Recent studies on the epidemiology, clinical features and pathogenic mechanisms of HTLV-I associated myelopathy (HAM/TSP) and other diseases associated to HTLV.
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Blood Component Removal↗
Biomedical subjects
F Umehara
Publications and source records attributed to F Umehara.
HTLV-I associated myelopathy (HAM): review and recent studies.
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Blood Transfusion↗
Neuropathology of HTLV-1-associated myelopathy (HAM/TSP).
In order to clarify pathogenesis of HAM/TSP, we performed a detailed neuropathologic analysis of seven autopsy patients with HAM/TSP. Inflammatory infiltrates of mononuclear cells and degeneration of myelin and axons were noted in the middle to lower thoracic spinal cords and were continuously extended 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 equally present 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-1 proviral DNA amounts in the freshly frozen spinal cord measured by quantitative PCR were well correlated with the numbers of infiltrated CD4+ cells. In situ PCR of HTLV-1 proviral DNA using multi-primary pairs demonstrated the presence of HTLV-1 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-1 infected CD4+ T cells infiltrating the spinal cord.
Apoptosis↗
Expression of adhesion molecules and monocyte chemoattractant protein -1 (MCP-1) in the spinal cord lesions in HTLV-I-associated myelopathy.
Leukocyte adhesion molecules to endothelium plays an important role in the pathogenesis of inflammatory diseases, including HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). To help define the role of adhesion molecules in HAM/TSP, we studied the expression of lymphocyte function-associated antigen-1 (LFA-1), Mac-1, very late antigen-4 (VLA-4), Sialyl Lewisx (SLex), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the spinal cord lesions of HAM/TSP. The results indicate that spinal cord lesions of HAM/TSP have greater VCAM-1 expression on endothelium compared with those of controls. Infiltrating mononuclear cells, especially perivascular lesions, expressed VLA-4. Although the expression of ICAM-1 in the spinal cords was not distinctive between HAM/TSP and controls, infiltrating mononuclear cells in the spinal cords of HAM/TSP strongly expressed LFA-1 and Mac-1. ELAM-1 was expressed on endothelium in the inactive-chronic lesions from three of five HAM/HAM/TSP, but was not detectable in the spinal cords of controls. SLex reactions was detectable on occasional perivascular cells in the spinal cord of HAM/TSP, but not in those controls. MCP-1 was detectable on perivascular infiltrating cells and vascular endothelium in active-chronic lesions. This study suggest that VLA-4/VCAM-1 interaction may play an important role for lymphocyte migration into the central nervous system (CNS) and MCP-1 may also be involved in inflammatory cell recruitment to the CNS in HAM/TSP.
Aged↗
HAM/TSP: recent perspectives in Japan.
Neurologic diseases associated with human T-cell lymphotropic virus type I (HTLV-I) infection have a clinical spectrum that includes myelopathy (HTLV-I-associated myelopathy/tropical spastic paraparesis, HAM/TSP) as the central manifestation. Many clinical signs of involvement outside the central nervous system (CNS) have been described in some patients with HAM/TSP and have triggered and advanced the discovery of some HTLV-I-associated concepts in HTLV-I-infected individuals without signs of CNS involvement. Most of these HTLV-I-associated diseases exhibit common 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. These facts suggest that the vulnerable tissue(s) in some HTLV-I-infected individuals may not be defined by an exclusive tissue specificity, but that common steps of HTLV-I-versus-host interactions may have an important role in the pathologic process(es) in these diseases. This review summarizes the recent perspectives of the clinical spectrum and the pathogenesis of HAM/TSP in Japan. Furthermore, the feasible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the affected tissues is emphasized.
Adult↗
[Medullary infarction due to vertebral dissecting aneurysm in a patient with Behçet's disease].
A 65-year-old man with Behçet's disease was admitted to our hospital because of an acute left occipital headache and truncal ataxia. He had been treated with prednisolone since the age of 40. MRI showed a hyperintense lesion on T2-weighted images on the left of the medulla oblongata. Left vertebral angiogram showed findings consistent with a dissection at the V4 segment of the artery. After admission, the patient showed marked improvement and was discharged 1 month later without neurological deficits. This is a very rare case of medullary infarction due to vertebral dissecting aneurysm in a patient with Behçet's disease.
Aged↗
[Dural arteriovenous fistulas of the posterior fossa associated with lateral sinus thrombosis presenting as progressive visual impairment].
A 62-year-old man was admitted because of progressive visual impairment since 2 months ago. Ophthalmological examination revealed impaired visual acuity with papillary edema in both eyes. Right carotid angiograms showed dural arteriovenous fistulas of the lateral sinus mainly fed by the right occipital artery. On the angiograms, the right transverse sinus was completely occluded. Endovascular embolization via jugular vein and via occipital artery was performed. Dural AVF disappeared and visual acuity was improved with normalized intracranial tension.
Arteriovenous Fistula↗
[Clinical features of allergic granulomatosis and angiitis (Churg-Strauss syndrome). Association with asthma symptoms].
