In this large prospective cohort study, HTLV-I– and -II–infected participants had increased odds of motor and sensory neurologic signs and bladder symptoms compared with HTLV-seronegative participants. In general, both HTLV-I– and -II–infected participants were more likely than HTLV-seronegative participants to report bladder dysfunction and manifest examination abnormalities, including leg weakness, impaired gait, hyperreflexia, and impaired vibration sense. Neither group had a higher frequency of sensory peripheral neuropathy compared with HTLV-seronegative participants after adjusting for potential confounding variables. These results support some, but not all, previous studies that demonstrated the association of HTLV with a spectrum of neurologic abnormalities other than HAM.
These data also provide the strongest evidence to date that HTLV-II, as well as HTLV-I, is associated with an array of predominantly motor and bladder neurologic findings. Although a limited number of studies have shown that HTLV-II–infected individuals are more likely than uninfected individuals to develop neurologic disability,20
and progressive myelopathy,23
the role of HIV and/or drug-related factors could not be excluded. In this study, subjects were seronegative for HIV and only a small percentage reported injection drug use, which we adjusted for in our analysis. Although the role of HTLV-II in the development of neurologic disorders has been less clear than that of HTLV-I in the literature, our findings show similar odds of neurologic abnormalities across both groups of infected subjects. In addition, HTLV-II subjects had a significantly higher number of work-loss days compared with HTLV-seronegative subjects, even after adjusting for socioeconomic factors, which provides support for increased morbidity, though not necessarily neurologic. HTLV-II subjects may have had more work-loss days as a result of their higher frequency of neurologic abnormalities or because of their higher incidence of respiratory tract infections and arthritis.10
We have previously reported 4 cases of HAM among HTLV-II patients in the HOST cohort,4
and there are a number of other HTLV-II HAM case reports in the literature.28–34
These results, in addition to the spectrum of milder abnormalities found in our study, support the neuropathologic effects of this virus.
Our negative results on HTLV-I infection and peripheral sensory neuropathy contradict those of previous studies.6–8,13
However, all but one of the studies consisted of uncontrolled case reports, so results could not be appropriately compared with HTLV-seronegative persons. Because peripheral neuropathy has multiple causes,35
the use of a control group is critical. Confounding by other causes of peripheral neuropathy may account for some reports in the literature that lacked the kind of multivariate analysis we performed.
In contrast to our negative findings on impaired fine touch, we did find a higher incidence of impaired vibration sense among HTLV-I and -II subjects compared with seronegative subjects. Potential age-related differences in vibration sensation between HTLV groups and seronegative subjects were excluded by multivariate analysis. Decreased vibration sense is among the main neurologic manifestations of HAM as defined by the World Health Organization,36
but it has rarely been studied in HTLV-infected individuals without HAM. It is noteworthy that we found abnormality in vibration sense but not fine touch. The anatomy of spinal cord structures involved in advanced HAM is well known and includes the corticospinal tracts, anterior horn cells, and posterior columns.37
The clinical findings among our subjects suggest that spinal cord involvement associated with HTLV-I or -II infection may affect single or multiple spinal cord structures across a clinical spectrum from asymptomatic to mild or severe involvement. Our data also suggest that peripheral sensory nerves are not a focus of HTLV neuropathology. The reasons for these sensory differences could be explored more fully in animal models.
Our current finding of a highly significant increased likelihood of prevoid and postvoid urgency and incontinence in both HTLV-I– and -II–infected subjects is consistent with other reports of HTLV-related neurogenic bladder in the literature, including our own.10–12,38
Because we did not perform evaluations for urinary tract infections (UTI), it is conceivable that unrecognized UTI could account for our findings. However, a recent cross-sectional study of 157 HTLV-I–infected individuals found that only 19% of 64 subjects with bladder symptoms had positive urine cultures, indicating that the majority of urinary symptoms were due to neurogenic bladder.12
Furthermore, this study performed urodynamic studies on a subgroup of 21 symptomatic individuals with negative urine cultures and found evidence of neurogenic bladder in 81% of these individuals. These results argue that HTLV-I and -II subjects should have careful, periodic neurologic evaluation to document and symptomatically treat bladder as well as gait manifestations. Future prospective studies should include urodynamic evaluations and urine cultures.
Strengths of this study include its large sample size, prospective cohort design, standardized examinations, and long-term follow-up of both HTLV-infected and seronegative individuals. In addition, we conducted multivariate repeated-measures analyses to control for confounders that could obscure the relationship of HTLV with its neuropathologic features, although residual confounding may still have influenced the magnitude of the associations we observed. A potential weakness is the lack of blinding of participants and research nurses, which may have biased the association of HTLV infection and neurologic abnormalities upward. However, because our cohort consisted of voluntary blood donors, who are known to be healthier than the general population, it is likely that the absolute rates of neurologic abnormalities reported in our study are underestimates. Although we used rising from a chair without using the hands to screen for leg weakness, it is possible that balance, muscle, or joint abnormalities unrelated to motor function may explain difficulty in performing this maneuver.
Until longer follow-up of our cohort is achieved, it is difficult to speculate whether the neurologic abnormalities identified in subjects without HAM will remain stable or progress to a full diagnosis of HAM. Although our results suggest that some neurologic manifestations of HTLV-I and -II infection are isolated and do not reach the clinical threshold for the diagnosis of myelopathy, they remain consistent with the syndromic symptoms and signs of HAM. Our anecdotal data on abnormal neurologic examinations in 4 cohort participants who developed incident cases of HTLV-I or -II HAM further support the hypothesis that some participants with abnormal neurologic examinations will later progress to HAM.
Because only a small percentage of infected individuals develop HAM, HAM may simply be the “tip of the iceberg” of a broader spectrum of stable neurologic manifestations associated with HTLV infection.39
This view is supported by recent clinical evidence of increased HTLV-I proviral loads, similar to those of HAM patients, in patients with neurologic abnormalities other than HAM compared with asymptomatic carriers.40
These findings suggest that viral regulatory genes, genetic determination of the host’s immunologic response, or both may be responsible for both HAM and the more subtle spectrum of neurologic abnormalities that we report. Virologic and immunologic studies of symptomatic non-HAM cases may help to clarify the etiology of HTLV neurologic outcomes.