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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Pediatr. Author manuscript; available in PMC 2010 November 1.
Published in final edited form as:
PMCID: PMC2764792

Early neurologic abnormalities associated with human T-cell lymphotropic virus type 1 infection in a cohort of Peruvian children

Emily A. Kendall, A.B.,1 Elsa González, M.D.,2 Iván Espinoza, M.D.,2,3 Martín Tipismana, M.D.,2,4 Kristien Verdonck, M.D.,2,6 Daniel Clark, Ph.D.,2,7 Sten H. Vermund, M.D., Ph.D.,1 and Eduardo Gotuzzo, MD, FACP.2,5



Because human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) may occur in some children infected with HTLV-1-infected, we sought to determine the prevalence of neurologic abnormalities and any associations with infective dermatitis in these children.

Study design

We enrolled 58 children infected with HTLV-1 and 42 uninfected children (ages 3-17) of mothers infected with HTLV-1 in a family study in Lima, Peru. We obtained medical and developmental histories, surveyed current neurologic symptoms, and conducted a standardized neurologic examination without prior knowledge of HTLV-1 status.


HTLV-1 infection was associated with reported symptoms of lower extremity weakness/fatigue (OR=6.1, CI:0.7–281), lumbar pain (odds ratio [OR] = 1.7, 95% confidence interval [CI]:0.4–8), and paresthesia/dysesthesia (OR=2.6, CI:0.6–15.8). HTLV-1 infection was associated with lower-extremity hyperreflexia (OR=3.1, CI:0.8–14.2), ankle clonus (OR=5.0, CI:1.0–48.3), and extensor plantar reflex (OR undefined; p = 0.2). Among children infected HTLV-1, a history of infective dermatitis was associated with weakness (OR=2.7, CI:0.3–33), lumbar pain (OR=1.3, CI:0.2–8), paresthesia/dysesthesia (OR=2.9, CI:0.5–20), and urinary disturbances (OR=5.7, CI:0.5–290).


Abnormal neurologic findings were common in Peruvian children infected with HTLV-1, and several findings were co-prevalent with infective dermatitis. Pediatricians should monitor children infected with HTLV-1 for neurologic abnormalities.

Keywords not in title: Tropical Spastic Paraparesis, Infective dermatitis

Human T cell lymphotropic virus type 1 (HTLV-1) infection affects 10-20 million people worldwide and is endemic in parts of Japan, the Caribbean, Africa, Italy, and South America1, including Peru2. Seroprevalence rates exceed 1% in endemic regions3 and in high-risk subpopulations of nonendemic countries including the United States4,5. Transmission can occur sexually, by blood transfusion or needle sharing, or from mother to child via breastfeeding. Infected individuals are at risk to develop severe diseases including HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH)3.

HAM/TSP is a progressive, nonremitting spastic paraparesis with associated bladder dysfunction, constipation, and sensory symptoms6. It often develops slowly over a decade or more7; factors associated with relatively rapid progression include female sex6, age >50 years, and high proviral load8. It is an immune-mediated disease of the central nervous system, particularly the pyramidal tracts, whose pathogenesis may involve a virus-triggered autoimmune reaction or a by-stander effect of the cytotoxic destruction of adjacent infected T cells6,9. In addition to the classic spastic paraparesis picture, other neurologic symptoms including isolated peripheral neuropathy, ataxia7, cognitive deficits9, myopathy and sympathetic dysautonomia6 are becoming recognized as part of a broader complex of HTLV-1-related neurologic disease.

Development of HAM/TSP most commonly follows sexual HTLV-1 transmission during adulthood and appears in the fourth or fifth decade of life10-12. However, HAM/TSP also can occur following vertical HTLV-1 transmission during infancy, and multiple cases in children and adolescents are described13-21. A study of asymptomatic Jamaican children infected with HTLV-1 suggested hyperreflexia as an early HTLV-1-associated abnormality22. Despite these suggestive reports, the overall neurologic impact of HTLV-1 infection in children remains poorly defined due to the very small sample sizes and the limited scope of neurologic examinations in prior studies.

