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.     

An association of human T-cell lymphotropie virus type I infection with vascular dementia

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropie virus type I (HTLV-I) gag 100–130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130,18.5%) than in those without dementia (11/139, 7.9%) ( P =0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48,23%) ( P =0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.     

Active production of anti-human T-lymphotropic virus type I (HTLV-I) IgM antibody in HTLV-I-associated myelopathy

We investigated the presence of anti-human T-lymphotropic virus type I (HTLV-I) IgM in sera and cerebrospinal fluid from patients with HTLV-I-associated myelopathy (HAM) by Western blot analysis. Analyses of 36 serum samples revealed that most patients (31/36; 86.1%) had anti-HTLV-I IgM, whereas only four of 23 (17.4%) HTLV-I carriers had it. In studies of cerebrospinal fluid, anti-HTLV-I IgM was detected in 24 of 36 (66.7%) HAM patients, whereas none was detected in nine HTLV-I carriers. The differences were statistically significant (p less than 0.01). These results suggest that persistent active replication of HTLV-I occurs in the central nervous system as well as in the peripheral blood of HAM patients, and may contribute to the development of HAM.     

A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma

Malignant lymphoma may present prominent peripheral nervous system disorders with variable etiologies. We describe a patient who presented with chronic relapsing polyradiculoneuropathy accompanied by right facial nerve palsy. Gadolinium enhancement of the right facial nerve and cervical spinal roots was noted on magnetic resonance imaging (MRI). Sural nerve biopsy specimens showed mononuclear cell infiltration around the vessels in the epineurium. Histopathological and immunohistochemical investigations of sural nerve specimens revealed perivascular infiltration of lymphocytes with T-cell dominancy. No apparent direct invasion of lymphoma cells was seen. The results of nerve conduction studies, sural nerve biopsy and cerebrospinal fluid examination were suggestive of immune-mediated inflammatory demyelinating neuropathy. The chronic and relapsing fashion and unique radiological findings in our patient expand on the previously reported features of peripheral neuropathy associated with peripheral T-cell lymphoma.     

Chronic sensory neuronopathy associated with human T-cell lymphotropic virus type I infection.

We described two patients with chronic sensory neuronopathy who had anti-HTLV-I antibody in serum and cerebrospinal fluid but no signs of myelopathy. A sural nerve specimen revealed severe degeneration of myelinated and unmyelinated axons. The second patient had subclinical Sj?gren's syndrome suggestive of a possible link among human T-cell lymphotropic virus type I (HTLV-I), Sj?gren's syndrome and sensory neuronopathy, respectively. The broad spectrum of neurologic disorders associated with HTLV-I infection now would include chronic sensory neuronopathy.     

Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.     

Presence of human T lymphotropic virus type I in two patients with progressive myelopathy in Puerto Rico

Two patients from Puerto Rico with progressive paraparesis had serum positive for human T lymphotropic virus type I (HTLV-I) antibodies by ELISA and Western blot, and one patient had HTLV-I antibodies in CSF by the ELISA method. Although the Caribbean basin is considered to be an endemic area for tropical spastic paraparesis, this is the first report of the isolation of HTLV-I antibodies in the serum and CSF of patients with chronic myelopathies in Puerto Rico.     

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     

Analysis of the provirus genome integrated in 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 three patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). To elucidate the possible changes of the provirus nucleotide sequences integrated in HAM-derived T cell line cells, DNA from these cells was digested with PstI, which cleaved the provirus genome of HTLV-I at several sites, and three common bands were detected by Southern blot analysis in all cases. These bands were identical in size to those detected in T cell lines established from peripheral blood lymphocytes of adult T cell leukemia (ATL) patients. These results were confirmed with restriction enzymes HindIII and BamHI. These findings suggest that the provirus genome detected in T cell lines derived from CSF of HAM patients is identical to HTLV-I.     

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.     

Detection of human T-cell leukemia/lymphoma virus type I in a transfusion recipient with chronic myelopathy

A white man with a progressive spastic paraparesis that began 15 months after sustaining severe trauma in a motor vehicle accident was positive for antibodies to human T-lymphotropic virus type I (HTLV-I) by enzyme-linked immunosorbent assay. Serum antibody to HTLV-I was confirmed by Western blot and radioimmunoprecipitation assay. We detected specific proviral DNA in peripheral blood lymphocytes by the polymerase chain reaction. Because the incidence of HTLV-I is generally restricted to Southern Japan and Caribbean black populations, the most likely source of HTLV-I infection in this patient was multiple intraoperative blood transfusions. The relatively short interval between transfusion and development of HTLV-I-associated myelopathy is consistent with the more rapid evolution of this clinical syndrome compared with adult T-cell leukemia.     

