Physalin F, a seco-steroid from Physalis angulata L., has immunosuppressive activity in peripheral blood mononuclear cells from patients with HTLV1-associated myelopathy.

Human T-lymphotropic virus type 1 (HTLV-1) induces a strong activation of the immune system, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Physalin F is a secosteroid with potent anti-inflammatory and immunomodulatory activities. The present study aimed to investigate the effects of physalin F on peripheral blood mononuclear cells (PBMC) of HAM/TSP subjects. A concentration-dependent inhibition of spontaneous proliferation of PBMC from HAM/TSP subjects was observed in the presence of physalin F, as evaluated by (3)H-thymidine uptake. The IC50 for physalin F was 0.97 ± 0.11 µM. Flow cytometry analysis using Cytometric Bead Array (CBA) showed that physalin F (10 µM) significantly reduced the levels of IL-2, IL-6, IL-10, TNF-α and IFN-γ, but not IL-17A, in supernatants of PBMC cultures. Next, apoptosis induction was addressed by using flow cytometry to evaluate annexin V expression. Treatment with physalin F (10 µM) increased the apoptotic population of PBMC in HAM/TSP subjects. Transmission electron microscopy analysis of PBMC showed that physalin F induced ultrastructural changes, such as pyknotic nuclei, damaged mitochondria, enhanced autophagic vacuole formation, and the presence of myelin-like figures. In conclusion, physalin F induces apoptosis of PBMC, decreasing the spontaneous proliferation and cytokine production caused by HTLV-1 infection.

Interferon beta-1a treatment in HTLV-1-associated myelopathy/tropical spastic paraparesis: a case report.

Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

Interferon beta11a treatment in htlv-1-associatd myelopathy/tropical spastic pparaparesis: a case report / Tratamento com interferon beta-1a em mielopatia associada ao HTLV-1/paraparesia espástica tropical: relato de caso

Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

Descreve-se caso de mielopatia associada ao HTLV-1/paraparesia espástica tropical tratada com interferon beta-1a em paciente jovem de 21 anos e com história de dermatite infecciosa na infância. Foi estabelecida clinicamente paraparesia espástica tropical (HAM/TSP), confirmada laboratorialmente pela presença de anticorpos para HTLV-1 no LCR e excluídas caxumba, citomegalovirus, Epstein-Barr, esquistossomose, herpes virus 1 e 2, rubéola, sarampo, toxoplasmose varicela-zoster, hepatite, HIV e sífilis por sorologias. Foi diagnosticada bexiga neurogênica, com quadro clínico de nictúria, urgência urinária, parestesia no membro inferior esquerdo e discreta redução de força muscular nos membros superiores, mais acentuada nos membros inferiores. Na 4a semana de tratamento com interferon beta-1a houve desaparecimento da urgência urinária e da parestesia e melhora da clínica motora.

Molecular and clinical effects of betamethasone in human T-cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.

There is no effective therapy for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Glucocorticoids are effective to reduce the motor disability in these patients, but its role as anti-spastic drugs is unknown. Here it is reported the use of corticosteroids in HAM/TSP. The goal was to find reliable molecular markers linked to treatment effectiveness. The clinical efficacy of corticosteroids was studied in 22 HAM/TSP. The treatment was a single dose of 7.0 mg of systemic betamethasone. Pre-treatment samples were obtained immediately before steroid administration and post-treatment samples were collected after 5 days. Neurological disability was evaluated by the Osame's Motor Disability Scales. Relative levels of Tax, Foxp3, IL-10, TGF-ß, CTLA-4, and GITR mRNA were measured and the percentage of CD4(+) Foxp3(+) and CD4(+) Tax(+) populations was quantified in PBMCs by real-time PCR and flow cytometry, respectively. The same parameters were studied in eight untreated carriers. Betamethasone treatment showed neurological improvement in 21 HAM/TSP patients, with one patient without response to treatment. This therapy was associated with a decrease in Tax mRNA load and CD4(+) Tax(+) T cells in HAM/TSP. Simultaneously, an increase in Foxp3 mRNA and CD4(+) Foxp3(+) T cell was detected in these patients. The other markers studied had no significant changes after treatment. Clinical improvement in betamethasone-treated HAM/TSP was associated with an inverse relationship between a decrease in Tax and an increase in Foxp3 at the mRNA and protein levels. These results suggest that both Tax and Foxp3 may represent potential biomarkers for drug treatment assessments in HAM/TSP.

