HTLV-I associated myelopathy with macular degeneration

The authors report a case of macular involvement in a patient with HTLV-I associated myelopathy (HAM). The patient was a 10-year-old girl who noticed sudden decreased vision in her right eye in November 1987. The corrected visual acuity was 0.01 in the right eye and 1.0 in the left eye. Fundus examination of the right eye disclosed mild optic disc pallor. The macula appeared to have pigmentary mottling with superficial irregular retinal reflex that was three disc diameters in size. Fluorescein angiography revealed a discoid hypofluorescent area in the macula, surrounded by mottled hyperfluorescent areas. She had no contributory family history of ocular disease, but had a history of blood transfusion during an operation for patent ductus arteriosus and ventricular septal defect at the age of 8 months. In November 1990, she developed gait disturbance due to spastic paraparesis and was admitted to our hospital. Antibodies to HTLV-I were markedly elevated in serum (titer, 1:8192) and in cerebrospinal fluid (titer, 1: 1024). She was diagnosed as HAM. Two months later, she developed encephalopathy and bilateral optic disc atrophy.     

Human T lymphotropic virus type I (HTLV-I)-specific T helper cell responses from HTLV-I seronegative patients with chronic myelopathy and MS in Japan

Human T lymphotropic virus type I (HTLV-I) is a human retrovirus etiologically linked to Adult T cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although most HAM/TSP patients have high anti-HTLV-I antibody titers in their sera, HTLV-I infected but seronegative patients with neurological diseases have been reported. To clarify whether seronegative, HTLV-I related neurological disease may exist, we have developed a method that measures the production of interleukin-2 (IL-2) from HTLV-I synthetic peptide-stimulated peripheral blood lymphocytes (PBL) of HTLV-I infected persons. This method is sensitive enough to detect exposure to HTLV-I before seroconversion or even before detection by PCR. We examined 12 patients with chronic progressive myelopathy and eight patients with multiple sclerosis (MS) in central Japan, where the prevalence rate of HTLV-I is between one and four percent among asymptomatic blood donors, using the IL-2 production assay. None of them were positive by the assay, suggesting seronegative HTLV-I myelopathy is very rare among patients with chronic progressive myelopathy and MS in Japan.     

No evidence of HTLV-I proviral integration in lymphoproliferative disorders associated with cutaneous T-cell lymphoma

Several recent studies have reported detection of HTLV-I genetic sequences in patients with cutaneous T-cell lymphoma (CTCL) including mycosis fungoides and Sezary syndrome. The purpose of this study was to determine whether HTLV-I was detectable in lesional tissues of patients suffering from diseases known to be associated with CTCL. Thirty-five cases were obtained from diverse geographical locations including Ohio, California, Switzerland, and Japan. Six of them had concurrent CTCL. Cases were analyzed using a combination of genomic polymerase chain reaction (PCR)/ Southern blot, dot blot, and Southern blot analyses. All assays were specific for HTLV-I provirus. Sensitivity ranged from approximately 10(-6) for PCR-based studies to 10(-2) for unamplified genomic blotting. Lesional DNA from patients with lymphomatoid papulosis (fourteen cases), Hodgkin's disease (twelve cases), and CD30+ large-cell lymphoma (nine cases) was tested for the HTLV-I proviral pX region using a genomic PCR assay followed by confirmatory Southern blot analysis with a nested oligonucleotide pX probe. All cases were uniformly negative. All of the Hodgkin's disease cases, eight of the large-cell lymphoma cases, and six of the lymphomatoid papulosis cases were then subjected to dot blot analysis of genomic DNA using a full-length HTLV-I proviral DNA probe that spans all regions of the HTLV-I genome. Again, all cases were negative. Finally, eleven of the Hodgkin's disease cases were also subjected to Southern blot analysis of EcoRI-digested genomic DNA using the same full-length HTLV-I probe. Once again, all cases were negative. These findings indicated that, despite utilization of a variety of sensitive and specific molecular biological methods, HTLV-I genetic sequences were not detectable in patients with CTCL-associated lymphoproliferative disorders. These results strongly suggest that the HTLV-I retrovirus is not involved in the pathogenesis of these diseases.     