We reported clinical and laboratory findings of 5 patients with Churg-Strauss syndrome (CSS), especially association with asthma symptoms. Subjects included 3 males and 2 females with a mean age of 53.8 year-old. In all 5 patients symptoms of neuropathy; mononeuritis multiplex and in some patients, other vasculitic symptoms; fever, diarrhea, abdominal pain and skin eruptions, were noted. These clinical features and laboratory findings; marked peripheral eosinophilia and elevation of serum ECP were normalized after steroid therapy. We investigated the relation between the occurrence of CSS and the symptoms of asthma. The mean duration of asthma in this series was 17.2 years, and 4 cases were atopic and one was non-atopic asthma. In previous publications, asthmatic symptoms were severe at the onset of the disease and progressed thereafter. In our 5 cases, however, the severities of bronchial asthma were mild of two cases, moderate of two and severe of only one, moreover severe asthmatic attacks were shown in only 2 cases when the manifestation of systemic vasculitis occurred. In conclusion, although CSS has been thought that one of complications of bronchial asthma, the occurrence of CSS are not necessarily correlated with symptoms of bronchial asthma.
Adult↗
[A case of paranasal sinusitis-cavernous sinusitis with ophthalmoplegia externa].
A 15-year-old man was admitted because of diplopia and bilateral ptosis which occurred a few days after initial clinical signs, such as fever up, nausea, vomiting and headache. His pupils were anisocoric (Rt. phi 3.5 mm < Lt. phi 6.0 mm). In his left eye, light reflex was absent and its movements were limited in all directions. Brain MRI revealed the findings of paranasal sinusitis in bilateral ethmoidal and sphenoidal sinuses and swelling of bilateral cavernous sinus. Combination of intravenous antibiotic therapy and drainage improved his clinical symptoms and MRI findings. It was diagnosed as the inflammation originated in the sphenoid and ethmoid sinuses, which extended to the cavernous sinus and then involved III, IV, and VI cranial nerves. In conclusion, MRI was very useful to detect the cavernous sinusitis secondary to sphenoidal sinusitis.
Adolescent↗
Magnetic resonance tomographic angiography: diagnostic value in trigeminal neuralgia.
A combination of MRI, MR angiography and MR tomographic angiography (MRTA) was used to study the relationship of the root exit zone of the trigeminal nerve to surrounding vascular structures in seven patients with trigeminal neuralgia (TN) and ten patients with no evidence at a lesion in this region. MRTA is the technique for showing the relationship between vessels, cranial nerves and brain stem. MRTA clearly demonstrated the presence of a vessel at the root exit zone of the trigeminal nerve in all patients with TN. In the ten other patients, examination of 20 trigeminal nerves revealed that only one nerve (5%) was in contact with a vessel at the root exit zone. This study supports vascular compression of trigeminal nerves as a cause of TN, and demonstrates the value of MRTA as noninvasive technique for demonstrating compression.
Arteries↗
Familial spastic paraplegia with mental impairment and thin corpus callosum.
We described four patients in two families of unique familial spastic paraplegia (FSP) which was thought to be possibly autosomal recessive inheritance. All four patients had quite similar manifestations. Gait disturbance started at their second decade, then spastic paraparesis and mental deterioration progressed slowly. Cerebellar ataxia and sensory loss in the distal parts of four extremities were also slightly presented. In all patients, cranial MRI revealed marked thin corpus callosum with mild changes in the region of periventricular white matter and in the gray matter. Biopsied sural nerves of all patients showed chronic axonal degeneration with mild decrease of both large and small myelinated fibers. Electron microscopic study demonstrated crystalline-like inclusion bodies in the cytoplasm of Schwann cells in all patients. Despite extensive investigation for metabolic disorder, we could not find any abnormality. However an etiology have not established at the time presented, the combination of these clinical features suggested that the disorder could represent a specific clinical entity.
Adult↗
Deletion in chromosome 17p11.2 including the peripheral myelin protein-22 (PMP-22) gene in hereditary neuropathy with liability to pressure palsies.
We report the clinical, electrophysiological, and pathological findings of two unrelated Japanese families with hereditary neuropathy with liability to pressure palsies (HNPP) and confirm the findings of a deletion of peripheral myelin protein-22 (PMP-22) gene. Electrophysiological studies revealed slowing of nerve conduction velocities of the affected nerves. Sural nerve biopsy revealed regions of myelin duplication. The copy numbers of PMP-22 gene was lower than that of normal control, suggesting deletion of 17p11.2 including PMP-22 gene. Our results indicate that HNPP in these two Japanese families is attributable to deletion of 17p11.2 including PMP-22 gene.
Aged↗
Chronic inflammatory demyelinating polyneuropathy: histological and immunopathological studies on biopsied sural nerves.
We undertook histological and immunopathological studies on biopsied sural nerves from 9 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The diagnosis of CIDP was based on the research criteria proposed by the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. The nerve pathology in these patients comprised macrophage-associated active demyelination and subsequent remyelination of various proportions. The presence of T cells in the endoneurium correlated with activity of demyelination. An analysis of T cell subsets demonstrated that the number of CD8-positive cells predominated over that of CD4-positive ones. Infiltration of B cells, and depositions of immunoglobulin and complement were not seen. These observations suggest that a T cell-mediated process is of pathogenic significance in CIDP. Furthermore, a double immunofluorescence staining revealed that most HLA-DR antigen-positive cells in the nerves in which active demyelination was seen coexpressed a macrophage-specific determinant. Conversely, HLA-DR-positive Schwann cells were found in the nerves in which remyelination was predominant. The expression of HLA-DR antigen on Schwann cells might not play a pathogenic role in the active demyelination in CIDP.
