Tropical spastic paraparesis and HTLV-1 associated myelopathy: clinical, epidemiological, virological and therapeutic aspects.

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 Orthoretrovirinae 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 auxillary 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 lymphoproliferation, 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.