嗜人T淋巴细胞病毒I型（HTLV—I）相关HAM／TSP病

本文报道了应用田间免疫荧光法，从汕头地区９７例神经系统疾病患者血清中，检出嗜人Ｔ淋巴细胞病毒Ｉ型（ＨＴＬＶ－Ｉ）抗体阳性的ＨＴＬＶ－Ｉ相关ＨＡＭ／ＴＳＰ病患者５例，阳性率为５．１５％。并对ＨＴＬＶ－Ｉ相关ＨＡＭ／ＴＳＰ病的临床特点，伴发疾病，病理及发病机制，治疗等进行了讨论，认为国内进一步开展对ＨＴＬＶ－Ｉ相关ＨＡＭ／ＴＳＰ病的检测和研究是非常必要的。     

人类T细胞白血病病毒I型相关脊髓病四例报告

报道在日本经治的４个例人类Ｔ细胞白血病病毒Ｉ型（ＨＴＬＶ－Ｉ）相关脊髓病（ＨＡＭ），介绍了ＨＡＭ极流行学病学资料，认为在世界范围的ＨＴＬＶ－１多发区寻找ＨＡＭ是必要的，国内是否存在ＨＡＭ实应考虑。建议在国内在ＨＴＬＶ－１流行区注意切断各种传染作，这对预防我国ＨＡＭ发生及防止人类Ｔ细胞白血病扩散是非有价值的。     

人T淋巴细胞白血病Ⅰ型病毒致HAM／TSP一例报告

人Ｔ淋巴细胞白血病Ⅰ型病毒致ＨＡＭ／ＴＳＰ一例报告郑璇庄伟端陈显光杜登青我们于１９９５年５月检测１例人Ｔ淋巴细胞白血病Ⅰ型病毒（ＨＴＬＶ－１）抗体阳性及聚合酶链反应（ＰＣＲ）阳性的神经系统疾病患者，现报道如下。患者男，３４岁。因进行性双下肢乏力，行走...     

人类T细胞白血病病毒Ⅰ型相关脊髓病四例报告

报道在日本经治的４例人类Ｔ细胞白血病病毒１型（ＨＴＬＶ－Ⅰ）相关脊髓病（ＨＡＭ），介绍了ＨＡＭ临床及流行病学资料，认为在世界范围的ＨＴＬＶ－１多发区寻找ＨＡＭ是必要的，国内是否存在ＨＡＭ实应考虑。建议在国内ＨＴＬＶ－１流行区注意切断各种传染途径，这对预防我国ＨＡＭ发生及防止人类Ｔ细胞白血病扩散是非常有价值的。     

幼年大鼠皮质5—HT1A和5—HT2受体中介的膜电位变化

５－ＨＴ灌流幼年大鼠皮质脑片，２１．５％额叶后部ＩＶ层神经元出现慢超极化，膜电阻减小和ＥＰＳＰ抑制。此效应为５－ＨＴ１Ａ激动剂８－ＯＨ－ＤＰＡＴ模拟，为５－ＨＴ，拮抗剂ＮＡＮ－１９０阻抑，但ＥＰＳＰ抑制仍存在，超极化幅度随膜电位增大及胞外钾浓度增高而是减少，表明超极化由激活５－ＨＴ１Ａ受体导致钾外流增加所致，另有１１．８％神经元出现去极化伴膜电阻减小和ＥＰＳＰ抑制，５－ＨＴ２／５－ＨＴＩＣ拮抗剂Ｋ     

重症肌无力与人类嗜T淋巴细胞I型病毒抗原的关系

采用免疫荧光法检测２５例重症肌无力患者外周血细胞中人类嗜Ｔ淋巴细胞Ｉ型病毒（ＨＴＬＶ－１）抗原。结果显示，２０％（５／２５）的重症肌无力患者血细胞中ＨＴＬＶＩ抗原阳性，而对照组７１例全部为阴性。两组比较差异有极显著性意义。提示重症肌无力的发病可能与ＨＴＬＶ－１的感染有关。     

