Tropical spastic paraparesis and HTLV-1 associated myelopathy: Clinical, epidemiological, virological and therapeutic aspects
Tropical spastic paraparesis and HTLV-1 associated myelopathy: Clinical, epidemiological, virological and therapeutic aspects
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DOI：
10.1016/j.neurol.2011.12.006
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发表时间：
2012-03-01
影响因子：
3
通讯作者：
Mahieux, R.
中科院分区：
文献类型：
--
作者：
Gessain, A.;Mahieux, R.
1980年，人类T细胞白血病/淋巴瘤病毒1型（HTLV-1）是第一个被发现的致癌人类逆转录病毒。HTLV-1属于逆转录病毒科、正转录病毒亚科和三角转录病毒属。HTLV-1在体内优先感染CD4（+）淋巴样细胞。已经确定有三种分子可以结合和/或进入HTLV-1：硫酸肝素蛋白聚糖、神经磷脂-1和葡萄糖转运蛋白1。通过形成病毒突触和/或通过病毒膜结构，病毒可从被感染细胞有效地转移到靶细胞。与所有逆转录病毒一样，HTLV-1基因组具有三个主要的orf （gag， pol和env）编码结构蛋白和酶蛋白。HTLV-1还编码一些调控蛋白和辅助蛋白，包括具有转化活性的tax蛋白和在白血病细胞增殖和维持中起作用的HBZ蛋白。HTLV-1在世界各地都有高流行群，主要包括日本南部、加勒比地区、南美洲地区和热带非洲。全球HTLV-1感染人口估计约为1000万至2000万。HTLV-1有三种传播方式：(1)母婴传播，主要与母乳喂养时间过长有关；(2)：性传播，主要由男性传播给女性；(3)：被污染的血液制品。HTLV-1具有显著的遗传稳定性。HTLV-1主要是两种严重疾病的病因：恶性T CD4（+）细胞淋巴促增殖，预后非常差，称为成人T细胞白血病/淋巴瘤（ATLL），和慢性神经脊髓病，称为热带痉挛性截瘫/HTLV-1相关脊髓病（TSP/HAM）。HTLV-1携带者的终生风险估计约为0.25至3%。TSP/HAM主要发生在成年人中，平均发病年龄为40-50岁，女性比男性更常见。输血是发生TSP/HAM的主要危险因素。临床上，TSP/HAM主要定义为慢性痉挛性截瘫和轻微感觉体征。发病隐匿，常伴有步态障碍和泌尿系统症状。在超过90%的病例中，神经学特征包括：下肢痉挛和/或反射亢进，膀胱障碍，下肢肌肉无力，约50%的病例中，感觉障碍伴腰痛。中枢功能和脑神经通常不受影响。临床病程一般为进行性，无缓解。血液和脑脊液（CSF）中存在针对HTLV-1抗原的高水平抗体滴度。在血液中经常观察到高HTLV-1前病毒载量。脑脊液中可能出现轻度至中度的蛋白质升高。然而，鞘内产生特异性HTLV-1抗体指数提供了额外的数据来支持诊断。脑白质病变在磁共振成像上是常见的。胸脊髓轻度萎缩也可观察到。病理表现为慢性炎症伴血管周围淋巴细胞损伤和轻度实质淋巴细胞浸润。早期以CD4（+）细胞为主，晚期以CD8（+）细胞为主。锥体束损伤伴髓鞘和轴突损失，主要见于胸椎下部脊髓。TSP/HAM的发病机制尚不清楚，病毒和宿主因素作为原病毒载量和细胞免疫反应在疾病进展中起主要作用。TSP/HAM可与其他HTLV-1相关症状（葡萄膜炎、肌炎、感染性皮炎）相关。TSP/HAM的治疗仍然令人失望，对症治疗仍然是主要的治疗方法。(C) 2012 Elsevier Masson SAS。版权所有。
In 1980, Human T cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus to be discovered. HTLV-1 belongs to the Retroviridae family, the Orthore-trovirinae subfamily and to the deltaretrovirus genus. HTLV-1 preferentially infects CD4(+) lymphoid cells in vivo. Three molecules have been identified for binding and/or entry of HTLV-1: heparan sulfate proteoglycans, neuropilin-1, and glucose transporter 1. An efficient transfer of the virus from an infected cell to a target cell can occur through the formation of a viral synapse and/or by virofilm structure. As for all retroviruses, HTLV-1 genome possesses three major ORFs (gag, pol and env) encoding the structural and enzymatic proteins. HTLV-1 encodes also some regulatory and auxiliary proteins including the tax protein with transforming activities and the HBZ protein which plays a role in the proliferation and maintenance of the leukemic cells. HTLV-1 is present throughout the world with clusters of high endemicity including mainly Southern Japan, the Caribbean region, areas in South America and in intertropical Africa. The worldwide HTLV-1 infected population is estimated to be around 10-20 million. HTLV-1 has three modes of transmission: (1): mother to child, mainly linked to prolonged breast-feeding; (2): sexual, mainly occurring from male to female and (3): contaminated blood products. HTLV-1 possesses a remarkable genetic stability. HTLV-1 is the etiological agent of mainly two severe diseases: a malignant T CD4(+) cell lymphopro-liferation, of very poor prognosis, named Adult T cell Leukemia/Lymphoma (ATLL), and a chronic neuro-myelopathy named Tropical spastic paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). The lifetime risk among HTLV-1 carriers is estimated to be around 0.25 to 3%. TSP/HAM mainly occurs in adults, with a mean age at onset of 40-50 years and it is more common in women than in men. Blood transfusion is a major risk factor for TSP/HAM development. Clinically, TSP/HAM is mainly defined as a chronic spastic paraparesis and minor sensory signs. The onset is insidious with often gait disturbance and urinary symptoms. In more than 90% of the cases, the neurological features involve: spasticity and/or hyperreflexia of the lower extremities, urinary bladder disturbance, lower extremity muscle weakness, and in around 50% of the cases, sensory disturbances with low back pain. Central functions and cranial nerves are usually spared. The clinical course is generally progressive without remission. High levels of antibodies titers directed against HTLV-1 antigens are present in blood and cerebrospinal fluid (CSF). A high HTLV-1 proviral load is frequently observed in the blood. Mild to moderate increase of proteins may be present in the CSF. However, intrathecal production of specific HTLV-1 antibody index provides additional data to support the diagnosis. Brain white matter lesions on magnetic resonance imaging are frequent. A mild atrophy of the thoracic spinal cord can also be observed. Pathologically, it is characterized by a chronic inflammation with perivascular lymphocytic cuffing and mild parenchymal lymphocytic infiltrates. The cells are mostly CD4(+) in early disease and mostly CD8(+) in latter disease. Pyramidal tract damage with myelin and axonal loss, mainly in the lower thoracic spinal cord are observed. TSP/HAM pathogenesis is still poorly understood and viral and host factors as the proviral load and the cellular immune response play a major role in disease progression.TSP/HAM can be associated with other HTLV-1 associated symptoms (uveitis, myositis, infective dermatitis). Therapy of TSP/HAM remains disappointing and symptomatic treatment remains still the mainstay of therapy. (C) 2012 Elsevier Masson SAS. All rights reserved.