Leukoencephalopathy in HTLV-I-associated myelopathy/tropical spastic paraparesis: MRI analysis and a two year follow-up study after corticosteroid therapy.

Magnetic resonance imaging (MRI) of the brain was studied in 35 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 19 HTLV-I seropositive carriers without HAM/TSP (non-HAM/TSP carriers), 18 patients with HTLV-I seronegative spastic spinal paraparesis (SSP), and 82 HTLV-I seronegative controls with other neurological disorders. The incidence of white matter lesions was significantly higher in HAM/TSP (66%) than in the controls (23%) and SSP (11%). HAM/TSP exceeded non-HAM/TSP carriers significantly in the incidence of multiple white matter lesions (37% vs 10%). HAM/TSP affected the deep and subcortical cerebral white matter multifocally, sparing the periventricular regions. None of the lesions were enhanced by gadolinium-DTPA. HAM/TSP patients with the white matter lesions had both a longer duration of disease and a greater disability than did those without lesions. The white matter lesions gradually increased in number, as the disability status became worse, in spite of the high dose corticosteroid treatment. All these observations suggest that the MRI abnormalities of the HAM/TSP brain may reflect the chronic perivascular inflammation with progressive gliosis (chronic disseminated encephalomyelitis). We propose that brain MRI can be successfully utilized as a reliable and non-invasive measure for following the disease progression in HAM/TSP.     

Familial cases of HTLV-I-associated myelopathy

We studied two familial cases of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy from the Kii Peninsula, an area of endemic adult T-cell leukemia-lymphoma (ATLL) in Japan. Incidence of familial clustering of HTLV-I-associated myelopathy was about 20%. Type C retrovirus was isolated from cultured cerebrospinal fluid and peripheral blood lymphocytes in both cases. Modes of transmission seem to be similar to those described in ATLL, although there are no reports of both HTLV-I-associated myelopathy and ATLL occurring in the same family. We suggest three possibilities: (1) that the virus associated with HTLV-I-associated myelopathy is different from the virus causing ATLL, although they seem to be morphologically and immunologically similar; (2) that HTLV-I-associated myelopathy may be determined by the ATLL-causing virus plus a specific genetic background; and (3) some combination of factors 1 and 2.     

HTLV-I-associated myelopathy with adult T-cell leukemia

We report a 42-year-old Japanese woman with HTLV-I-associated myelopathy (HAM) combined with adult T-cell leukemia (ATL). Combination of the 2 diseases has been extremely rare. The infrequency is explained by HLA types unique to each disease. Our patient suggests that the HAM-associated HLA haplotype does not prevent the development of ATL.     

HTLV-I-associated myelopathy and polymyositis in a US native

A patient who had always lived in the United States had an HTLV-I infection and a chronic myelopathy clinically mimicking amyotrophic lateral sclerosis. Needle EMG and nerve conduction studies were consistent with anterior horn cell disease but muscle biopsy showed denervation and an inflammatory myopathy. Serum HTLV-I antibody tests were positive and HTLV-I DNA was present in peripheral leukocytes. This is the 1st reported US native with HTLV-I-associated myelopathy and polymyositis.     

Increased replication of HTLV-I in HTLV-I-associated myelopathy

To estimate the replication of the human T-cell leukemia virus type I (HTLV-I) in patients with HTLV-I-associated myelopathy (HAM), or tropical spastic paraparesis (TSP), HTLV-I DNA integrated into lymphocyte genomes was analyzed by Southern blot hybridization. HTLV-I DNA was detected in 125 (82%) of 153 patients and most showed random integration. This incidence was much higher than the 29% found in asymptomatic carriers. Therefore, HAM/TSP development is associated with a high level of HTLV-I replication. In addition, lymphocytes from 3 patients with HAM/TSP showed monoclonal integration of HTLV-I DNA, indicating adult T-cell leukemia.     

HTLV-I-associated myelopathy manifested after renal transplantation

We report a patient with HTLV-I-associated myelopathy (HAM), who developed symptoms of myelopathy 4 years after cadaveric renal transplantation. Since he was seronegative before the transplantation, it is suggested that HTLV-I infection was transmitted via renal graft transplantation. He has been treated with immunosuppressive agents such as cyclosporin A (CsA), mycophenolate mofetil (MMF), and prednisolone (PSL) to prevent graft rejection. This case suggested that these immunosuppressive agents are poorly effective in suppressing either the onset or progression of HAM/TSP.     