重症肌无力与人类嗜T淋巴细胞：I型病毒抗原的关系

采用免疫荧光法检测２５例重症肌无力患者外周血细胞中人类嗜Ｔ淋巴细胞Ｉ型病毒（ＨＴＬＶ－１）抗原。结果显示，２０％（５／２５）的重症肌无力患者血细胞中ＨＴＬＶ－１抗原阳性，而对照组７１例全部为阴性。两组比较差异有极显著性意义。提示重症肌无力的发病可能与ＨＴＬＶ－１的感染有关。     

中枢5－HT相对代谢率与精神分裂症临床特征分析

应用高压液相色谱（ＨＰＬＣ）对符合ＣＣＭＤ－２精神分裂症诊断标准的６７例患者脑脊液中５－ＨＴ、５－ＨＩＡＡ进行了测试，并以５－ＨＩＡＡ／５－ＨＴ作为相对代谢率，并以其中位数为界值分为高５－ＨＩＡＡ／５－ＨＴ比值组和低５－ＨＩＡＡ／５－ＨＴ比值组，结果发现，低比值组的ＢＰＲＳ阳性症状显著高于高比值组，而ＢＰＲＳ及其阴性症状和非特异症状两组无显著差异。相关分析发现，５－ＨＩＡＡ与ＢＰＲＳ及其阳性症状呈显著负相关，５－ＨＩＡＡ／５－ＨＴ与ＢＰＲＳ的阳性症状呈显著负相关，提示５－ＨＴ代谢低下与阳性症状有关。     

中枢5—HT相对代谢率与精神分裂症临床特征分析

应用高压液相色谱对符合ＣＣＭＤ－２精神分裂症诊断标准的６７例患者脑脊液中５－ＨＴ、５－ＨＩＡＡ进行了测试，并以５－ＨＩＡＡ 作为相对代谢率，并以其中位数为界值分为高５－ＨＩＡＡ／５－ＨＴ比人且和低５－ＨＩＡＡ／５－ＨＴ比值组，结果发现，低比值组的ＢＰＲＳ阳性症状显著高于高比值组，而ＢＰＲＳ及其阴性症状和非特异症状两组无显著差异。相关分析发现，５－ＨＩＡＡ与ＢＰＲＳ及其阳性症状呈显著负相关，５－ＨＩ     

老人院内痴呆患病率及其主要原因的研究（附临床与病理对照资料）

对某老人院内３７６例老年人进行了痴呆患病率和痴呆病因调查，并在此基础上对其中１５例死亡患者进行了病理和临床对照研究。主要结果：（１）临床痴呆调查发现，３７６例中，痴呆及可疑痴呆者１２０例，占调查总数３１．９％；其中ＨＤＳ在１０分以下的肯定痴呆患者４４例，占调查总数１１．７％，占ＨＤＳ异常得分者总数３６．７％。不同年龄及文化背景各组中ＨＤＳ异常者的比率无显著异差．（２）对４４例肯定痴呆患者进行临床诊断分类，结果显示痴呆患者中可能为ＳＤＡＴ者２７例（６０％）；ＭＩＤ者８例（１７．５％）；ＭＩＸ者９例（２２．５％），ＳＤＡＴ比例大于ＭＩＤ和ＭＩＸ，Ｐ＜０．０１．（３）１５例脑病理检查结果表明，７例临床检查有痴呆症状的患者中，４例经病理组织学证实为ＳＤＡＴ，３例符合ＭＩＤ诊断．８例临床智力正常者，无１例发现ＳＤＡＴ改变．上述结果表明ＳＤＡＴ在我国老年人中的发病率可能高于ＭＩＤ．     

The recent advances of HAM/TSP research]

