The recent advances of HAM/TSP research]

The ninth international conference on HTLVs and related disorders was held on April 5-9, 1999 at Kagoshima, Japan under the conference chairperson, Dr. Mitsuhiro Osame. In this meeting, world-wide epidemiological data on HTLV-I carriers, ATL patients, and HAM/TSP patients were summarized as shown in the table. The total number of them was supposed to be more than 2.2 millions, 1,200, and 3,000, respectively. To elucidate the localization of HTLV-I proviral DNA directly, double staining using immunohistochemistry and PCR in situ hybridization in the spinal cords of HAM/TSP patients were performed. HTLV-I proviral DNA was localized only to OPD 4-positive cells (Matsuoka et al, 1998). The localization of HTLV-I messenger RNA was the same (Moritoyo et al, 1996). A novel technique to detect HTLV-I tax protein was also developed. In HAM/TSP patients, 0.04-1.16% of the CSF cells and 0.02-0.54% of PBMCs were positive for HTLV-I tax protein (Moritoyo et al, 1999). It was also hypothesized that HLA alleles control HTLV-I proviral load and thus influence susceptibility to HAM/TSP. Two hundred and thirty-two cases of HAM/TSP were compared with 201 randomly selected HTLV-I seropositive asymptomatic blood donors. It was shown that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (p < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02 positive healthy HTLV-I carriers have a proviral load one-third that (p = 0.0114) of HLA-A*02 negative HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility was also identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02 (Jeffery and Usuku et al, 1999).     

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.     

Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP

In order to examine the effect of HTLV-I proviral load on the pathogenesis of HAM/TSP, we measured the HTLV-I proviral load in peripheral blood mononuclear cells (PBMC) from a large number of HAM/TSP patients and asymptomatic HTLV-I carriers. To measure the proviral load, we used an accurate and reproducible quantitative PCR method using a dual-labeled fluorogenic probe (ABI PRISM 7700 Sequence Detection System). The mean +/- standard error of mean (s.e.m.) HTLV-I proviral copy number per 1 x 10(4) PBMC was 798 +/- 51 (median 544) in 202 HAM/TSP patients; 120 +/- 17 (median 34) in 200 non HAM-related (general) asymptomatic HTLV-I carriers (RC); and 496 +/- 82 (median 321) in 43 asymptomatic HTLV-I carriers genetically related to HAM/TSP patients (FA). The prevalence of HAM/TSP rises exponentially with log (proviral load) once the proviral load exceeds 1% PBMC. The HTLV-I proviral load of female patients with HAM/TSP was significantly higher than that of male patients, however there was no significant difference in proviral load between sexes in RC. There was a significant correlation between the proviral load and the concentration of neopterin in CSF of HAM/TSP patients. These results indicate that the HTLV-I proviral load in PBMC may be related to the inflammatory process in the spinal cord lesion. The increased proviral load in FA suggests the existence of genetic factors contributing to the replication of HTLV-I in vivo.     

HTLV-I specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral load in peripheral blood of infected individuals

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurological disease caused by HTLV-I infection. It has been shown that HAM/TSP patients have high proviral loads and an extraordinarily high frequency of circulating CD8 + cytotoxic T lymphocytes specific for HTLV-I in their peripheral blood when compared to asymptomatic HTLV-I carriers (AC). We have previously described an intracellular cytokine detection assay, in which interferon-gamma (IFN-gamma) + CD8 + lymphocytes are specific for HTLV-I in infected individuals. Here, we have established a competitive polymerase chain reaction assay to measure the proviral load of patients and investigate a potential relationship between proviral load and virus-specific CD8 + lymphocytes. Genomic DNA was extracted from peripheral blood lymphocytes (PBL) from eight HAM/TSP patients and seven AC for the measurement of HTLV-I measuring proviral loads. The same PBL were analyzed for intracellular IFN-gamma expression by flow cytometry. In the HAM/TSP patients and AC, the average proviral loads were 34,482 and 9784 copy/microg DNA (P = 0.021), and the average of IFN-gamma + CD8 + lymphocytes in total PBL were 1.47 and 0.08% (P = 0.001), respectively. It was confirmed that HAM/TSP patients have both high proviral loads and increased HTLV-I-specific CD8 + lymphocytes. Furthermore, we found a positive correlation between both factors in the patients with HAM/TSP (P = 0.044) but not in the AC (P = 0.508). These findings suggest that the high number of HTLV-I-specific lymphocytes may result from the increased proviral load in HAM/TSP patients.     