Case reports of HAM/TSP in children and adolescents, although varied, describe initial disease presentations that may include weakness, difficulty running, leg or back pain, and/or urinary incontinence14,15. The course of disease progression in children can be atypically slow and erratic23 or exceptionally rapid20 compared with adults. The eventual outcome, however, is typical HAM/TSP clinical picture including weakness, spasticity, clonus, constipation, extensor plantar reflexes (Babinski sign), and occasionally finger flexor reflexes (Hoffman sign), other pyramidal signs, and sensory or cerebellar deficits14,15,24,25.

A more commonly recognized health effect of HTLV-1 infection in children is a recurrent infected eczema, known as infective dermatitis associated with HTLV-1 (IDH)26. IDH has been reported in association with both concurrent and later HAM/TSP14-16,21,27,28 and adult T-cell leukemia/lymphoma (ATLL)21,29,30. One study diagnosed HAM/TSP in 6 of 20 children with infective dermatitis who underwent neurologic evaluation, although familial clustering may have been a factor in that study population's high prevalence of neurologic disease 14. Learning delay also has been reported in children with HTLV-1 infection in association with IDH and early HAM/TSP development 15, although at least one small Peruvian study of early development found no significant differences between 10 children infected with HTLV-1and 38 uninfected children studied31. Investigation of the link between IDH and HAM/TSP is ongoing. Both involve a proinflammatory microenviroment and dysregulated host-pathogen interactions, including activated but ineffective CD8+ T cells32,33. Both IDH and HAM/TSP patients also have high levels of anti-HTLV-1 antibodies15,20, which may reflect a high proviral load as a shared pathogenetic factor34. In IDH, viral antigens and bacterial superantigens increase T-lymphocyte stimulation, enlarging the population of dividing cells that HTLV-1 can infect, and thereby increasing the possibility for other HTLV-related disease35. Finally, in both instances of immune hyperactivation, human lymphocyte antigen (HLA) factors play a role, and certain HLA types have been identified as shared risk factors for both IDH and HAM/TSP33,36.

In this study, we sought to examine the prevalence, as well as the association with IDH, of neurologic abnormalities in a cohort of Peruvian children with and without HTLV-1 infection.


We conducted standardized, blinded neurological evaluations of children with and without HTLV-1 infection of mothers infected with HTLV-1 in Lima, Peru, where the estimated prevalence of HTLV-1 infection in pregnant women is 1.7%37. Study participants were drawn from an ongoing HTLV-1 family cohort study (n>600 families) at the Institute of Tropical Medicine “Alexander von Humboldt” in Lima2, comprised primarily of families of patients who have visited or been referred to the hospital for HTLV-1-related illnesses, along with families of asymptomatic HTLV-1-infected blood donors. Children in these families were eligible if they were between 3 and 17 years of age and were born to an cohort participant with HTLV-1-infection. An attempt was made to contact all eligible cohort families living within the province of Lima by visiting their homes.

Study approval was obtained from the Institutional Ethics Committee of the Universidad Peruana Cayetano Heredia and the Institutional Review Board of Vanderbilt University. All participants and their parents or guardians received written and verbal explanations of study purpose and procedures, and parents/guardians gave written informed consent, and children gave age-appropriate assent.

Children and their mothers or other guardians were interviewed immediately following study enrollment by an interviewer (EAK) blinded to HTLV-1 infection status. The data gathered included age, sex, and grade in school; information about factors related to HTLV-1 transmission including peripartum events, past blood transfusions, and duration of breastfeeding; and family history of HTLV-1-associated diseases. Mothers/guardians were asked to recall the age of several early developmental milestones: crawling, walking, speaking, and cessation of diaper use. They also were queried about their child's medical history, including any HTLV-1-associated diseases (infective dermatitis – defined by previous physician's diagnosis or by clear description of the characteristic rash – as well as crusted scabies, Strongyloides stercoralis hyperinfection, or uveitis), any other illnesses or hospitalizations, and HIV infection status. Children (and/or their guardians for children less than 6 years old) also were queried about a set of symptoms often associated with HAM/TSP onset, as described by WHO guidelines38 and recently revised diagnostic criteria39: subjective lower extremity weakness or fatigability causing difficulty running or playing; paresthesias or dysesthesias in the lower extremities; radiating lumbosacral pain; bladder disturbances; and constipation. Subjects or their guardians reported and described each symptom they experienced, and the interviewer assigned a 0-4 severity rating for each symptom.