Therapeutic strategies in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic progressive myelopathy characterized by bilateral pyramidal tracts involvement with sphincteric disturbances. HTLV-I infects approximately 10-20 million people worldwide. There are large endemic areas in southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa. Since the primary neuropathological feature of HAM/TSP is chronic inflammation caused by HTLV-I infection in the spinal cord, various treatments focusing on immunomodulatory or anti-viral effects were performed for HAM/TSP patients until now. However, there are still many of problems, such as insufficient effects, side effects and expensive costs in long-term treatments, etc., in these treatments. Therefore, an ideal therapeutic strategy against HAM/TSP is still not established yet. Although only a small proportion of HTLV-I-infected individuals develops HAM/TSP, neurological symptoms are certainly progressive once myelopathy develops, leading to deterioration of the quality of life. Therefore, we now need the therapeutic regimens to protect the development, or be able to commence the treatments as soon as possible after the development safely and inexpensively even in long-term course or lifelong course of treatment. As HTLV-I-infected CD4(+) T cells are the first responders in the immunopathogenesis of HAM/TSP, the ideal treatment is the elimination of HTLV-I-infected cells from the peripheral blood. In this article, we will review the therapeutic strategies against HAM/TSP up to now and will introduce our new therapeutic approach focusing on the targeting of HTLV-I-infected cells in HAM/TSP patients.

Corticosteroid therapy in TSP/HAM patients: the results from a 10 years open cohort.

BACKGROUND: The use of corticosteroids for treating tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) has yielded controversial results. We report the use of corticosteroids for the treatment of TSP/HAM in an open cohort. METHODS: The clinical efficacy of long-term, high dose of corticosteroid therapy was studied in thirty-nine TSP/HAM patients. Disability and motor dysfunction was evaluated based on the Disability Status Scale (DSS), Osame's Motor Disability Scales (OMDS), and Incapacity Status Scale (ISS), before and after treatment. Treatment included use of methyl-prednisolone, 1 g/day for three days, every 3-4 months. The primary end-point was a change in the scores of the neurological scales from baseline until the fifth visit after therapy. RESULTS: After a mean follow-up of 2.2 years and an average of four pulses per patient, we noted a significant neurological improvement, reaching 24.5% according to the ISS score. No statistically significant differences in scores according to the OMDS and DSS scales were noted. CONCLUSION: We observed neurological improvement with the use of corticosteroids, with physical therapy and antispastic-drugs as adjunctive treatment. However, randomized clinical trials should be done to assess the use of corticosteroids and other potentially useful immune-based therapies for TSP/HAM treatment.

Paraparesia espástica tropical: a propósito de un caso clínico / Tropical spastic paraparesis: report of a case

Se presenta el caso clínico de una paciente con diagnóstico inicial de hipotiroidismo, cuadro que ameritó internación, compensado adecuadamente con levotiroxina. A pesar de existir buena respuesta al tratamiento instaurado, persiste la presencia de sintomatología de compromiso neurológico por lo que se solicita evaluación por dicha especialidad; se encuentran datos sugestivos de un cuadro de paraparesia espástica tropical, enfermedad producida por el HTVLI. El diagnóstico es confirmado mediante examenes de laboratorio. Es tratada con pentoxifilina y vitamina C con respuesta clínica inicial buena, pero posteriormente presenta exacerbación de las manifestaciones neurológicas, como sucede habitualmente en esta patología. nuestro país se encuentra en una regíon endemica de la infección mencionada, y sin embargo el diagnóstico es mas bien esporádico. Se discute en este artículo la epidemiología, las dificultades diagnósticas que planteo este caso en particular y las posibilidades terapéuticas de esta enfermedad neurológica.