Progressive myelopathy caused by human T-cell lymphotropic virus type I (HTLV-I) in 3 patients in The Netherlands]

Liability to neural tube defects is increased by maternal dietary deficiency, and children with neural tube defects show a possibly related seasonal variation in date of birth. Since maternal dietary insufficiency may also increase liability to cleft lip, with or without cleft palate (CLP), we wondered if children with CLP would also show a seasonal variation in birth date. The multifactorial-threshold model predicts that any such effect would be more apparent in males than females, since CLP is more frequent in males. Month of birth was obtained from records of 598 children with CLP seen at The Montreal Children's Hospital between 1950 and 1996. Children with syndromes or associated malformations were excluded. There was a significant tendency for children with CLP to be born more often in the summer than in winter. The difference was greater in males than in females. The seasonal fluctuation in month of birth of children with CLP is consistent with the presence of an environmental factor increasing liability, with a maximal effect in November-December. This might be related, at least in part, to a seasonal fluctuation in maternal nutrition. The data support the prediction that analyzing the data for the sexes separately would amplify the effects of variation in liability for a multifactorial threshold trait that has a different frequency in males and females. This approach could be useful in the study of other gene-environment interactions.     

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.     

Defective human T-cell lymphotropic virus type I (HTLV-I) provirus in 10 Chilean seronegative patients with tropical spastic paraparesis or HTLV-I-associated myelopathy

We studied the presence of tax and ltr genes from human T-cell lymphotropic virus type I (HTLV-I) provirus in the peripheral blood mononuclear cells from 15 seronegative patients with tropical spastic paraparesis or HTLV-I-associated myelopathy by PCR. Only a region of the tax gene from 10 patients was amplified. The nucleotide homologies of six Chilean isolates to the ATK-1 clone ranged between 98.7 and 99.4%.     

Movement disorders in Japanese encephalitis

Movement disorders in Japanese encephalitis (JE), although reported, have not been analyzed systematically. In this study, we report an analysis of movement disorders in 14 out of 17 JE patients, correlated with the radiological findings. All patients had at least a four fold rise of IgG antibodies against JE in a haemagglutination inhibition test. The patients' ages ranged between 2 and 54 years and 4 of them were women. Extrapyramidal signs, such as hypokinesia, hypophonia and masking of the face, were present in all patients by the first month as the patients came out of the coma-except for 1 patient. Eight patients had axial and 3 tongue dyskinesia; rigidity was present in 6 and tremor in 2 patients. At 3 months, these symptoms improved considerably in 6 patients. Cranial CT scan revealed thalamic involvement in 10, which was bilateral in 9 patients. Two patients had brain stem and one had cerebellar involvement. Cranial MRI was carried out in 9 patients and revealed additional findings in lentiform nucleus, midbrain and pons in 3 each and cerebellum in 4 patients. Bilateral thalamic involvement on MRI was seen in all the patients, including two patients whose CT scans were normal. SPECT studies using 99mTc-ECD revealed bilateral thalamic hypoperfusion in all (n = 7) and frontal hypoperfusion in 3 patients. In JE, movement disorders are common and may be due to thalamic involvement in isolation or in combination with basal ganglia or midbrain or both.     

Movement sequencing disorders in Parkinson's disease

Ten PD patients and ten age-matched normal controls learned a sequence of 3 or 4 different hand movements to a criterion of 5 consecutive correct trials. They also performed a control sequence of 3 or 4 movements which involved the repetition of the same hand posture. Trials to reach criterion, errors, total response time and its components, response time for each movement and inter-response time were examined. There were no group differences in trials to criterion or errors. Total movement time as well as response and inter-response times were significantly longer for the PD patients, however, but only for sequences involving different hand movements not for the repetitive sequences. The relative timing of the responses was also different with the PD patients spending proportionately more time on each response and the controls spending more time between responses. The implications of these findings for understanding the movement sequencing impairments in PD are discussed.     

Chronic myelopathy associated with human herpesvirus-6

Human herpesvirus-6 (HHV-6) is implicated in a variety of neurologic diseases. We report a previously healthy elderly woman with progressive spastic paraparesis. At autopsy the spinal cord showed widespread demyelination, axonal loss, and chronic inflammation. HHV-6 DNA was amplified, using polymerase chain reaction, from spinal cord tissue, and glial cells were immunoreactive with an HHV-6 antibody. These findings suggest that HHV-6 may cause myelopathy.     

Analysis of HAM rat disease with HTLV-I infection, an animal model for HAM/TSP in human-immunohistochemical, immuno-electron microscopic and flow cytometrical analyses of microglia/macrophages in the affected spinal cord]

HAM rat disease is a demyelinating disease in the spinal cord and peripheral nerve of WKAH rats with HTLV-I infection and has been described as an animal model for human T lymphocyte virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in humans. The histopathological characteristic in the affected lesions is a vacuolar myelopathy, with the apoptosis of oligodendrocytes and the massive infiltration of microglia/macrophage lineage cells. To investigate the pathogenetic role of the infiltrating microglias/macrophages in the lesion, the author carried out chronological analyses with immunohistochemistry, immuno-electron microscopy and flow cytometry on the spinal cord specimens of HAM rats. Many OX-42 positive cells were identified as microglias either irregular or plump in shape. Both MHC Class II and LFA-1 expressions were increased in these cells, suggesting they were activated in the lesion. Moreover, many microglias/macrophages showed PCNA positivity, indicating they proliferated locally. Some apoptotic microglias/macrophages were evidenced by immuno-electron microscopy. Flow cytometrical analysis revealed that the majority of the infiltrating cells in the affected lesion was originated from resident microglias, and macrophages from the blood stream appeared to be minimum. Collective evidence suggests that the activated and proliferated resident microglias with HTLV-I infection may play a critical role in the disease course through the production of cytotoxic factors such as TNF-alpha.     