Within 2 months following the initial interview, subjects visited our clinic for an evaluation by a neurologist (IE or MT). The neurological evaluation included a thorough history and examination. Children's height and weight were recorded, and a weight-for-age percentile was determined based on the U.S. Centers for Disease Control and Prevention year-2000 standard growth curves. For children under 6 years of age, a single examiner (EAK) also conducted the Denver Developmental Screening Test II (DDST).

HTLV-1 infection was determined by serum enzyme linked immunosorbent assay (ELISA). Positive ELISA results were repeated and then confirmed by either Western blot or line immunoassay, depending upon availability of reagents. Subjects with indeterminate results (N=3) were excluded from analysis.

To maintain a blinded evaluation, the interviewer and neurologists were unaware of children's HTLV-1 infection status. Medical records were unavailable to them prior to the interview/exam; the patients were unfamiliar to them; and parents/guardians and subjects were instructed not to reveal children's infection status, if known, to the research personnel. Serum samples were collected and analyzed by staff without knowledge of infection status or interview/exam results. Data were linked to HTLV-1 serostatus by a third party after all evaluations were completed, with personal identifiers removed to ensure confidentiality.

Statistical methods

Population characteristics were analyzed with Fisher exact tests (with two-tailed p values) or unpaired t-tests as appropriate. Fisher exact tests were used to test for associations between infection and neurologic symptoms, and between infection and neurological exam findings, with one-tailed p values; two-tailed p values were determined for associations between neurologic signs/symptoms and infective dermatitis history. Ninety-five percent exact confidence intervals for odds ratios were computed. A minimum severity score of 2 out of 4 was taken to represent a significant positive neurologic symptom, although trends are similar when other cut-offs are used. Because of non-normality, the Wilcoxon-Mann-Whitney rank-sum test was used to test for associations between infection status and ages of attainment of developmental milestones.


According to records for >600 HTLV-1 cohort families, 104 families had children eligible for this study. Of these, 66 families were reached and agreed to participate, ultimately yielding 103 eligible study participants from 63 families: 58 children were infected with HTLV-1 and 42 children were uninfected (and 3 excluded based on indeterminate serological results). None had previously-recognized HAM/TSP. Age and sex profiles are similar for HTLV-1-infected and uninfected subject groups (Table I). Almost all children in both groups were breastfed, but children with HTLV-1 infection breastfed until a later age (p=0.02). No children reported blood transfusions or sexual activity prior to HTLV-1 diagnosis. Nearly all mothers had been HIV-tested in pregnancy and none were HIV-infected; many children also had confirmed HIV-negative serologies. Infected subjects were slightly more likely to have been born prematurely and/or required extended hospital stays as neonates, and also had somewhat lower weights for their age (Table I).

Table 1
Demographic and perinatal characteristics of enrolled study subjects.

Some participants only completed one of the two major portions of the study; 96 were interviewed and 75 examined. There were no significant differences between participants with complete and incomplete data. Of the 63 families who had children included in analysis, 9 families contributed 3 participants each (all but 1 of these families contributing both infected and uninfected participants), and 19 families contributed 2 participants each (with concordant infection status in 10, discordant in 9). The remaining 35 participants did not have siblings in the study.

Children infected with HTLV-1 reported leg weakness, lumbar pain, paresthesias/dysesthesias, urinary incontinence, and constipation more frequently than uninfected children (Table II). Both clonus and lower extremity hyperreflexia were significantly associated with HTLV-1 infection. Most children with any neurologic exam abnormality had lower extremity hyperreflexia, with or without some additional abnormality. Extensor plantar reflex, finger flexor reflex, lower extremity weakness, fasciculations, cranial nerve signs, and cerebellar syndrome were also found exclusively in children infected with HTLV-1, although these findings were infrequent and not associated with statistical significance (Table III).