We present the case of a female patient who initially was diagnosed with hypothyroidism, and adequately compensated with levotiroxin . In spite of the otherwise successfultreatment, neurological symptoms persisted. The neurological examination showed datasuggestive of tropical spastic paraparesis,a disease caused by HTVL-1.The diagnosis was confirmed by laboratory tests. The patient was treated with pentoxifiline and vitamin C, initially with a good clinical response. Later on, however, exacerbation of the neurological symptoms resulted, as usually happens in this disease. In our country, tropical spastic paraparesis is endemic but only sporadically diagnosed. We review the most relevant aspects of epidemiology, the diagnostic difficulty in this case, and the therapeutic options for this neurological disease.

Multiple clinical manifestation of HTLV1 infection in a single patient

HTLV-1 infection is endemic in the Caribbean and several publications have reported the clinical disease entities seen in this population of patients. This case report is an account of a patient admitted to Kingstown General Hospital, St Vincent and the Grenadines, who had severe infective dermatitis, tropical spastic paraparesis (TSP) and Non-Hodgkin's Lymphoma (NHL). As far as we are aware, all three diseases have not been described in a single patient

Multiple clinical manifestation of HTLV1 infection in a single patient.

HTLV-1 infection is endemic in the Caribbean and several publications have reported the clinical disease entities seen in this population of patients. This case report is an account of a patient admitted to Kingstown General Hospital, St Vincent and the Grenadines, who had severe infective dermatitis, tropical spastic paraparesis (TSP) and Non-Hodgkin's Lymphoma (NHL). As far as we are aware, all three diseases have not been described in a single patient.

HTLV-I (Human T- cell lymphotropic virus), algo que decir? / HTLV-I (Human T-cell lymphotropic virus): something to say?

El virus HTLV-I se asocia a varias patologías siendo las más relevantes la paraparesia espástica y la leucemia/linfoma de células T del adulto. No tiene tratamiento específico y se han intentado varios esquemas terapéuticos para su manejo. Se revisa la literatura presentando los trabajos más actualizados en relación a la terapia.

Juvenile human T lymphotropic virus type 1-associated myelopathy.

We report the cases of 5 adolescents with human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis, acquired in all but 1 case from the mother. The first symptom in all patients was difficulty in running, which was present for many years before the final diagnosis was made. Follow-up showed an indolent progression, regardless of treatment strategy.

[Potentially treatable subacute forms of infection due to the HTLV-1]. / Formas subagudas de infección por el virus HTLV-I potencialmente tratables.

INTRODUCTION: Tropical spastic paraparesis due to HTLV-I virus is diagnosed at very advanced stages, when there is spinal atrophy present and so only symptomatic treatment can be given. Early diagnosis of HTLV-I infection in unusual syndromes and the use of corticosteroids may help to slow the development of the disease. CLINICAL CASES: We describe two Brazilian patients who developed symptoms due to HTLV-I present for less than one year: subacute myelopathy with a sensory level and an ataxic pyramidal syndrome associated with axonal neuropathy, which partly improved after treatment with corticosteroids. RESULTS: A 50 year old woman presented with progressive paraparesis following pain, cramps, feeling that her legs had 'gone to sleep' and sphincter dysfunction over the previous eleven months. Spinal MR showed a diffuse spinal hypersignal at D2. The 60 year old man had developed an ataxic syndrome and axonal polyneuropathy over the previous ten months. In both patients the anti-HTLV antibodies in blood and CSF were positive on ELISA as later confirmed by Western-blot. Thorough biochemical study ruled out other infectious etiologies. Both patients were treated with corticosteroids (i.v. methylprednisolone and oral prednisone respectively) and their symptoms improved, particularly the joint pains, ataxia and the 'gone to sleep' sensation of the legs. CONCLUSIONS: The ataxic syndrome and myelopathy due to HTLV-I, when these have been diagnosed early, may benefit from corticosteroid treatment and progression of the disorder be prevented. The myelitic phase of HTLV-I infection is associated with diffuse myelopathy, which was unusually seen in our first patient on spinal MR.

Paraparesia espástica tropical/mielopatia associada ao HTLV-I: relato de dois casos diagnosticados em Cuiabá, Mato Grosso / Tropical spastic paraparesis/HTLV-I associated myelopathy: report of 2 cases diagnosed in Cuiabá, Mato Grosso, Brazil

Descrevemos dois casos clínicos de paraparesia espástica tropical/mielopatia associada ao HTLV-I, obedecendo os critérios da OMS-1989. Estes são os primeiros casos diagnosticados em Cuiabá. Em um dos casos houve resposta clínica ao uso de prednisona.

