Neuropathology of human T lymphotropic virus type I-associated myelopathy

In order to clarify pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) a detailed neuropathological analysis of eight autopsy patients with HAM/TSP was performed. Inflammatory infiltrates of mononuclear cells and degeneration of myelin and axons were noted in the middle to lower thoracic spinal cords and were extended continuously to the entire spinal cord. Horizontal distribution of inflammatory lesions was symmetric at any spinal levels. Immunohistochemical analysis demonstrated T cell dominance. The numbers of CD4+ T cells and CD8+ T cells were present in equal numbers in patients with shorter clinical course. Apoptosis of helper/inducer T cells were observed in the presence of TIA1+ cytotoxic T cells in these active inflammatory lesions. Inflammatory infiltrates were markedly decreased and CD8+/TIA1- T cells were predominated over CD4+ cells in patients with prolonged clinical course. HTLV-I proviral deoxyribonucleic acid (DNA) amounts in the freshly frozen spinal cord measured by quantitative polymerase chain reaction (PCR) were well correlated with the numbers of infiltrated CD4+ cells. In situ PCR of HTLV-I provial DNA using multi-primar pairs demonstrated the presence of HTLV-I infected cells exclusively in the mononuclear infiltrates of perivascular areas. From these findings, it is suggested that the target of the inflammatory process seen in HAM/TSP lesions may be HTLV-I infected CD4+ T cells infiltrating the spinal cord.     

Immunopathogenesis of human T cell lymphotropic virus type I-associated myelopathy

Human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis is a chronic progressive inflammatory neurological disease. Aspects of human T cell lymphotropic virus type I biology, host genetic susceptibility, and immune responses to this agent are important factors that are associated with disease progression. The use of novel immunological and molecular methods has improved our understanding of the pathophysiological mechanisms that are operative in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. Co-existing high proviral loads and virus-specific CD8 T cells are important features of this disorder, in which a high cellular immune response continuously driven by this virus may contribute to the inflammatory process within central nervous system lesions in patients with this disease.     

Pathological mechanisms of human T-cell lymphotropic virus type I-associated myelopathy (HAM/TSP)

The recent studies have greatly improved our understanding of the pathological mechanisms of human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathological mechanisms of HAM/TSP based on the histopathological, immunological, and molecular analysis with emphasis on the longitudinal alterations of the disease will be discussed. Immunohistological examination revealed the existence and the activation both of HTLV-I-infected CD4+ cells and HTLV-I-specific CD8+ cytotoxic T lymphocytes in the spinal cord lesions, which suggest that they play an important role in the pathogenesis. Increased expression of several cytokines, Fas/Fas ligand, adhesion molecules, and molecules influencing T cell migration in the lesions have been reported. These cell infiltrates and cytokines they secrete in the lesions may damage bystander neural tissue. Furthermore, longitudinal alterations in the affected spinal cords suggest that the inflammatory process is gradually decreased. Epidemiological studies show that less than 5% of infected individuals develop HAM/TSP and indicate that increased proviral load of HTLV-I is a strong predictor for the development of HAM/TSP. A recent study has shown that the autoantibody for the ribonuclear protein-A1 can cross-react with HTLV-I Tax protein and inhibit neuronal firing ex vivo, indicating that a molecular mimicry of the humoral immune response may be involved in the pathogenesis of HAM/TSP. Based on these studies, two hypotheses can be proposed for the pathogenesis of HAM/TSP, where cellular and humoral immune responses both play important roles.     

Quantitative assessment of spasticity in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis

People with human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develop spasticity. The authors examined 34 patients with HAM/TSP in Perú using a device that measures tone in the gastroc-soleus-Achilles tendon unit and provides a quantitative spasticity assessment (QSA). Tone in the 34 patients was more than double that of women with asymptomatic HTLV-I infection. The device may help to track progression in HTLV-I infection.     

Abnormalities of spinal magnetic resonance images implicate clinical variability in human T-cell lymphotropic virus type I-associated myelopathy

This study investigated the role of human T-cell lymphotropic virus type I HTLV-I infection in 11 patients who developed slowly progressive myelopathy with abnormal spinal cord lesions. The authors performed clinical and neuroradiological examinations and calculated the odds that an HTLV-I-infected individual of a specific genotype, age, and provirus load has HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Anti-HTLV-I antibodies were present in both the serum and cerebrospinal fluid in all of the patients. Abnormal magnetic resonance imaging (MRI) lesions were classified as cervical to thoracic type (CT type), cervical type (C type), and thoracic type (T type). In each type, there was swelling of the spinal cords with high-intensity lesions, which were located mainly in bilateral posterior columns, posterior horns, or lateral columns. Virological and immunological analyses revealed that all patients showed a high risk of developing HAM/TSP. These 11 patients may have developed HAM/TSP, as manifested by spinal cord abnormalities shown on MRI. These MRIs implicate clinical variability of HAM/TSP, which may indicate active-early stages of HAM/TSP lesions.     