Neuronal molecular mimicry in immune-mediated neurologic disease

Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immunemediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP.     

Diagnosis of HAM/TSP based on CSF proviral HTLV-I DNA and HTLV-I antibody index

The contribution of human T-cell lymphotropic virus (HTLV-I) DNA by PCR in CSF and the intrathecal synthesis of antibodies to HTLV-I by the antibody index (AI) to the diagnosis of HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were evaluated. Cases of spastic paraparesis compatible with HAM/TSP had increased AI for HTLV-I (60/73) and HTLV-I proviral sequences in CSF (25/27). Among 27 patients with other neurologic diseases, three had increased AI and another three had positive HTLV-I DNA in CSF. Thus, the combination of PCR for proviral DNA and AI for HTLV-I in CSF provides consistent criteria for the diagnosis of HAM/TSP.     

Increased HTLV-I proviral DNA in HTLV-I-associated myelopathy: a quantitative polymerase chain reaction study

Using the polymerase chain reaction, we quantitated the amount of human T-lymphotropic virus type I (HTLV-I) proviral DNA in peripheral blood mononuclear cells from 18 patients with HTLV-I--associated myelopathy/tropical spastic paraparesis; 17 HTLV-I carriers without HTLV-I--associated myelopathy/tropical spastic paraparesis, with or without other autoimmune or inflammatory diseases; and 19 seronegative control subjects. The HTLV-I proviral DNA was 10- to 100-fold higher in the patients and in the HTLV-I carriers without HAM/TSP who had autoimmune or inflammatory diseases than in the carriers without autoimmune or inflammatory diseases. The patients who had had onset of myelopathy at a younger age (15 to 39 years) had an extremely high level of HTLV-I proviral DNA in the early phase, as compared with findings in those with a late onset of myelopathy (at 44 to 61 years). The large increase in HTLV-I proviral DNA in peripheral blood mononuclear cells is presumably closely related to the development of autoimmune or inflammatory processes in HTLV-I carriers, including HTLV-I--associated myelopathy/tropical spastic paraparesis.     

Interferon-beta1a therapy in human T-lymphotropic virus type I-associated neurologic disease

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune-mediated inflammatory disorder of the central nervous system. Immune activation in the host, which results from high levels of persistent antigenic stimulation and from transactivation of host immunoregulatory genes by HTLV-I, appears important in the pathogenesis of HAM/TSP. In a single-center, open-label trial, 12 patients with HAM/TSP were treated with doses of interferon-beta1a of up to 60mug twice weekly, based on its antiviral and immunomodulatory effects. Primary end points were immunological and virological measures that are potential biomarkers for HAM/TSP. Interferon-beta1a therapy reduced the HTLV-I tax messenger RNA load and the frequency of potentially pathogenic HTLV-I-specific CD8(+) cells. The HTLV-I proviral DNA load remained unchanged. Spontaneous lymphoproliferation, a marker of T-cell activation in HAM/TSP, also was reduced. Some measures of motor function were improved, and no significant clinical progression occurred during therapy. These results indicate that interferon-beta1a may beneficially affect the immune mechanisms central to the pathogenesis of HAM/TSP.     

