Cyclosporine for the Treatment of HTLV-1-Induced HAM/TSP

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) remains a challenging disease. Treatment options are scarce, and their safety and efficacy are currently a matter of concern. We present a case report describing our experience using cyclosporine in a patient with early HAM/TSP who started with a gait disturbance at Vall d’Hebron University Hospital (Barcelona) from August 2012 to October 2013. After 62 weeks of treatment, clinical improvement was observed and proviral load diminished. No safety concerns were observed. Cyclosporine seems to be effective in new-onset HAM/TSP or in chronic HAM/TSP that develops a relapse. However, the duration and safety profile of this steroid-sparing therapy remain unknown and should be further investigated. (Medicine 94(1):e382) Abbreviations: HAM/TSP = HTLV-1-associated myelopathy/ tropical spastic paraparesis, HTLV = human T-lymphotropic virus, IPEC = Instituto de Pesquisa Clı́nica Evandro Chagas disability score, SF-36 = SF-36 health survey scale, SPAST-88 = spasticity scale-88 score, TLL = T-cell leukemia/lymphoma. INTRODUCTION H uman T-lymphotropic virus (HTLV) was the first retrovirus to be described. Currently, 4 types of HTLV have been reported, with HTLV-1 being the most clinically relevant. Approximately, 20 million people are infected with HTLV-1 and 5 million with HTLV-2 worldwide. HTLV-1 infection is mainly present in the Sub-Saharan region, Japan, the Caribbean region, and some parts of Latin America, whereas HTLV-2 infection predominates in specific ethnic groups in Africa and America. Additionally, HTLV-2 infection has been found in D, Estrella Caballero, MD, and Israel Molina, MD and 0.08% for HTLV-2. HTLV-1 was mainly diagnosed in the migrant population. The HTLV-1 infection has been associated with 2 lifethreatening diseases, T-cell leukemia/lymphoma (TLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Other manifestations, such as eye and skin involvement, have also been related with HTLV-1. HAM/TSP is an inflammatory disease of the central nervous system. The incidence of HAM/TSP was 5.3 cases per 1000 HTLV-1-seropositive cases per year in a study carried out in Brazil. Symptoms of the disease are insidious and difficult to interpret at the onset of the disease. Paraparesis, spasticity, urinary incontinence, lower back pain, and hyperreflexia are common but not specific findings, hindering both diagnosis and follow-up. A new classification to make monitoring of the therapeutic response easier was developed recently using onset, progression, and activity criteria. Although HAM/TSP has been known for decades and its consequences are devastating, treatment options are still scarce. Initially, antiretroviral therapy was used with contradictory results. Once the immune-mediated theory emerged, immunosuppressive therapy was studied. To date, cyclosporine and interferon-a are the preferred immunosuppressive agents, even though the evidence regarding their efficacy is limited. Host–virus interaction is crucial for the HTLV-1 spread and the development of lymphocyte-mediated related diseases. Immunomodulation with cyclosporine after HTLV-1 infection in a rabbit model has shown a decrease of proviral load. In a recent proof-of-concept study, 7 patients with HAM/TSP in an early/progressive stage of the disease were treated with cyclosporine with encouraging results. Based on the cyclosporine proof-of-concept study, we relate our experience with cyclosporine in a patient diagnosed with an early HAM/TSP. We utilized the same stage classification and outcome criteria as described by Martin et al. The institutional review board of the Vall d’Hebron University Hospital approved the study. The patient signed a written informed consent for publication of the case report. CASE A 40-year-old woman from the Dominican Republic presented at the emergency room in August 2012 with an 8-month history of gait disturbances and falls. The patient had been living in Spain for the last 14 years and reported no travel history in the last 5 years. Her previous medical status unveiled a treated hyperthyroidism with a normal hormonal study in the follow up, a major depression disorder, and urinary bladder appeared during the previous year and nother center. She was under treatment lifenacin succinate. www.md-journal.com | 1 A more accurate medical history revealed blurred vision and muscle spasms. On physical examination on admission, the patient had normal axillary temperature, blood pressure values, and heart rate. Heart, lung, and abdominal examinations were unremarkable. Skin examination showed a pruriginous papular rash in the lower abdomen and scalp. Muscle strength was slightly reduced in the lower limbs, where the deep tendon reflexes were brisk and the reflex area expanded. Moreover, the lower limbs were spastic and vibratory sensation was diminished. The Babinski sign was presented bilaterally. On eye examination, uveitis was diagnosed. In the blood test, the white cell count only showed a total eosinophil count of 1000 cells/mm (10.2%). Biochemical parameters remained within the normal range. Serological tests for hepatitis B and C, human immunodeficiency virus, and Strongyloides stercoralis were negative. Vitamin deficits and autoantibody battery study were also within normal ranges. Feces samples were negative for helminths. The tuberculin skin test was performed twice with negative results. A cranial and spinal magnetic resonance imaging demonstrated small demyelinating focal lesions in the subcortical white matter, mainly around the posterior portion of both oval centers, conditioning Wallerian degeneration in the pyramidal tracts bilaterally. The lesions showed no signs of activity. The cerebrospinal fluid showed lymphocytic pleocytosis. An oligoclonal band study was negative and microscopy did not observe any atypical cells. On electromyography examination, a severe involvement of pyramidal and somatosensorial tracts for all 4 limbs was diagnosed, suggesting demyelination. No signs of peripheral neuropathy or motor neuron disease were detected. Furthermore, a skin punch examination of the papular rash of the lower abdomen demonstrated an atypical T phenotype lymphoid infiltrate, suggesting an indolent lymphoma form; however, T-cell receptor g, T-cell receptor b, and immunoglobulin heavy chain reassortment studies were negative. T CD8 lymphocytes in the epidermis also suggested infective dermatitis. Skin cultures were positive for methicillin-sensitive Staphylococcus aureus. A definitive HAM/TSP diagnosis was made with the Sánchez-Montalvá et al information above, plus a positive serology for HTLV (enzyme immunoassay Murex HTLV IþII; DiaSorin) and a positive HTLV-1 proviral load in peripheral blood. The seropositivity TABLE 1. Clinical and Laboratory Outcomes