Pathological changes in skeletal muscle in HTLV-I-associated myelopathy

The main lesion site of HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the pyramidal tract. In some HAM patients, clinical symptoms and findings indicate neuromuscular involvement, such as muscular atrophy, fasciculation, elevated serum creatine kinase (CK) or significant electrophysiological data. Cases of HAM/TSP complicated with polymyositis or motor neuron disease have been reported. But no investigation has been directed to muscular pathology in many patients of HAM/TSP. We conducted muscle biopsies on 13 HAM patients. Four patients showed neurogenic changes. Six patients showed histological findings indicative of inflammatory myopathy. We investigated surface marker of invading cells in these 6 patients. In all patients, T lymphocytes were more predominant than B lymphocytes and in three of them T helper/inducer cells were more predominant than T supressor cells. In 2 patients, only slight myopathic change could be seen, such as variation in fiber diameter and increase in the number of internal nuclei. In 1 patient, type 2 fiber atrophy was seen, and was possibly the result of disuse. Disturbance of secondary motor neurons or inflammatory myopathy is thus shown to be possibly associated with HAM/TSP.     

Systemic interferon-alpha in the treatment of HTLV-I-associated myelopathy

Treatment with interferon-alpha (IFN-alpha) was undertaken in 16 patients with human T-lymphotropic virus type I-associated myelopathy (HAM). All patients had progressive spastic paraparesis before treatment. Twelve patients were enrolled in an open therapeutic trial with a dose of 3.0 x 10(6) IU/day of IFN-alpha and 4 in a randomized, double-blind, multidose (3.0 x 10(6), 1.0 x 10(6) or 0.3 x 10(6) IU/day) trial. IFN-alpha was injected intramuscularly for 28 days. Eight of 12 patients enrolled in an open trial and 2 patients receiving a dose of 3.0 x 10(6) IU/day of IFN-alpha in a randomized trial showed clinical improvements during and after the treatment. The results showed that, although not for all patients, systemic IFN-alpha with a dose of 3.0 x 10(6) IU/day is effective in the treatment of HAM.     

Parkinsonism in the course of HTLV-I-associated myelopathy.

Parkinsonian syndromes may represent a complication of viral infection. Human T cell lymphotropic virus I (HTLV-I) is a cause of a chronic myelopathy in which encephalic involvement has been also found. We report on the case of a 60-year-old man with HTLV-I-associated myelopathy, complicated with bradykinesia, resting tremor, and cogwheel rigidity. These findings suggest that parkinsonian features may represent a neurological disorder associated with HTLV-I infection.     

Impairment of cell-mediated immune responses in HTLV-I-associated myelopathy

In order to assess in vivo cell-mediated immune functions in HTLV-I-associated myelopathy (HAM), we immunized 18 HAM patients with dinitrochlorobenzene (DNCB). Of 18 patients, the skin reaction to DNCB was negative in 15. All those 15 patients also showed anergy to PPD-tuberculin and 9 of 15 patients had a persistent lymphocytopenia (<1500/mm³). In vitro lymphoproliferative responses to mitogens, assayed by a flow fluorocytometric method, were also significantly depressed in HAM patients when compared to normal controls. The results thus indicate that cell-mediated immune functions are significantly impaired in HAM patients.     

Interleukin-6 in cerebrospinal fluid of HTLV-I-associated myelopathy

We demonstrated significant titers of interleukin-6 (IL-6) in the CSF from 6 of 11 patients with HTLV-I-associated myelopathy (HAM). The patients positive for IL-6 generally had more severe clinical symptoms and signs than those negative for IL-6. There was no correlation between the value of IL-6 and inflammatory findings in the HAM CSF.     

Magnetic resonance imaging findings of HTLV-I-associated myelopathy

Magnetic resonance imaging (MRI) of the brain was evaluated in 12 HAM (HTLV-I-associated myelopathy) patients (4 males and 8 females, mean age of 54 yrs) and compared with 36 non-HAM controls (16 males and 20 females mean age of 52 yrs). MRI of the brain was performed using a 0.5 Tesla superconducting unit. Imaging in all patients was done with the long spin echo (TR = 2,000msec, TE = 100msec) sequences, and 10mm contiguous axial slices of the entire brain were obtained in all cases. Except for two cases, MRI of the brain was abnormal in 10 (83%) HAM patients, while in controls, 18 (50%) cases were abnormal. The abnormalities were high intensity lesions through SE 2000/100 sequences (T2 weighed image), and consisted of small isolated hemisphere lesions in 9 patients, periventricular changes in 9 patients, bilateral thalamic lesions in 2 patients and pontine lesions in 3 patients. We found that the factor of age was very important. In patients with ages below 59 yrs, 6 of 8 HAM patients (75%) had abnormalities, while in control cases, 6 of 23 (23%) had abnormalities in periventricular area. And in isolated hemisphere, 6 of 8 HAM patients (75%) had abnormalities, while in control cases, 3 of 23 (13%) had abnormalities. On the other hand, in patients with ages over 60 yrs, 3 of 4 (75%) HAM patients had abnormalities in periventlicular area, while in controls, 10 of 13 cases (77%) had abnormalities, and in isolated hemisphere, 3 of 4 (75%) HAM patients had abnormalities, and in controls, 10 of 13 cases (77%) had abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activated T cells in HTLV-I-associated myelopathy: autologous mixed lymphocyte reaction