SYBR Green-based quantitation of human T-lymphotropic virus type 1 proviral load in Peruvian patients with neurological disease and asymptomatic carriers: Influence of clinical status, sex, and familial relatedness

To evaluate the human T-lymphotropic virus type 1 (HTLV-1) proviral DNA load in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and asymptomatic HTLV-1 carriers, a SYBR Green-based real-time quantitative polymerase chain reaction (qPCR) assay was developed. HTLV-1 proviral DNA in peripheral blood mononuclear cells (PBMCs) was quantified using primers targeting the pX region and the HTLV-1 copy number normalized to the amount of ERV-3 (Endogenous Retrovirus 3) cellular DNA. Thirty-three asymptomatic HTLV-1 carriers (ACs) and 39 patients with HAM/TSP were enrolled. Some participants were relatives of HAM/TSP cases (16 ACs and 7 patients with HAM/TSP). On multiple linear regression analysis, the authors found a significant association between clinical status and HTLV-1 proviral load (P < .01), but only among women. ACs showed a median proviral load of 561 copies per 104 PBMCs (interquartile range: 251-1623). In HAM/TSP patients, the median proviral load was 1783 (1385-2914). ACs related to HAM/TSP patients presented a relatively high proviral load (median 1152); however, the association between relatedness to a HAM/TSP patient and proviral load was not significant (P = .1). In HAM/TSP patients, no association was found between proviral load and disease duration, progression or severity. The fact that the effect of HAM/TSP upon the HTLV-1 proviral load differed between sexes and the finding of a high proviral load among asymptomatic relatives of HAM/TSP patients suggest that not yet identified genetic or environmental factors influence the pathogenesis of HTLV-1 infection.     

HTLV-I proviral load correlates with progression of motor disability in HAM/TSP: analysis of 239 HAM/TSP patients including 64 patients followed up for 10 years

To clarify clinical and laboratory findings that may be related to the pathomechanism of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we analyzed these findings in 239 patients with HAM/TSP, including 64 patients followed up for 10 years after their first examinations, with special interest in the HTLV-I proviral load in peripheral blood mononuclear cells (PBMCs). The proviral load in PBMCs did not differ in terms of modes of HTLV-I transmission. However, the proviral load in patients with age of disease onset greater than 65 years tended to be higher than those with a younger age of onset. In the 64 patients followed up for 10 years, the clinical symptoms deteriorated in 36 patients (56%), unchanged in 26 patients (41%), and improved in 2 patients (3%). HTLV-I proviral load also appeared to be related to the deterioration of motor disability in these patients. To our knowledge, the present study is the first longitudinal study concerning the relationship between the clinical course of HAM/TSP and HTLV-I proviral load. It is suggested that HTLV-I proviral load is related to the progression of motor disability and is an important factor to predict prognosis of patients with HAM/TSP.     

Chronic progressive cervical myelopathy with HTLV-I infection: variant form of HAM/TSP]

We report four patients with slowly progressive cervical myelopathy. The four patients had several features in common; 1) progressive cervical myelopathy with a duration of several months to years, 2) abnormal lesions in the cervical to upper thoracic cord levels with or without gadolinium enhancement, 3) anti-HTLV-I antibodies were positive both in serum and CSF, 4) high levels of HTLV-I proviral load in PBMC. The calculated risk of HAM/TSP in two patients showed a high value, comparable to those of HAM/TSP, and higher than those of healthy HTLV-I carrier. Because the clinical and laboratory findings of these four cases show similarities to those of HAM/TSP, we propose that these four cases may be a variant form of HAM/TSP.     

Diversity of intrathecal antibody synthesis against HTLV-I and its relation to HTLV-I associated myelopathy

The humoral immune response against human T-cell lymphotropic virus type I (HTLV-I) in the central nervous system (CNS) compartment and in the blood was investigated by enzyme immunoassay using 16 synthetic peptides corresponding to HTLV-I core and envelope sequences. We evaluated paired samples of cerebrospinal fluid and serum from HTLV-I seropositive Japanese patients, classified as follows: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP;n = 39), patients with spinal cord disease ascribed to either HAM/TSP or to some concomitant, HTLV-I-unrelated disease (possible HAM/TSP;n = 6) or carriers without any clinical signs of HAM/TSP (n = 15). HTLV-I-peptide-specific intrathecal antibody synthesis was found in 79% of HAM/TSP patients, but only in 20% of carriers without HAM/TSP. The group of carriers without HAM/TSP showed local synthesis for some peptides (on average 0.3 peptides per patient). In most HAM/TSP patients, however, there was a diverse intrathecal immune response to several HTLV-I synthetic peptides (on average against 3.6 peptides per HAM/TSP patient), most frequently againstgag p19 100–130,env gp21 458–488, andenv gp46 175–199 and 288–317. The intrathecal antibody synthesis against several HTLV-I determinants may represent a pathogenic immune response in HAM/TSP and is possibly related to the infiltration of virus-infected T-cells in the spinal cord.     