A patient with progressive myelopathy and antibodies to human T-cell leukemia virus type I and human immunodeficiency virus type 1 in serum and cerebrospinal fluid

A 52-year-old human immunodeficiency virus type 1-seropositive bisexual black man was evaluated at UCLA because of the recent onset of progressive lower-extremity weakness. Initial neurologic examination showed that the patient's distal weakness was greater than his proximal weakness, with bilateral foot drop and electrophysiologic evidence of denervation in the distal lower extremities. Magnetic resonance imaging of the brain and spinal cord disclosed no abnormalities. Subsequent neurologic evaluation 8 months later showed a myelopathy, with progression of lower-extremity weakness, spasticity, and flexor spasms, and urinary incontinence, as well as the peripheral neuropathy noted previously. A second magnetic resonance imaging scan of the brain showed patchy foci of increased signal intensity in white matter and cortex, with mild generalized cerebral and cerebellar atrophy and no lesions in the spinal cord. Specimens of the patient's serum and cerebrospinal fluid contained antibodies to human immunodeficiency virus type 1. Additionally, specimens of his serum and cerebrospinal fluid were tested for antibody to human T-cell leukemia virus type I by Western blotting and radioimmunoprecipitation, and found to be positive for human T-cell leukemia virus type I gag, env, and tax antibodies. The primary cause of severe myelopathy in this patient may be infection with human T-cell leukemia virus type I rather than with human immunodeficiency virus type 1. Treatment with prednisolone resulted in improvement of the lower-extremity weakness, reduction in flexor spasms, and slower but significant improvement in urinary symptoms. Patients who are infected with human immunodeficiency virus type 1 and have unusual motor findings should be tested for concomitant human T-cell leukemia virus type I infection.     

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.     

Seroreactivity to human T cell leukemia/lymphoma virus type 1 and related retroviruses in multiple sclerosis patients from Denmark and the Faroes

A total of 40 multiple sclerosis (MS) patients from Denmark and 10 from the Faroes were examined for antibodies with affinity to human T cell leukemia/lymphoma virus type 1 (HTLV-I) and human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2). Using ELISA, MS patients and a group of healthy controls did not differ significantly in their reactivities to HTLV-I. However, elevated reactivities were recorded with 5 MS sera, whereas only 2 of the sera from the controls produced highly values. Ten patients with other neurological diseases all seemed to exhibit low reactivity in HTLV-I ELISA. The reactivities of 2 MS sera decreased considerably by absorption with an HTLV-I lysate. In immunofluorescence assay, two other MS sera reacted with HTLV-I transformed cell lines as well as with non-infected cells. Examined by Western blotting (WB), a single MS serum produced a distinct HTLV-I p19 band. With ELISA for detection of HIV-1 and HIV-2 antibodies, 2 MS sera exhibited borderline reactions. Further examination of these two sera by WB revealed weak reactivities against p24 and p53 of HIV-1. One the whole, the present observations do not suggest that a putative MS retrovirus would be closely related with HTLV-I, HIV-1 or HIV-2.     

Two cases of necrotizing myelopathy associated with malignancy caused by herpes simplex virus type 2

Summary Two cases of necrotizing myelopathy were autopsied; one was complicated with lung carcinoma and the other with chronic type adult T cell leukemia (ATL leukemia). To our knowledge, they were the first cases of their type in Japan. In both cases, necrosis of the spinal cord was observed in the gray and white matter along most of its extent. Marked changes were found in the lumbar segment. The patients were not treated with intravenous cancer chemotherapy or irradiation. Immunohistochemical and electron microscopic examination revealed an extremely strong infection of herpes simplex virus (HSV) type 2. However, HSV type 1 and cytomegalovirus antigens were not detected.     

Subacute meningoencephalitis associated with human T-lymphotrophic virus Type I (HTLV-I) Report of a case

We present a case of subacute meningoencephalitis associated with human T-lymphotrophic virus Type I (HTLV-I) infection, for HTLV-I antibody being positive in serum and cerebrospinal fluid. Necropsy findings disclosed leptomeningeal and parenchymal mononuclear cell infiltration with multinucleate giant cells, which are similar to those seen in subacute encephalitis with acquired immunodeficiency syndrome (AIDS).