Table 2
Reports of neurologic symptoms commonly associated with HAM/TSP, by 55 children infected with HTLV-1 and 42 children uninfected with HTLV ages 3-17 in Lima, Peru.
Table 3
Neurologic exam findings in 47 children infected with HTLV-1 and 28 children uninfected.

Two study participants, both teenage females, were diagnosed with HAM/TSP by study neurological evaluations. One was a 17-year-old girl with symptoms of constipation and urinary incontinence that had progressed over the previous 2 years to profound patellar hyperreflexia, diminished Achilles tendon reflexes, lower extremity spasticity, lower extremity weakness, bilateral clonus and extensor plantar reflex, and a sensory deficit (diminished fine touch and vibratory sensation below T8). The other was a 16-year-old girl reporting recent-onset lumbar pain, subjective weakness, paresthesias, urinary urgency, and frequent constipation; exam revealed bilateral lower extremity hyperreflexia, clonus, and extensor plantar reflexes.

Of the 53 HTLV-1-infected study participants whose dermatologic histories were obtainable, 23 (43%) reported infective dermatitis. There was a weak positive association between IDH and each neurologic abnormality for except clonus and constipation (Table IV).

Table 4
Neurologic symptoms and abnormal exam findings in 48 children infected with HTLV-1 with and without histories of HTLV-1-related infective dermatitis

Neurodevelopmental milestones, as based on parental or guardian recall, did not differ between children with and without HTLV-1 infection. Median age for crawling was 8 months for children both infected and uninfected; for walking, 12 months for both groups; for first word, 9 months for infected and 10 months for uninfected groups; and for potty training, 18 months in both groups (p > 0.7 for all comparisons).

The Denver Developmental Screening Test II was also conducted for children less than 6 years of age. The sample size is too small to allow substantial analysis: 7 children with infection and 6 children uninfected in the appropriate age range. However, delayed performances meriting “failures” and “cautions” appeared to occur more frequently in the infected group for all categories of the test (fine motor, gross motor, language, and personal-social). Differences were notable in gross motor skills (3 cautions and 4 normal performances in the infected group, 6 normal in the uninfected group, p = 0.07).


We found that childhood HTLV-1 infection was associated with lower pyramidal tract signs and neuromuscular symptoms consistent with early HAM/TSP. Nearly all of the signs and symptoms considered were present more frequently in children with infection, and, although differences for some infrequent findings may have been due to chance, overall there is a significant association of infection with an abnormal examination. The association of HTLV-1 infection with lower extremity hyperreflexia is consistent with the previously-mentioned Jamaican study22, although the prevalence of hyperreflexia at a single time point in our participants (34% among infected, 14% among uninfected) was higher than the prevalence of persistent hyperreflexia (8% among infected, 2% among uninfected children) found in Jamaica.

More than half of study participants were infected with HTLV-1. This is higher than the usual prevalence of HTLV-1 infection among offspring of infected mothers. The predominance of infected status may be due in part to the long average duration of breast feeding in our population, which as expected is highest for children infected with HTLV-1. The predominance also may reflect symptom-related detection of infection in children and higher rates of vertical transmission from mothers with HTLV-associated diseases. Although none of our participants presented for medical care because of neurologic symptoms, many did present and were enrolled into our cohort because they had IDH. Others were enrolled because their mothers had diseases such as HAM/TSP or ATLL, which reflect a high maternal proviral load and a higher risk of transmission via breast feeding40-43. A limitation of our study is the absence of full neurological exams of the mothers; we cannot comment on whether HAM/TSP in a mother predicted neurologic abnormalities in her children.

With respect to early childhood development, the similarity between infected and uninfected groups may indicate that the infected group was not notably disadvantaged prior to infection, despite having a higher percentage of preterm births, neonatal hospitalizations, and low childhood weight. Peripartum transmission occurs in <5% of pregnancies44,45 and transmission rates to children breastfed <6 months are similarly around 5%, possibly because of protective maternally-acquired antibodies41,46-48, whereas transmission exceeds 30% for children breastfed >1 year40,49. Therefore, these early milestones are attained before most subjects are likely to have become infected. Our finding of poorer DDST performance in children with infection, particularly in gross motor skills, would be consistent with neurologic effects of HTLV-1 on somewhat later childhood development, but our sample size is too small to permit conclusions.