Demyelination and remyelination in spinal cord lesions of human lymphotropic virus type I-associated myelopathy

Summary We describe postmortem findings in a patient with human T lymphotropic virus type I (HTLV-I)-as-sociated myelopathy (HAM). The patient developed the disease 8 years after blood transfusion and showed good response to corticosteroid treatment but died of cardiac failure. Histologically, chronic, mild meningoence-phalomyelitis was noted predominantly involving the bilateral lateral and anterior columns of the middle to lower thoracic segments. The spinal cord lesions showed obvious loss of myelinated nerve fibers and fibrillary gliosis with minimal inflammatory cell infiltration. Electron microscopy of the lesion revealed disintegration of the myelin sheaths, regular separation of the minor dense line of the myelin sheaths, and completely demyelinated axons. In addition, remyelinated fibers with thin central myelin sheaths and disproportionately large axons were seen frequently. These findings indicate that primary demyelination and remyelination by oligodendrocytes occur in the spinal cord lesions of HAM.Supported in part by a Grant (4-63A) from the National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan     

Increased adherence of T cells to human endothelial cells in patients with human T-cell lymphotropic virus type I-associated myelopathy.

We investigated the adherence of T cells to human umbilical vein endothelial cells in seven patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy. The adherence of T cells to endothelial cells increased significantly in all the patients with HTLV-I-associated myelopathy when compared with the adherence in the seronegative controls (1.3- to 2.8-fold) and compared with the adherence in the anti-HTLV-I-seropositive non-HTLV-I-associated myelopathy carriers (1.4- to 2.8-fold). Prior treatment of the endothelial cell monolayer with recombinant interferon gamma (50 IU/mL) enhanced the T cell-endothelial cell adhesion in both the controls and patients with HTLV-I-associated myelopathy. However, values after prior treatment in the patients with HTLV-I-associated myelopathy were significantly higher than those in seronegative controls and carriers. The results suggest that the significantly increased T cell-endothelial cell adherence may be related to the initial stages of lymphocyte migration from the blood to the central nervous system in patients with HTLV-I-associated myelopathy.     

Abnormal spinal MRI findings in human T-cell lymphotrophic virus type I-associated myelopathy

We describe three cases of HTLV-I-associated myelopathy (HAM) with abnormal spinal magnetic resonance imaging (MRI) findings. The serum and cerebrospinal fluid (CSF) of all 3 patients tested positive for anti-HTLV-I antibody. Swelling of the spinal cord with high-intensity lesions on T2-weighted images was observed. Corticosteroid treatment in the case of two patients gradually improved the symptoms, decreased the protein and IgG levels as well as the cell count, and reduced the abnormal MRI findings. To confirm the assumption that abnormal spinal MRI findings are reflective of active inflammation, we compared the clinical parameters, namely, the protein content, IgG level, and cell count, in the CSF of patients exhibiting abnormal spinal MRI findings with those in the case of patients without spinal MRI lesions. The protein contents, IgG levels, and number of cells in the CSF of patients with MRI lesions were significantly higher than those in the CSF of patients without lesions. These findings support the fact that abnormal MRI findings in the spinal cord may be reflective of active inflammation in the early stages of rapidly progressive HAM.     

Dysautonomia in human T-cell lymphotrophic virus type I-associated myelopathy/tropical spastic paraparesis.

The frequency and importance of dysautonomia in human T-cell lymphotrophic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) have not been fully investigated. We describe the characteristics of dysautonomia in such patients in a case-control study. Our results indicate that autonomic disturbances are more frequent in HAM/TSP than has been previously suggested, with a predominance of sympathetic nervous system dysfunction. In some of these patients, the symptoms may be severe enough to warrant specific treatment.     

Retrovirus from human T-cell leukemia virus type I-associated myelopathy is the same strain as a prototype human T-cell leukemia virus type I

A retrovirus was isolated from a T-cell line that was established from lymphocytes in the cerebrospinal fluid of a patient with human T-cell leukemia virus type I-associated myelopathy (HAM), and its genome was sequenced. The nucleotide sequence of the 3' half of the total genome was identical in 99.5% of the nucleotides to that of the prototype human T-cell leukemia virus type I that was derived from a patient with adult T-cell leukemia. These results indicate that the same retrovirus human T-cell leukemia virus type I is associated with both a neurological disease, HAM, and a lymphoproliferative disease, adult T-cell leukemia.     

