Peripheral neuropathy in HTLV-I infected individuals without tropical spastic paraparesis/HTLV-I-associated myelopathy

Abstract. Tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM) is the classical neurological manifestation of HTLV-I. Only a few studies have described isolated peripheral neuropathy (PN) among HTLV-I infected individuals. 335 infected individuals without TSP/HAM were evaluated for the presence of PN and 45 of them showed evidences of peripheral nervous system involvement. Of these 21 patients had isolated PN, defined by clinical and/or electrophysiological criteria. Sural nerve biopsies revealed inflammatory infiltrates in 2, axonal degeneration in 2 and segmental demyelination in 1. Therefore, peripheral neuropathy can be found as an isolated manifestation of HTLV-I infection. We conclude that HTLV-I infection should be investigated in patients with PN of unknown origin.     

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.     

Neutralizing antibodies against HTLV-I in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and asymptomatic carriers.

We tested serum specimens from patients with HAM/TSP and asymptomatic HTLV-I carriers from endemic areas of Japan, Jamaica, Colombia, and Chile for neutralizing antibodies against HTLV-I. The data suggest a trend for neutralizing activity to be found more frequently in the sera from HAM/TSP patients than in sera from asymptomatic carriers. The result of this study emphasizes the importance of determining biologic properties of the envelope glycoprotein of HTLV-I.     

Treatment of HTLV-I-associated myelopathy/tropical spastic paraparesis: toward rational targeted therapy

The treatment of HAM/TSP is a challenge. No agent has shown to significantly modify the long-term disability associated with HAM/TSP. Advances in our understanding of the pathogenesis of HAM/TSP have led to the identification of several biomarkers and therapeutic targets. Clinical trials in HAM/TSP continue to be opportunities for further qualification and refinement of biomarkers and therapeutic targets. The validation of HAM/TSP relevant biomarkers and the identification of new targets remain key challenges in the development of effective targeted therapy in HAM/TSP.     

Sensory dysfunction in HTLV-I-associated myelopathy/tropical spastic paraparesis. A comprehensive neurophysiological study.

We performed a comprehensive clinical and neurophysiological evaluation of function of the large- and small-caliber afferent pathways in 29 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Sensory symptoms, particularly cutaneous paresthesias, were present in 11 (37.9%) patients. On examination, a mild distal impairment of vibration and sense of position were found in 14 (48.2%) and 5 (17.2%) patients, respectively. Ten (34.4%) patients had distal tactile hypoesthesia and 7 (24.1%) presented pinprick hypoesthesia. Quantitative somatosensory thermotest showed cold hypoesthesia in 58.6% of patients. Nerve conduction studies and electromyography were normal. Tibial somatosensory evoked potentials were abnormal in 88.5% of patients. All of the sensory abnormalities found were restricted to sensations carried by myelinated (A-beta and A-delta) fibers. Unmyelinated C fibers mediating warm sensation and thermal pain appeared unimpaired. Our findings indicate that the sensory dysfunction in HAM/TSP patients is probably due to a lesion restricted to the central nervous system.     

Elevated levels of interleukin-6 in serum and cerebrospinal fluid of HTLV-I-associated myelopathy/tropical spastic paraparesis

A significant elevation of interleukin-6 (IL-6) level was observed both in serum (mean 0.455 +/- 0.251) and in cerebrospinal fluid (CSF) (mean 0.043 +/- 0.016) obtained from 13 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) when compared to that of either asymptomatic carriers (mean 0.181 +/- 0.074 and 0.021 +/- 0.015, respectively) or controls (mean 0.208 +/- 0.119 and 0.021 +/- 0.015, respectively). The differences were statistically significant between HAM/TSP and asymptomatic carrier for serum (P less than 0.05) or CSF (P less than 0.01). The correlation indexes between serum IL-6 and anti-HTLV-I antibody titers in serum and CSF were 0.61 (P less than 0.06) and 0.67 (P less than 0.05), respectively. Both the cell count and protein level in CSF correlated with CSF IL-6 activity at 0.68 (P less than 0.01) and 0.56 (P less than 0.05), respectively. The results demonstrate that IL-6 may contribute to the production of anti-HTLV-I antibody, and signs of slight inflammation are present in the central nervous system in HAM/TSP.     

HTLV-I associated myelopathy/tropical spastic paraparesis in a 7-year-old boy associated with infective dermatitis

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by a slowly progressive spastic paraparesis and sphincter disturbances beginning in adulthood. Only eight well-documented cases occurring in childhood and adolescence have been described. Infective dermatitis associated to the HTLV-I (IDH) is a chronic eczema of childhood occurring in vertically infected carriers. Here we describe a 7-year-old boy with HAM/TSP and IDH. The neurological manifestations were spastic gait, hyperreflexia of lower limbs, clonus and bilateral Babinski's sign. High levels of HTLV-I antibodies in the serum and in the cerebrospinal fluid were observed. The association of these two diseases and the early onset of HAM/TSP are probably related to a strong humoral anti-HTLV-I response.     

HTLV-1-associated myelopathy/tropical spastic paraparesis with pseudohypoparathyroidism

In many short-stature patients with human T-lymphotrophic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), signs and symptoms were manifested during childhood. Successive investigations revealed 12 of 14 short-stature patients with pseudohypoparathyroidism (PHP) from the findings of short metacarpi, parathyroid hormone infusion test, immunoblotting of erythrocyte membrane, or lymphocytic Northern blotting of Gsalpha. Patients with PHP probably showed HAM/TSP based on their modified immunologic status. Human T-lymphotrophic virus type I infection did not induce PHP, but PHP may be a risk factor for the occurrence of HAM/TSP.     

HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with amyotrophic lateral sclerosis-like manifestations

To clarify the existence of HAM/TSP presenting amyotrophic lateral sclerosis (ALS)-like manifestations, we assayed HTLV-I proviral load in peripheral blood mononuclear cells (PBMC) in 15 patients with anti-HTLV-I antibody in serum and ALS-like manifestations (upper motor neuron involvement in at least one region and lower motor neuron involvement in at least two limbs) by quantitative PCR, and compared the proviral load with that of 233 HAM/TSP patients and of 213 HTLV-I carriers. Five of 15 patients with ALS-like manifestations had proviral loads as high as those in the 233 patients with HAM/TSP. Anti-HTLV-I antibody in cerebrospinal fluid (CSF) was present in all of five patients. The proviral load in the remaining 10 patients was similar to that in HTLV-I carriers. Four of five patients with a high proviral load met the diagnostic criterion of HAM/TSP except for lower motor neuron involvement. These four patients showed high neopterin levels in CSF. On the basis of HTLV-I proviral load in PBMC and the clinical symptoms, our tentative conclusion is that these four patients are HAM/TSP presenting ALS-like manifestations.     

Antibody titers to HTLV-I-p40tax protein and gag-env hybrid protein in HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with increased HTLV-I proviral DNA load.

We studied the relationship between antibody titers to recombinant HTLV-I p40tax protein and gag-env hybrid protein in serum (by an enzyme-linked immunosorbent assay) and HTLV-I proviral DNA load in peripheral blood mononuclear cells (by a quantitative polymerase chain reaction method) in 18 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 17 HTLV-I carriers without HAM/TSP and 16 HTLV-I uninfected controls. The IgG and IgA antibody titers to either of the proteins correlated significantly with the HTLV-I pX (coding p40tax protein) and pol DNA amounts in HTLV-I infected subjects. HAM/TSP patients had significantly higher titers of IgG and IgA antibodies to the HTLV-I proteins than did the HTLV-I carriers without HAM/TSP. While the IgM antibodies to the HTLV-I proteins were found in only 6% of HTLV-I carriers without HAM/TSP, they were found in 40% of HAM/TSP patients, especially those having both a high HTLV-I proviral DNA load and high titers of the IgG and IgA antibodies. HAM/TSP patients with the IgM antibodies had a tendency to deteriorate more frequently on the Kurtzke's disability status scale and magnetic resonance imaging of the brain (leukoencephalopathy) than did those without in the two-year follow-up. Thus, the presence of IgM antibody and high titers of IgG and IgA antibodies to the HTLV-I proteins, together with the increased HTLV-I proviral DNA load, appears to distinguish HAM/TSP patients from HTLV-I carriers without HAM/TSP.     

Cellular immune surveillance against HTLV-I infected T lymphocytes in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP).

To investigate the cellular immune surveillance against HTLV-I infected T lymphocytes in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), we studied the cytotoxic T lymphocytes (CTL) activity against an HTLV-I infected human T cell line (MT-2) and the natural killer (NK) cell activity in 15 HAM patients, 6 HTLV-I carriers, and 15 controls. The activity of CTL against MT-2 cells was found to be significantly elevated in HAM compared with that in the controls. This cytotoxicity in HAM was higher than in HTLV-I carriers, although the difference was not statistically significant. There was an HLA class I restriction in this CTL activity against MT-2 cells in HAM. On the other hand, NK cell activity was significantly lower in HAM than in controls. Cold target inhibition studies suggested that NK cells could not lyse MT-2 cells effectively. There was a positive correlation between the CTL activity against MT-2 cells and the serum antibody titers to HTLV-I in HAM.     

Acupuncture in the treatment of HTLV-I-associated myelopathy / tropical spastic Paraparesis

We investigate the possible effects of acupuncture on the improvement of neurological problems in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)disease. Twenty patients with HAM/TSP were studied in this pre and post-test clinical trial. Urinary incontinence, global motor disability, spasticity, and pain severity were evaluated before, one month, and three-month after the intervention. Analyses demonstrated a significant reduction of urinary symptoms one month after acupuncture (P?=?0.023). A significant improvement was observed in patients’ pain and the spasticity at the upper extremity joints, one and three-month after the intervention (P?<?0.05). This study suggests that body acupuncture can be used as a complementary treatment to improve HAM/TSP neurological symptoms.

     

HTLV-1-associated myelopathy/tropical spastic paraparesis accompanied with psoriasis

Two adult females developed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and psoriasis. Both showed chronic progressive paraparesis and sharply demarcated erythematous scaling plaques on their extremities and trunk. One patient had polymyositis while in the other anti-thyroid antibodies, antinuclear antibodies and SS-A antibody, all autoantibodies, were positive. Both patients were treated by intramuscular injections of interferon-alpha for 2 to 4 weeks, resulting in amelioration of paraparesis. After the therapy psoriasis and polymyositis markedly improved in one patient without any additional therapy, while in the other simultaneous use of topical corticosteroids was effective. This is the first report to describe occurrences of psoriasis in HAM/TSP patients. Although there are several reports indicating interferon-alpha induces or exacerbates psoriasis, our experience suggests that psoriasis associated with HAM/TSP can be successfully managed even during interferon-alpha therapy.     

Reduction in HTLV-I proviral load and spontaneous lymphoproliferation in HTLV-I–associated myelopathy/tropical spastic paraparesis patients treated with humanized anti-tac

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0,2,6,10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I–infected, activated CD4⁺ lymphocytes.