Presence of HTLV-I proviral DNA in central nervous system of patients with HTLV-I-associated myelopathy.

The polymerase chain reaction (PCR) method was used to determine the presence and amount of human T lymphotropic virus type I (HTLV-I) proviral DNA in central nervous system (CNS) tissue obtained at autopsy from 6 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 1 patient with adult T-cell leukemia (ATL) and CNS infiltration of leukemic cells, and 9 control subjects with other neurological disorders. HTLV-I pX and env but not pol DNA were detected in CNS tissue from 5 of 6 patients with HAM/TSP. The ATL samples were positive for pX, env, and pol DNA by PCR. None of the control samples was consistently positive for HTLV-I by PCR, but all showed positive bands on beta-globin PCR. Quantitative PCR combined with histological studies showed no correlation between HTLV-I proviral DNA amounts and extent of perivascular mononuclear cell infiltration in the HAM/TSP CNS. Also, the amounts of pX and probably env DNA were greater in the HAM/TSP samples than in the ATL sample, although the extent of mononuclear cell infiltration was far less in the HAM/TSP samples than in the ATL sample. Therefore, in addition to infiltrating mononuclear cells, constituent cells of the CNS may harbor the HTLV-I genome, at least in the pX and env regions, in patients with HAM/TSP.     

Molecular mimicry: cross-reactive antibodies from patients with immune-mediated neurologic disease inhibit neuronal firing

Recent data indicate that molecular mimicry may play a role in the pathogenesis of human-T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disease of the central nervous system (CNS). Specifically, HAM/TSP patients developed antibodies that cross-react with heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an antigen highly expressed in neurons. Antibodies to HTLV-1-tax cross-reacted with hnRNP A1, suggesting molecular mimicry between the two proteins. In support of this hypothesis, HAM/TSP IgG and antibodies to hnRNP A1 and HTLV-1-tax inhibited neuronal firing, suggesting that these antibodies can be pathogenic. We extended these observations by carrying out studies on over 20 different neurons. We also tested IgG isolated from six different HAM/TSP patients and two HTLV-1 seronegative controls and added experiments that control for antibody isotype, antibody target, and neuron viability. In these studies, IgG was infused into the extracellular space during whole-cell current clamp recordings of neurons. Our results confirm that in contrast to normal IgG, IgG from all HAM/TSP patients completely inhibited neuronal firing. Affinity-purified antibodies specific for hnRNP A1 and a monoclonal antibody to HTLV-1-tax (which reacted with hnRNP A1 and whose epitope overlaps the human immunodominant epitope of tax) also inhibited neuronal firing. Monoclonal antibodies to neurofilament did not change neuronal firing. These data indicate that antibodies to neurons can be pathogenic, that biologic activity can be affected by a cross-reactive epitope between HTLV-1-tax and hnRNP A1, and that molecular mimicry may play a role in the pathogenesis of HAM/TSP.     

Accumulation of human T-lymphotropic virus type I (HTLV-I)-infected cells in the cerebrospinal fluid during the exacerbation of HTLV-I-associated myelopathy

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive, inflammatory disease of the central nervous system (CNS). We report a patient with transverse myelitis, who exhibited acute onset and rapid progression of the disease and whose symptoms resembled those observed in multiple sclerosis with spinal cord presentation. During neurological exacerbation of the condition, the HTLV-I proviral load in the cerebrospinal fluid (CSF) increased to 10 times that in the peripheral blood. This suggests that the accumulation of HTLV-I-infected cells in the CNS contributes to neurological exacerbation. Based on the increased proviral load in the CSF, we diagnosed the disease as acute progressive HAM/TSP. The measurement of the HTLV-I proviral load in the CSF is useful for the diagnosis of HAM/TSP and for monitoring its progression.     