Adolescent↗
[Case of hypertrophic meningitis with vasculitis syndrome].
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Azathioprine↗
HTLV-I proviral DNA amount correlates with infiltrating CD4+ lymphocytes in the spinal cord from patients with HTLV-I-associated myelopathy.
A quantitative method utilizing polymerase chain reaction was employed to evaluate the amount of human T-cell leukemia virus type I (HTLV-I) proviral DNA in the affected spinal cords from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Central nervous system (CNS) tissues were obtained at post-mortem from five patients with HAM/TSP, who vary in the duration of illness from 2.5-10 years, and one patient with adult T-cell leukemia (ATL), who had leukemic cell infiltration in the CNS. The presence of HTLV-I pX and pol sequences in the CNS tissues were demonstrated in all patients examined. In HAM/TSP, the proviral DNA quantified in the thoracic cord was 0.002-2 copies per 100 tissue cells, and that in the peripheral blood mononuclear cells (PBMC) was 2-8 copies per 100 PBMC. The proviral DNA amount in the thoracic cord of the patient with ATL was 0.4 copies per 100 tissue cells. An apparent propensity for the amount of integrated HTLV-I in the thoracic cord to decrease with the disease duration in patients with HAM/TSP was observed. The decline in HTLV-I proviral DNA amount in the thoracic cord lesions was paralleled with the alteration of proportion of CD4+ T lymphocytes in patients with HAM/TSP. These findings suggest that preferential virus reservoir may be infiltrating CD4+ T lymphocytes in the spinal cord lesions of patients with HAM/TSP, and HTLV-I infection in the CNS of patients is declining with the disease duration in spite of the chronic course of neurological manifestations at least in some patients with HAM/TSP.
Aged↗
Cytokine expression in the spinal cord lesions in HTLV-I-associated myelopathy.
Immunocytochemical staining of spinal cords from five autopsied patients with HTLV-I-associated myelopathy/tropical spastic paraparesis was performed using a panel of monoclonal or polyclonal antibodies reactive with interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-beta, IFN-gamma and transforming growth factor (TGF)-beta. In the spinal cords of patients with a shorter duration of illness, IL-1 beta, TNF-alpha, and IFN-gamma were expressed on perivascular infiltrating macrophages, astrocytes and microglia in active-chronic inflammatory lesions. In striking contrast, we rarely noted cytokine expression except for IFN-gamma in inactive-chronic lesions of patients with longer durations. In situ expression of these cytokines on microglia and astrocytes, in addition to infiltrating mononuclear cells, suggests that glial cells participate in the inflammatory process, especially in active lesions. In addition, the cytokine expression was gradually downregulated along with duration of illness.
Aged↗
Apoptosis of T lymphocytes in the spinal cord lesions in HTLV-I-associated myelopathy: a possible mechanism to control viral infection in the central nervous system.
Immunocytochemical staining of spinal cords from five autopsied patients with HAM/TSP was performed using the monoclonal antibody TIA-1, a marker of cytotoxic T lymphocytes (CTL). Many TIA-1+, CD8+ cells are distributed in active inflammatory lesions. The number of TIA-1+ cells is related to the amount of HTLV-I proviral DNA in situ. The protein TIA-1 has been associated with the induction of apoptosis in target cells. In active inflammatory lesions, we found cells undergoing apoptosis, most of them identified as helper-inducer CD45RO T lymphocytes, which were consistent with in vivo cellular tropism of HTLV-I in patients with HAM/TSP. These findings suggest that CTL-induced apoptosis of T lymphocytes may be one of the possible mechanisms which eliminate HTLV-I-infected cells from the central nervous system. In addition, many T lymphocytes in the inflammatory lesions expressed bcl-2 oncoprotein, suggesting that infiltrated T lymphocytes may be resistant to apoptosis. Expression of bcl-2 oncoprotein may explain the longstanding inflammatory process in the central nervous system of HAM/TSP.
Antibodies, Monoclonal↗
Paraneoplastic vasculitic neuropathy: immunohistochemical studies on a biopsied nerve and post-mortem examination.
We studied a patient with paraneoplastic vasculitic neuropathy (PVN) associated with a carcinoma of the common bile duct. Immunohistochemical analysis of the biopsied sural nerve showed that the cellular infiltrates in the vascular lesions were composed primarily of CD8-positive T lymphocytes and macrophages. Pathogenic significance of the T-cell-mediated immunological reaction was suggested. Post-mortem examination revealed the absence of systemic vasculitis, which may be a characteristic feature of PVN. The patient responded to immunosuppressive treatment. We discuss the efficacy and the risk of immunosuppressive therapy for PVN.
Adenocarcinoma↗