The ninth international conference on HTLVs and related disorders was held on April 5-9, 1999 at Kagoshima, Japan under the conference chairperson, Dr. Mitsuhiro Osame. In this meeting, world-wide epidemiological data on HTLV-I carriers, ATL patients, and HAM/TSP patients were summarized as shown in the table. The total number of them was supposed to be more than 2.2 millions, 1,200, and 3,000, respectively. To elucidate the localization of HTLV-I proviral DNA directly, double staining using immunohistochemistry and PCR in situ hybridization in the spinal cords of HAM/TSP patients were performed. HTLV-I proviral DNA was localized only to OPD 4-positive cells (Matsuoka et al, 1998). The localization of HTLV-I messenger RNA was the same (Moritoyo et al, 1996). A novel technique to detect HTLV-I tax protein was also developed. In HAM/TSP patients, 0.04-1.16% of the CSF cells and 0.02-0.54% of PBMCs were positive for HTLV-I tax protein (Moritoyo et al, 1999). It was also hypothesized that HLA alleles control HTLV-I proviral load and thus influence susceptibility to HAM/TSP. Two hundred and thirty-two cases of HAM/TSP were compared with 201 randomly selected HTLV-I seropositive asymptomatic blood donors. It was shown that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (p < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02 positive healthy HTLV-I carriers have a proviral load one-third that (p = 0.0114) of HLA-A*02 negative HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility was also identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02 (Jeffery and Usuku et al, 1999).     

Elevated antibodies to synthetic peptides of HTLV-1 envelope transmembrane glycoproteins in patients with HAM/TSP

We studied the antibody response to various kinds of well-characterized synthetic peptides of human T lymphotropic virus type 1 (HTLV-1) envelope glycoproteins in patients with HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and non-HAM/TSP HTLV-1 carriers. The serum antibody titers to most of the synthetic peptides were significantly higher in patients with HAM/TSP than those in non-HAM/TSP HTLV-1 carriers. However, the degree of the increase of antibody titers to the synthetic peptides corresponding to the transmembrane portions of HTLV-1 envelope glycoproteins (env-p20E), such as p20E 332-352, 374-392, 426-448 and 458-488, was greater than those to synthetic peptides of exterior portions of HTLV-1 envelope glycoproteins (env-gp46) in sera from patients with HAM/TSP. Antibodies to env-p20E 332-352 and 374-392 were elevated in the cerebrospinal fluid (CSF) only from patients with HAM/TSP but not from non-HAM/TSP HTLV-1 carriers. These data indicate that the increase of antibody titers to transmembrane portions of HTLV-1 envelope glycoproteins in sera and CSF is a characteristic feature of antibody response in patients with HAM/TSP and may be closely associated with the development of HAM/TSP from non-HAM/TSP HTLV-1 carriers.     

Diagnosis of HAM/TSP based on CSF proviral HTLV-I DNA and HTLV-I antibody index

The contribution of human T-cell lymphotropic virus (HTLV-I) DNA by PCR in CSF and the intrathecal synthesis of antibodies to HTLV-I by the antibody index (AI) to the diagnosis of HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were evaluated. Cases of spastic paraparesis compatible with HAM/TSP had increased AI for HTLV-I (60/73) and HTLV-I proviral sequences in CSF (25/27). Among 27 patients with other neurologic diseases, three had increased AI and another three had positive HTLV-I DNA in CSF. Thus, the combination of PCR for proviral DNA and AI for HTLV-I in CSF provides consistent criteria for the diagnosis of HAM/TSP.     