If children with HTLV-1-infection are at an increased risk for neurologic or psychomotor abnormalities, it would be helpful to identify indicators of children most at risk. The weak positive associations we found between IDH and subjective weakness, lumbar pain, paresthesia, and urinary incontinence – often some of the first symptoms noted in cases of childhood HAM/TSP – as well as with most abnormal neurological exam findings, are consistent with previous reports14-16 suggesting IDH as such a risk indicator. Given that HAM/TSP most often affects adult women, we also considered age and sex as risk factors for developing neurologic disability in the context of HTLV-1 infection. Symptoms and abnormal examinations were positively correlated with age, but the correlations were weak and none are statistically significant (spearman's rho ≤ 0.3, p values 0.1-0.8). There was no consistent trend associating sex with abnormal symptoms or signs. We note, however, that the two participants most severely affected were relatively older females.

We believe we have minimized several potential sources of bias in our study. Our children with and without HTLV-1 infection were quite similar in overall demographic profile, and we believe that including children whose mothers had confirmed HTLV-1 infection helped control for any potential sociodemographic contributions to disease. Clustering of HAM/TSP within families has been observed previously15,50,51. However, the large number of distinct families participating in our study and the even distributions of most siblings between cohort groups would reduce effects of familial clustering of abnormalities. Although investigators were blinded, many participants and/or their guardians knew their infection status, but as reports of early developmental milestones were not associated with infection status, we do not think that this knowledge biased the reporting of symptoms. We recognize the possibility of seronegative paraparesis, caused by incomplete or defective HTLV-1 proviruses that have been detected inconsistently in seronegative patients with HAM/TSP-like clinical disease 52-55, occurring within our HTLV-1 “uninfected” group. This would result in a higher-than-expected frequency of abnormalities in uninfected children and decrease the statistical power of our study to find differences between the infected and uninfected children, but this would not reverse any positive findings.

Our sample size of 58 children with infecion and 42 children without infection (with incomplete examinations of many subjects) is a notable limitation, precluding substantial analysis. Data will be useful for future meta-analysis to combine data from multiple cohorts, assuming that neurologic assessments are blinded and conducted with methodologic symmetry across surveys.

Our study suggests that children and adolescents infected with HTLV-1 are at significant risk for developing HAM/TSP-like neurologic abnormalities. Early clinical evaluation may identify otherwise-unrecognized neurologic disease in infected children, as has been possible in adults56. Frequent screening of children infected with HTLV-1 for neurologic abnormalities is important, because the best window for intervention appears to be in the first year of disease57, and also because children may benefit from symptomatic treatment of neuropathy or spasticity as well as from psychosocial support. The link with infective dermatitis may be useful as a clinical marker for children most at risk. However, because children with and without history of IDH were affected in our study, all children with HTLV-1 infection require neurologic monitoring. The frequency at which infected children appear to be neurologically affected also highlights the need for prevention of vertical transmission, particularly through elimination or reduction in duration of breast feeding. Most importantly for infected children is to discover antiretroviral drugs, immunomodulatory strategies, or other therapies that, if applied early, might delay or prevent disease progression.


We thank health care field workers Viviana Quintana and Yessica Ramos, RN for their substantial assistance in home visits, and Joe Zunt, MD, for helpful suggestions on the manuscript.

This study supported by the Directorate-General for Development Cooperation of the Belgian Government through a Framework Agreement with the Institute of Tropical Medicine in Antwerp (DGOS-II); the Flemish Interuniversity Council Programme (VLIR); Vanderbilt University School of Medicine Emphasis Program; the Vanderbilt-Meharry Center for AIDS Research (NIH grant #P30AI054999); and the Vanderbilt-Meharry Framework Program for Global Health (NIH grant #R25TW007766). The authors declare no potential conflicts of interest.

List of abbreviations used

human T-cell lymphotropic virus type 1
HTLV-1-associated myelopathy/tropical spastic paraparesis
Infective dermatitis associated with HTLV-1
Adult T-cell Leukemia/Lymphoma
human lymphocyte antigen
confidence interval
odds ratio
enzyme linked immunosorbent assay
Denver Developmental Screening Test


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