[Tropical spastic paraparesis/HTLV-I associated myelopathy. Report of 2 cases diagnosed in Cuiabá, Mato Grosso, Brazil]. / Paraparesia espástica tropical/mielopatia associada ao HTLV-I. Relato de dois casos diagnosticados em Cuiabá, Mato Grosso.

We describe two cases of tropical spastic paraparesis/HTLV-I associated myelopathy, according to the criteria of World Health Organization-1989. These are the first cases diagnosed in Cuiabá (Mato Grosso State, Brazil). One of them had a good response with the treatment with prednisone.

[HTLV-I-associated myelopathy/tropical spastic paraparesis: report of 2 cases diagnosed in Florianópolis, Santa Catarina, Brazil]. / Paraparesia espástica tropical/mielopatia associada ao HTLV-I. Relato de dois casos diagnosticados em Florianópolis, Santa Catarina.

We describe two cases of tropical spastic paraparesis/HTLV-I associated myelopathy, according to the criteria of World Health Organization-1989. These are the first cases diagnosed in Florianópolis (Santa Catarina State-Brazil). One of them had a good response with the treatment with methylprednisolone.

Paraparesia espástica tropical / Mielopatia associada ao HTLV-I: relato de dois casos diagnosticados em Florianópolis, Santa Catarina / HTLV-I associated myelopathy / tropical spastic paraparesis: report of two cases diagnosed in Florianópolis, Santa Catarina - Brazil

Descrevemos dois casos clínicos de paraparesia espástica tropical / mielopatia associada ao HTLV-I (PET/MAH), segundo os critérios da OMS-1989. Estes sao os primeiros casos diagnosticados em Florianópolis (SC-Brasil). Em um dos casos houve resposta clínica ao uso de metilprednisolona.

Paraparesia espástica familiar: tratamento da espasticidade através de bloqueio com toxina botulínica do tipo-A BOTOX e fenol / Congenital spastic paraparesia: treatment of spasticity by block with botulinum toxin type BOTOX and phenol

Foram estudados 6 pacientes portadores de Paraparesia Espástica Familiar, 2 mulheres e 4 homens, com idades variando de 4 a 45 anos, mediana 41,5 anos em relaçäo ao tratamento da espasticidade de membros inferiores, através de bloqueios com Toxina Botulínica e Fenol. Os resultados mostraram-se significamente positivos com melhoras nas avaliaçöes imediata aos bloqueios e final tanto para o Escore Geral (E.G.) como para a Escala de Ashword modificada (E.A.M.) com percentuais de melhora de 12,7 por cento, 34,45 por cento para o Escore Geral e de 19,91 por cento e 55,51 por cento para a escala de Ashword modificada.

Efecto del núcleo CMP forte en 46 pacientes con paraparesia espástica progresiva: estudio randomizado y ciego / Effect of CMP forte nucleus in 46 patients with progressive spastic paraparesis: randomized and blind study

Idiopatic or HTLV-1 associated progressive spastic paraparesis does not have a clear etiology or treatment. To assess the effects of a medication containing cytidinmonophosphate, uridintriphosphate and vitamin B 12 in the treatment of progressive spastic. Patients with the disease were randomly assigned to receive the Nucleus CMP forte (containing dysodic cytidinmonophosphate 5 mg,trisodic uridintriphosphate 3 mg and hydroxicobalamin 2 mg) tid or placebo during 6 months. Gait, spasticity, degree of neurogenic bladder and somatosensitive evoked potentials were assessed during treatment. Forty six patients aged 25 to 79 years old were studied, 24 were female and 29 HTLV-1 positive. Twenty two were treated with the drug and the rest with placebo. Gait and spasticity improved in 7 of 22 patients receiving the drug and 1 of 24 receiving placebo (p<0.05). Neurogenic bladder improved in 10 of 22 receiving the drug and 4 patients treated with the drug and in two of seven treated with placebo. The medication caused a modest improvement in patients with progressive spastic paraparesis and was free of side effects