in some patients with HAM/TSP and have triggered the discovery of some HTLV-I-associated concepts in the infected individuals without signs of CNS involvement. Most of these HTLV-I-associated diseases exhibit common possible viroimmunologic characteristics that include a distributional bias of HTLV-I activation between the blood flow and the affected lesions and accumulated cellular immune responses in the lesions. This review summarizes the recent perspectives of the molecular pathogenesis of HAM/TSP and other HTLV-I-associated diseases. Furthermore, the feasible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the affected tissues is emphasized (bystander auto-aggressiveness).

Humans↗
PubMed2003

Intrathecal administration of morphine, but not small dose, induced spastic paraparesis after a noninjurious interval of aortic occlusion in rats.

UNLABELLED: We sought to investigate the dose-response relationship for the effect of intrathecal morphine on the transient spastic paraparesis after short-lasting spinal ischemia in rats. Spinal ischemia was induced by aortic occlusion for 6 min with a balloon catheter in rats previously implanted with an intrathecal catheter for drug delivery. After ischemia, the animals were allowed to recover, and 3, 10, or 30 microg of morphine or saline was injected intrathecally at 30 min after reperfusion. In a separate group, the quantal bioassay for the effect of intrathecal morphine on neurological function after ischemia was performed to calculate 50% effective dose values for inducing paraparesis at 2 h of reperfusion. Subsequently, histopathology of the spinal cord was assessed at 48 h of reperfusion. Intrathecal injection of 30 or 10 micro g of morphine, but 3 micro g of neither morphine nor saline, caused a progressive development of hindlimb spasticity. The 50% effective dose values for inducing paraparesis were 16.1 +/- 1.5 microg in assessing behavioral analysis at 2 h after intrathecal morphine. Histopathological analysis of spinal cords in the 30- microg group revealed the presence of dark-staining alpha-motoneurons in lumbosacral segments. We conclude that spinal administration of a large dose of morphine after transient aortic occlusion may be associated with a potential risk of paraparesis and the corresponding development of neurological dysfunction. Careful attention should be paid when intrathecal morphine is used for pain control after thoracoabdominal aortic aneurysm repair. IMPLICATIONS: Spinal administration of large-dose morphine after transient aortic occlusion may be associated with a potential risk of irreversible spinal neuronal degeneration and the corresponding development of neurological dysfunction.

Analgesics, Opioid↗
PubMed2000

Central nervous system activation of the indoleamine-2,3-dioxygenase pathway in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

Human T cell lymphotropic virus type I (HTLV-I) is associated with a chronic neurologic disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The potential mechanisms of HAM/TSP pathogenesis were assessed by examination of 2 pathways initiated by interferon-gamma, a predominant cytokine in HAM/TSP. Jamaican HAM/TSP patients (n=17) were compared with patients with other neurologic diseases (ONDs; n=13) with respect to cerebrospinal fluid levels of the following: neopterin; nitrite plus nitrate, a stable indicator of nitric oxide; and tryptophan and kynurenine, metabolites of the indoleamine-2,3-dioxygenase (IDO) pathway. HAM/TSP patients had significantly elevated levels of neopterin (P=.003) and kynurenine (P=.05) and a significantly decreased level of tryptophan (P=.003), compared with patients with ONDs. These results support immune activation within the central nervous system and activation of the IDO pathway. Thus, activation of the IDO pathway may play a role in HAM/TSP.

Adult↗
PubMed1986

Epidemic spastic paraparesis in Bandundu (Zaire).

Epidemiological findings of twenty sporadic cases of epidemic spastic paraparesis (buka-buka) in three areas of Bandundu (Zaire) are reported. These findings suggest the involvement of an infectious agent and do not support the hypothesis of a dietary cyanide intoxication, which has been advanced to explain the outbreak of a very similar disease (Mantakassa) in Mozambique.

Adult↗
PubMed2005

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.

BACKGROUND: SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10-40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP). OBJECTIVE: To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories. METHODS: 146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms. RESULTS: The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations. CONCLUSIONS: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.

Adenosine Triphosphatases↗
PubMed1993

Demonstration of human T-cell lymphotropic virus type I (HTLV-I) from an HTLV-I seronegative south Indian patient with chronic, progressive spastic paraparesis.

Here we describe a human T-cell lymphotropic virus type I (HTLV-I) seronegative patient from South India with a chronic, progressive spastic paraparesis from which HTLV-I has been isolated from peripheral blood lymphocytes. HTLV-I pol and tax viral sequences were detected in DNA from fresh peripheral blood lymphocytes (PBL) by polymerase chain reaction (PCR) and liquid hybridization techniques. Southern blot analysis of the PCR products demonstrated a low copy number of HTLV-I at the level of one viral copy per 10,000 fresh PBL. A long-term CD4+ T-cell line was established from PBL of this patient using recombinant interleukin-2, OKT3, and feeder cells. DNA from these cultured lines was amplified and portions of the HTLV-I long terminal repeat (U3), pol, env, and tax regions were sequenced (a total of 1,115 bp). The sequence data showed that the HTLV-I associated with this patient was 98.8% homologous to prototype HTLV-I. Southern blot analysis also confirmed the presence of full-length HTLV-I. These results indicate that HTLV-I can be demonstrated in an HTLV-I seronegative patient from South India with a chronic progressive neurological disorder.

Base Sequence↗
PubMed2003

A possible case of myelopathy/tropical spastic paraparesis in an Argentinian woman with human T lymphocyte virus type II.

A case of neurological disease featuring human T lymphocyte virus-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was diagnosed by serological (Western blot) and molecular (polymerase chain reaction) criteria as related to human T lymphocyte virus (HTLV)-II infection. This is, to our knowledge, the first case of this kind found in Argentina and is additional evidence that HAM/TSP solely related to HTLV-II infection occurs in HTLV-I-negative subjects.