HTLV-1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM/TSP patients: a marker of disease progression

A high proviral load of human T cell lymphotropic virus type 1 (HTLV-1) in peripheral blood mononuclear cells (PBMCs) has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of the present study was to investigate the role of HTLV-1 proviral load in PBMCs (expressed as the number of copies per 10(6) PBMCs) in HAM/TSP disease course. One hundred consecutive HAM/TSP patients were recruited and assigned on the basis of the disability score and disease duration to either a rapid (n=38) or a slow (n=62) progression group. Thirty-four asymptomatic HTLV-1 carriers were also included. HTLV-1 proviral load was quantified in all HAM/TSP patients and asymptomatic subjects. The mean HTLV-1 proviral load was 6-fold lower in asymptomatic carriers than in HAM/TSP patients (18,224+/-24,811 vs. 107,905+/-96,651, p<0.0001) and significantly higher in rapid progression patients than in slow progression patients (146,469+/-98,943 vs. 84,270+/-87,912, p=0.0002). HTLV-1 proviral load in HAM/TSP patients was independent of age at the time of study, age at onset, and disease duration, and was not related to ophthalmological-associated disease or Chisholm grade. A high level of pulmonary lymphocytosis correlated with high HTLV-1 proviral load level (p=0.01). Our results suggest that the level of HTLV-1 proviral load in PBMCs parallels the course of HTLV-1 infection, being low in asymptomatic carriers and high and very high, respectively, in slow and rapid progression HAM/TSP patients. The magnitude of the HTLV-1 proviral load in PBMCs can be used as a biological marker of disease progression and could be a useful marker of disease activity in the monitoring of therapeutic trials.     

Usefulness of proviral load measurement for monitoring of disease activity in individual patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis

High human T-lymphotropic virus type I (HTLV-I) proviral load in peripheral blood mononuclear cells (PBMCs) has been reported in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the proviral load has been reported to fluctuate in individual patients during the course of the disease. Clinical symptoms usually became stable after a prolonged period of symptom progression. However, the authors have experienced having some patients whose clinical manifestations suddenly became worse during the course of the disease. To clarify the role of high proviral load and its fluctuation in the pathogenesis of HAM/TSP, the authors measured the proviral load of serially taken PBMCs as well as of cerebrospinal fluid (CSF) cells from patients with HAM/TSP on long-term follow-up and compared these with their clinical manifestations. There was a wide distribution of proviral load, from 0.3 to 37.8 copies/100 PBMCs; however, the proviral load in individual patients was relatively stable during the course of the disease. Eighty-three percent of the patients with clinical worsening showed an increase in proviral load at the time point when clinical worsening was recorded, or at the preceding time point. The proviral loads in CSF cells were higher than those in PBMCs in individual patients. The ratio of proviral loads in CSF cells/in PBMCs, but not the absolute load, in either compartment, was significantly associated with clinically progressive disease and with recent onset of HAM/TSP. These findings indicate that clinical progression of HAM/TSP is associated with increased proliferation or immigration of HTLV-I-infected lymphocytes in the central nervous system.     

Detection of human T-lymphotropic virus type I (HTLV-I) tax RNA in the central nervous system of HTLV-I–associated myelopathy/tropical spastic paraparesis patients by in situ hybridization

Autopsy specimens from 3 patients with human T-lymphotropic virus (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients.     

The clinical and pathological features of peripheral neuropathy accompanied with HTLV-I associated myelopathy

We describe the clinical and pathological studies in HTLV-I associated myelopathy (HAM)/tropical spastic paraparesis (TSP) patients with peripheral neuropathy as proven by sural nerve biopsy. Sural nerve pathology in HAM/TSP patients revealed that the most common type of pathologic change is a combination of both demyelination and remyelination and axonal degeneration and regeneration, and this change is modified by the complications. The pathologic changes were correlated with neither the duration of disease nor human T lymphotropic virus type I (HTLV-I) proviral load. This study suggests that peripheral nerves could be involved in HAM/TSP.