Elevated levels of interleukin-12 and interferon-gamma in patients with human T lymphotropic virus type I-associated myelopathy

The levels of interleukin-12 (IL-12) (p70 heterodimer), total IL-12 (p70 heterodimer plus p40 chains), interferon-gamma (IFN-gamma) as Th1 cytokine, and those of interleukin-4 (IL-4) and interleukin-10 (IL-10) as Th2 cytokines in sera and cerebrospinal fluid (CSF) from 22 patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) were compared with those of 22 patients with other neurological diseases (OND), including nine anti-HTLV-I-seropositive carriers. Both serum IL-12 (total and p70 heterodimer) and CSF IFN-gamma, measured by the enzyme-linked immunosorbent assay (ELISA), were significantly elevated in patients with HAM as compared to the patients with OND, including the anti-HTLV-I-seropositive carriers. Serum IFN-gamma also was significantly elevated in the HAM patients as compared to the controls. There was no significant difference in the CSF levels of IL-12 (total and p70 heterodimer) between the HAM patients and controls, whereas, for the Th2 cytokines IL-4 was detected in the CSF of four anti-HTLV-I-seropositive carriers of the 13 control patients but not in any of the patients with HAM. No significant difference was found in the serum levels of IL-4 and IL-10, nor in the CSF levels of IL-10 in the patients with HAM and in the controls. These findings indicate that in patients with HAM, the immunological balance of helper T lymphocytes between Th1 and Th2 is toward Th1 in the periphery and that Th1-mediated immunological status in the central nervous system is involved in the pathogenesis of HAM.     

Human T-cell lymphotropic virus type I-associated facial nerve palsy in trinidad and tobago

To assess the association of the human T-cell lymphotropic virus type I (HTLV-I) and idiopathic facial nerve palsy of the lower motor neuron type, we studied 78 patients consecutively admitted to the Port of Spain General Hospital in Trinidad, the West Indies, with a confirmed diagnosis of idiopathic facial nerve palsy. Patients were compared with two control groups: a population-based group of persons 20 years and older and a hospital-based group of patients 15 to 84 years old admitted to the medical wards. Sixty-two patients were Trinidadians of African origin and 16 were Trinidadians of East Indian origin. None of the East Indian patients was HTLV-I antibody positive. Three Afro-Trinidadians were infected with human immunodeficiency virus type 1 and 1 was coinfected with this virus and HTLV-I. Of the remaining 58 Afro-Trinidadians, 12 (20.7%) were HTLV-I positive only. This rate was statistically higher than the HTLV-I seroprevalence in the Afro-Trinidadian general population (3.5%) and the hospital control group (5.6%). After age standardization, the HTLV-I prevalence for patients with facial nerve palsy remained significantly elevated. HTLV-I antibody assays should be performed on all patients with idiopathic facial nerve palsy of the lower motor neuron type who live in HTLV-I endemic areas or are migrants from these areas.     

Pathogenesis of chronic progressive myelopathy associated with human T-cell lymphotropic virus type I

Human T-cell lymphotropic virus type I (HTLV-I) induces a chronic demyelinating disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While only 0.25% of HTLV-I-infected individuals develop HAM/TSP, the mechanisms responsible for the progression of an HTLV-I carrier state to clinical disease are not clear. In particular, no specific sequence differences have been found between HTLV-I recovered from HAM patients and HTLV-I-infected carriers. Since CD4 T cells are the major reservoir of the virus, at least three hypotheses implicating CD4 T cells directly or indirectly have been proposed: 1) The cytotoxic hypothesis predicts that activated and HTLV-I-infected CD4 T cells migrate to the CNS and infect resident cells. Cytotoxic CD8 T cells may then recognize viral antigens on HTLV-I-infected CNS cells causing a cellularly mediated cytotoxic demyelination. 2) The autoimmune hypothesis predicts that either (a) virally reactive T cells cross-react with a CNS antigen, or (b) random infection of CD4 T cells eventually results in the infection of CNS-autoreactive CD4 T cells that, by virtue of the productive HTLV-I infection, become activated, expand and migrate to the CNS, where they encounter their antigen. This results in a specific immune response and demyelination, as is known to occur in experimental autoimmune encephalomyelitis. 3) The bystander damage hypothesis does not implicate a specific response against CNS cells. Instead this hypothesis suggests that the presence of IFN-γ-secreting HTLV-I-infected CD4 T cells and their recognition by virally specific CD8 T cells in the CNS induce microglia to secrete cytokines, such as TNF-α, which may be toxic for the myelin.     