Adult↗
PubMed2003

Decreased human T lymphotropic virus type I (HTLV-I) provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopathy/tropical spastic paraparesis.

To analyze the mechanism by which interferon (IFN)-alpha is effective against human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we investigated the T cell phenotype and HTLV-I provirus load in peripheral blood mononuclear cells from 25 patients with HAM/TSP that were obtained before and after administration of IFN-alpha. The frequency of memory (CD45RA(-)CD27(+)) T cells that were CD8(high+), CXCR3(+) cell populations, and HTLV-I provirus loads were significantly decreased after treatment. The proportion of memory T cells in the CD8(high+) cell population correlated well with HTLV-I provirus load, whereas the proportion of effector (CD45RA(+)CD27(-)) cells in the CD8(high+) cell population was inversely correlated with provirus load. Interestingly, the frequency of perforin expression in CD8(high+) cells was significantly decreased after treatment in patients who experienced clinical improvement, whereas patients who did not experience clinical improvement showed an increased frequency of perforin expression. Our data suggest that fluctuations in these cell subsets are associated with both the immunomodulatory effect of IFN-alpha and the observed clinical benefit of IFN-alpha treatment in patients with HAM/TSP.

Adjuvants, Immunologic↗
PubMed1995

Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis with acute type of adult T-cell leukemia.

We report a 47-year-old Japanese woman with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) combined with acute type adult T-cell leukemia (ATL). The susceptibility for HAM/TSP and acute type of ATL is hitherto explained by human leukocyte antigen (HLA) haplotype-linked immune responsiveness to HTLV-I. This patient's HLA (A24Cw1B54DR4DQ4/A24Cw3B51DR8DQ1) included a HAM-associated HLA haplotype. This suggests that HAM patients with HAM-associated HLA haplotype can also develop the acute type of ATL.

Adult↗
PubMed1995

HTLV-I positive progressive spastic paraparesis (TSP) associated with a lymphoid disorder in three Chilean patients.

We describe the clinical and laboratory features in three Caucasian Chilean patients with tropical spastic paraparesis (TSP) associated with/or preceded by a lymphoproliferative disorder involving cutaneous lesions and localised lymphadenopathy. The neurological symptoms and signs were characteristic of TSP and CSF examination revealed the presence of oligoclonal bands. All three patients had a moderate leucocytosis (10-14 x 10(9)/l) with eosinophilia and a minority (2-4%) of circulating atypical polylobed or ATLL-like lymphocytes. Lymph node histology showed a diffuse pattern of infiltration (1 case) and marked expansion of the paracortical zone with convoluted lymphocytes and immunoblasts (2 cases). Skin biopsy demonstrated a dermal lymphoid infiltration with epidermotropism. Antibodies to HTLV-I were detected in the serum and CSF in the three patients and Southern blot analysis of peripheral blood mononuclear cells showed a monoclonal integration of HTLV-I proviral DNA in one case whereas in the two others the pattern was indicative of low level polyclonal integration. All three patients were treated with prednisolone and one with PUVA with transient partial response on the skin and neurological manifestations. Two patients died months to 5 years from presentation and the other is alive 12 years from diagnosis with active neurological and skin disease. The simultaneous occurrence of HTLV-I associated TSP with smouldering ATLL and a cutaneous ATLL or pre-leukaemic form is discussed.

Adult↗
PubMed1996

Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with differing patterns of immune dysfunction. Biomarkers of immune activation may correlate with perturbations of immune function associated with these diseases. We conducted a pilot cross-sectional study to assess four candidate biomarkers of immune activation. beta 2-microglobulin, neopterin, tryptophan, and kynurenine levels were assayed in stored sera from asymptomatic, human T-cell leukemia virus type I (HTL V-I)-seronegative (HTLV-I-) and HTLV-I-seropositive (HTLV-I+) individuals, and ATL and HAM/TSP patients previously enrolled in seroepidemiological studies in Jamaica. Mean levels of beta 2-microglobulin, neopterin, and kynurenine were significantly elevated among ATL patients compared to the other study groups. Mean tryptophan levels were significantly lower among ATL and HAM/TSP patients than HTLV-I- and HTLV-I+ groups. No significant differences in biomarkers were found between the HTLV-I- and HTLV-I+ groups. Among HAM/TSP patients, a significant association was found between elevated neopterin levels and symptoms of less than 4 years duration. In Cox proportional hazards regression modeling, neopterin and tryptophan were found to be independent predictors of survival among ATL patients. This study demonstrates a differential pattern of biomarkers of immune activation among ATL and HAM/TSP patients compared to HTLV-I- and HTLV-I+ individuals. Neopterin and tryptophan may be useful clinical indicators of disease severity and prognosis among HAM/TSP and ATL patients.

Adult↗
PubMed1994

Pure hereditary spastic paraparesis: an exclusion map covering more than 40% of the autosomal genome.

Pure hereditary spastic paraparesis (HSP) is an upper motor neuron syndrome clinically characterized by slowly progressive weakness and spasticity of the legs. To determine the chromosomal location of the genetic defect, a five-generational Dutch family with autosomal dominant pure HSP was subjected to linkage studies. Analysis was carried out on 48 members spanning three generations, of whom 23 individuals are definitely affected. By screening the genome with a total of 167 microsatellite markers distributed over all autosomes, an exclusion map for HSP was constructed. Depending on the actual size of the human genome, our exclusion map covered between 40% and 65% of its autosomal length. Loci on chromosomes 1, 8, 13, 14, and 18 showed slightly positive lod scores. The areas around these loci were investigated more closely, but no conclusive evidence for, or against, linkage could be obtained.

Chromosome Mapping↗