Sequence heterogeneity of HTLV-I proviral DNA in the central nervous system of patients with HTLV-I–associated myelopathy

The nucleotide sequence of human T-lymphotropic virus type I (HTLV-I) in central nervous system tissue was determined in 3 autopsy cases with HTLV-I–associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 1 seropositive carrier without HAM/TSP but with multiple sclerosis. All HAM/TSP samples (3 spinal cords and 2 brains) and the sample from the seropositive carrier without HAM/TSP (brain) were positive for HTLV-I env (5146–6681), pX5′ (6549–7494), and pX3′ (7354–8276) regions by the two-step polymerase chain reaction method. A nucleotide sequence analysis of the pX5′ and pX3′ polymerase chain reaction products from nucleotides 6631 to 8259 revealed heterogeneity of the HTLV-I genome in all cases. It is notable that 13 of 50 clones derived from the pX3′ polymerase chain reaction products were defective in the tax open reading frame while 7 were defective in the rex open reading frame in the HAM/TSP samples. All 17 clones from 1 HAM/TSP case were defective in the pX open reading frame II. One nucleotide insertion at 7784 creating a frame shift in both tax and rex was seen in all 3 HAM/TSP cases but not in the HTLV-I carrier without HAM/TSP. The pX-defective mutants found frequently in the central nervous system may contribute to the neural damage, since the pX gene products are essential for the transactivation of various cellular genes as well as for viral replication.     

Neuronal molecular mimicry in immune-mediated neurologic disease

Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immunemediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP.     

Chronic progressive cervical myelopathy with HTLV-I infection: variant form of HAM/TSP]

We report four patients with slowly progressive cervical myelopathy. The four patients had several features in common; 1) progressive cervical myelopathy with a duration of several months to years, 2) abnormal lesions in the cervical to upper thoracic cord levels with or without gadolinium enhancement, 3) anti-HTLV-I antibodies were positive both in serum and CSF, 4) high levels of HTLV-I proviral load in PBMC. The calculated risk of HAM/TSP in two patients showed a high value, comparable to those of HAM/TSP, and higher than those of healthy HTLV-I carrier. Because the clinical and laboratory findings of these four cases show similarities to those of HAM/TSP, we propose that these four cases may be a variant form of HAM/TSP.     

Neuropathology of HTLV‐1‐associated myelopathy (HAM/TSP)

A series of our neuropathological studies was reviewed in order to clarify pathogenesis of human T lymphotropic virus type 1(HTLV‐1)‐associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The essential histopathologic finding was chronic inflammation in which inflammatory infiltrates of mononuclear cells and degeneration of myelin and axons were noted in the entire spinal cord. Immunohistochemical analysis demonstrated T‐cell dominance, and the numbers of CD4+ cells and CD8+ cells were equally present in patients with shorter clinical courses. Apoptosis of helper/inducer T‐cells were observed in these active inflammatory lesions. Horizontal distribution of inflammatory lesions was symmetric at all spinal levels and was accentuated at sites with slow blood flow in the middle to lower thoracic levels. HTLV‐1 proviral DNA amounts were well correlated with the numbers of infiltrated CD4+ cells. In situ PCR of HTLV‐1 proviral DNA and in situ hybridization of HTLV‐1 Tax gene demonstrated the presence of HTLV‐1‐infected cells exclusively in the mononuclear infiltrates of perivascular areas. From these findings, it is suggested that T‐cell mediated chronic inflammatory processes targeting the HTLV‐1 infected T‐cells is the primary pathogenic mechanism of HAM/TSP. Anatomically determined hemodynamic conditions may contribute to the localization of infected T‐cells and the formation of main lesions in the middle to lower thoracic spinal cord.     

Tropical spastic paraparesis treated with Combivir (lamivudine–zidovudine)

Tropical spastic paraparesis (TSP) or human T-cell leukemia virus–type 1 (HTLV–I)-associated myelopathy is caused by human T-lymphotropic virus type 1. It is a slow, progressive spastic paraparesis with significant morbidity and causing profound repercussions on quality of life. No therapies have been found to persistently improve the outcome in these patients. We present a patient with HTLV–1-associated myelopathy/TSP (HAM/TSP) who was treated with Combivir® (lamivudine–zidovudine, GlaxoSmithKline, London, UK). She was walker-dependent for several years but, soon after treatment with lamivudine–zidovudine, was able to walk using only a cane. The role of lamivudine–zidovudine should be investigated further in this patient population.     

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.