An autopsy case of human T lymphotropic virus type I-associated myelopathy (HAM) with a duration of 28 years

Summary An autopsy case of human T lymphotropic virus I-associated myelopathy (HAM) of a duration of 28 years in a 61-year-old man with serological confirmation of HTLV-I infection was reported. The spinal cord was grossly atrophic. There was severe symmetrical degeneration of the lateral funiculi, particularly of the bilateral pyramidal tracts, involving all levels of the spinal cord, but anterior horn cells were relatively well preserved. In the most severely damaged middle and lower thoracic segments, the white matter degeneration also involved the anterior funiculi. In the degenerated white matter, both the myelin and axons were equally lost and had been replaced by glial scars. Marked adventitial fibrosis was commonly seen in small parenchymal vessls in both the white and gray matter. Although there was no evidence of inflammation in the spinal cord, mild lymphocytic infiltration was occasionally observed in the subarachnoid and perivascular spaces in the brain stem, cerebellum and cerebrum. This case was considered as a burnt-out case of HAM.     

Human T lymphotropic virus type I-associated myelopathy. A report of 10 patients born in the United States.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) (tropical spastic paraparesis/HAM) has rarely been reported in the United States. We present 10 well-documented cases with positive Western immunoblot test results and polymerase chain reactions for HTLV-I. The clinical and laboratory features of these American-born patients resemble those previously reported series of tropical spastic paraparesis and HAM from the Caribbean and Japan, but important differences were observed. In our study there were equal numbers of whites and blacks and of men and women. Age at onset was younger than that reported from the Caribbean and Japan. Rate of progression to paraparesis varied but was more rapid than previously reported. Half were transfusion recipients but six had multiple sexual partners, with one regularly interacting with prostitutes and reporting a history of drug abuse. Although more rapid progression was seen in the transfusion recipients, this did not explain the earlier age of onset in this group of patients. The HTLV-I, and the associated myelopathy, are endemic in Florida, suggesting that immigration from, and proximity, to the Caribbean basin are contributing risk factors.     

Sensory neuronopathy heralding human T cell lymphotropic virus type I myelopathy

Neurological phenotypes of human T cell lymphotropic virus type I (HTLV-1) are numerous and rarely may not manifest the classic HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We report a case of HTLV-1-related sensory neuronopathy heralding the classic HAM/TSP.     

Subacute progression of human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis

Although human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is usually described as a chronic disabling disease, a rapid course over months or even weeks has been reported in some patients. The authors describe the clinical features of HAM/TSP in a Brazilian cohort and evaluate the prevalence of patients with a subacute progression of the disease. This was defined as the requirement of a wheelchair during the first 2 years after the onset of symptoms. Patients with this subacute course and patients with the chronic clinical course were compared in terms of their HTLV-I proviral loads (PLs) using real-time polymerase chain reaction (PCR). Seven out of 88 patients (7.9%) had a subacute progression. All patients were women and 5/7 acquired HTLV-I through sexual contact. There was no significant difference in the real-time PLs between the group with subacute evolution (mean 8.5 copies/100 cells, range 6.03 to 12.09) and those patients with a typical course of disease (mean 11.34 copies/100 cells, range 0.4 to 67.72) (P = .68), suggesting that factors other than the number of infected cells are implicated in the development of such an aggressive course of disease. Early recognition of this subgroup is important because immunosuppressive treatment might be beneficial if instituted promptly.     

Human T cell lines established from the cerebrospinal fluid of patients with human T lymphotropic virus type I-associated myelopathy (HAM)

T cell lines were established from the cerebrospinal fluid (CSF) lymphocytes of two patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). These two interleukin-2 (IL-2)-dependent T cell lines have been cultured for more than 8 months without any accessory cells. The surface phenotype of these cells was CD2(+), CD4(+), CD8(-), Ia(+) and Tac(+). Southern blot hybridization analysis revealed the presence of HTLV-I provirus in these cells and C-type retrovirus particles were identified by electron microscopy. These findings indicate the presence of HTLV-I infected helper T lymphocytes in the CSF of the patients with HAM. These HTLV-I(+) T cell lines may be valuable for investigating the possible neutrotropism of HTLV-I and the role of HTLV-I in the pathogenesis of HAM.