Recurrent acute transverse myelopathy associated with anticardiolipin antibodies

In three patients with recurrent episodes of acute transverse myelopathy, spinal MR imaging during each episode showed areas of hyperintensity on proton density- and T2-weighted images with inconsistent contrast enhancement. Cranial MR imaging, laboratory screenings, and CSF analysis showed only increased titers of anticardiolipin antibodies. Although a causative role in neurologic conditions has not been established conclusively, an association between these antibodies and acute transverse myelopathy and its recurrences cannot be ignored.     

A case of bilateral optic neuropathy and recurrent transverse myelopathy associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA)

The purpose of this study was to evaluate skeletal and dental effects of bionator headgear combination appliances on patients in development period with Class II, division 1 malocclusion. The comparison of computerized X-ray cephalometric measurements between the 26 treated children and 26 untreated children was made. The results showed that ANB angle was significantly reduced and horizontal mandibular growth development tended to be normal in the treated group. It was suggested that the bionator headgear combination appliance can restrain the maxillary growth early and promote the forward mandibular growth which contribute the functional jaws correction.     

Vertical transmission human T-cell lymphotropic virus type-I (HTLV-I)--genetic diagnosis and assessment of the probable routes of HTLV-I infection

Human T-cell lymphotropic virus type-I (HTLV-I) provirus DNA from peripheral lymphocyte of 39 infants delivered by 26 pregnant carriers was detected by the nested double polymerase chain reaction (PCR) method to identify vertical transmission (VT) of HTLV-I. The 39 infants included 12 breast-fed and 27 bottle-fed infants. Particle agglutination (PA) assay and indirect immunofluorescence (IF) test with 467 cells were performed to detect anti-HTLV-I antibody. In breast-fed infants, two (16.7%) cases were both seropositive and PCR-positive and others were both negative, so there was perfect agreement between seropositivity and PCR-positivity. In bottle-fed infants, two (7.4%) cases were seropositive but PCR-negative. This seropositivity was supposed to be due to the transplacental maternal anti-HTLV-I antibody. In 25 seronegative bottle-fed infants, 4 (14.8%) cases were PCR-positive. No significant difference was found in the PCR-positivity rate between the breast-fed and bottle-fed groups. Our study showed the usefulness of the PCR method in identifying VT, the existence of silent carriers especially in bottle-fed infants and the possibility of transplacental or birth canal routes of HTLV-I infection.     

Demonstration of human T lymphotropic virus type I (HTLV-I) tax-specific CD8+ lymphocytes directly in peripheral blood of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by intracellular cytokine detection

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-I infection and has been associated with elevated levels of several proinflammatory cytokines in both serum and cerebrospinal fluid. It is unknown what kind of cells secrete these cytokines and if HTLV-I Ags are associated with this phenomenon. Here, we investigated the expression of cytokines in PBL from eight HAM/TSP patients, nine HTLV-I-infected asymptomatic carriers, and seven healthy controls by flow cytometry combined with intracellular cytokine staining. PBL were cultured with brefeldin A without mitogen and IL-2 for 14 h. Under these conditions, CD8+ cells produced proinflammatory cytokines including IFN-gamma, TNF-alpha, and IL-2, which were significantly elevated in HAM/TSP patients. The proportion of CD8+ cells producing IFN-gamma in HAM/TSP patients, asymptomatic carriers, and healthy controls were, on average, 4.9, 0.4, and 0.3%, respectively. IFN-gamma production by these CD8+ cells was suppressed by anti-HLA-class I Ab. Purified CD8+ cells from an HLA-A2 HAM/TSP patient produced IFN-gamma by cocultivation with autologous CD4 cells, the main reservoir of HTLV-I in vivo, or allogenic HLA-A2+ B cells pulsed with a known immunodominant HTLV-I tax peptide. These data suggest that high levels of circulating HTLV-I-specific CD8+ T lymphocytes have the potential to produce proinflammatory cytokines and may promote inflammatory responses to HTLV-I in HAM/TSP patients.