We examined the autologous mixed lymphocyte reaction in human T-cell lymphotropic virus type I-associated myelopathy to elucidate the known increase in spontaneous proliferation of peripheral blood lymphocytes. Proliferative responses in the autologous mixed lymphocyte reaction test were significantly increased (34,205 cpm) in cells from 9 patients with the myelopathy, as compared with findings (18,695 cpm) in the control subjects. When non-T-cell fractions were depleted from autologous mixed lymphocyte reaction cultures, proliferative responses were completely suppressed in the control subjects, while proliferation of the peripheral blood lymphocytes from the groups with the myelopathy were not affected by depletion of non-T-cell fractions. The increase in spontaneous proliferation of peripheral blood lymphocytes in patients with the myelopathy is probably not related to an increase in autologous mixed lymphocyte reactions.     

HTLV-I-associated myelopathy and adult T-cell leukemia cases in a family

Familial cases of HTLV-I-associated myelopathy (HAM) and adult T-cell leukemia (ATL), developing in a daughter and father, respectively, are reported. The coexistence of both diseases in a family has not been reported before. This supports the recent findings that ATL and HAM may be brought about by an identical virus on an apparently different immunogenetic background.     

Treatment of HTLV-I-associated myelopathy with high-dose intravenous gammaglobulin

Summary Fourteen patients with HTLV-1-associated myelopathy were treated with high-dose intravenous gammaglobulin (IVGG). Ten received 10 g/day of IVGG and 4 received 400 mg/kg of body-weight/day of IVGG for 5 consecutive days. Improvement of spastic paraparesis was observed in 10 within 7 days of the commencement of IVGG. The therapeutic effects were sustained for more than 3 weeks in some patients. There were no side effects. Analysis of factors of relevance to the clinical improvement with IVGG showed that the beneficial response was preferentially found in patients having a high CSF titre of anti-HTLV-I antibodies, a high CSF IgG level and a marked brain MRI abnormality.     

CSF-chemokines in HTLV-I-associated myelopathy: CXCL10 up-regulation and therapeutic effect of interferon-alpha

We measured four chemokines in the cerebrospinal fluid (CSF) in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with ELISA. CXCL10/IP-10, a T cell type 1 (Th1)-associated chemokine, was significantly elevated in HAM/TSP compared with controls, and the values were even significantly higher in HAM/TSP than in multiple sclerosis (MS) in which CXCL10/IP-10 up-regulation was previously reported. Among Th2-associated chemokines, CCL17/TARC and CCL11/Eotaxin in HAM/TSP were not different from those in controls. As shown in MS, CCL2/MCP-1 was significantly lower in HAM/TSP than in control. Following interferon (IFN)-alpha therapy in HAM/TSP, CCL2/MCP-1 became significantly higher than that before therapy, which may reflect a Th2 induction, while CXCL10/IP-10 remained elevated.     

Nationwide survey of HTLV-I-associated myelopathy in Japan: association with blood transfusion

To study the epidemiology of human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan, we conducted two nationwide surveys between October 1986 and March 1989. A total of 710 patients with HAM (definite HAM, 589; probable HAM, 121) were reported. Of the 589 patients with definite HAM, 69% were residents of the areas with the highest prevalence HTLV-I in Japan. To determine the importance of blood transfusion in the pathogenesis of HAM/TSP, we performed a case-control study in the Kagoshima district in southern Japan. Significantly more patients with HAM reported a history of blood transfusion (26/129, or 20%) than did subjects in a health survey of the general population (41/1,290, or 3%; odds ratio = 7.7, p less than 0.001) or than did hospitalized neurological patients (6/119, or 5%; odds ratio = 4.8, p less than 0.001). Furthermore, the cumulative percentages of the intervals between blood transfusion and the onset of the symptoms of HAM fit a lognormal curve, suggesting that transfusion was an important common exposure. Blood transfusion probably transmitted HTLV-I to the patients with transfusion-associated HAM because there was a significant decrease in the number of patients with the transfusion-associated HAM who received blood after implementation of nationwide screening of blood donors in 1986 (p = 0.004). In the first 2 years, screening the blood supply in Japan appears to have decreased the number of reported patients with HAM by 16%.     

HTLV-I-associated myelopathy/tropical spastic paraparesis in the United States

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States, we sought reports of patients who were HTLV-I seropositive and had a slowly progressive myelopathy. Over a 2-year period, there were 25 patients reported, 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.