AAN.com Talks with Edward Murphy and Hope Biswas About the Neurologic Features of HTLV Infection

September 29, 2009

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Edward Murphy, MD, MPH, Professor of Laboratory Medicine and Epidemiology/Biostatistics at UCSF and Senior Investigator, Blood Systems Research Institute in San Francisco, and Hope Biswas, ScM, Staff Scientist at the Blood Systems Research Institute, discuss their paper "Neurologic abnormalities in HTLV-I– and HTLV-II–infected individuals without overt myelopathy," which was recently published in Neurology®. (2009;73:781-789). They spoke with AAN.com Science editor, José G. Merino, MD, M.Phil.

AAN.com: Can you briefly summarize the methodology and major findings of the study?

Authors: We analyzed the medical histories and screening neurologic examinations of patients in a large cohort of former blood donors, including individuals infected with HTLV-I and -II and HTLV-seronegative controls. We used a prospective cohort study design, which is ideal for testing the association of HTLV infection with neurologic abnormalities. Our study is unique because of our large sample size (541 participants with HTLV-I and -II infection and 810 seronegative controls) and long follow-up period (approximately 12 years).We used standardized measures, a three-level clinical assessment process (nurse screening exam, physician exam, neurologist exam), and a disease adjudication committee to minimize measurement bias. These methods allowed us to detect even subtle neurologic changes that developed gradually. We found that, compared to controls, participants with HTLV-I and -II infection were more likely to have abnormal neurologic signs and symptoms including leg weakness, impaired tandem gait, Babinski sign, impaired vibration sense, and urinary incontinence.

AAN.com: What are human T-cell lymphotropic viruses (HTLV), how are they transmitted, and how common are they?

Authors: Human T-cell lymphotropic viruses are RNA retroviruses that share approximately 60 percent genomic homology.HTLV-I is the cause of adult T-cell leukemia/lymphoma (ATL), as well as HTLV-associated myelopathy (HAM, also known as tropical spastic paraparesis).While HTLV-II does not cause ATL and has been considered nonpathogenic, the results of this and other studies increasingly support an association with neurologic disease.

Due to a lack of population-based studies of HTLV-I and -II, data from blood donors have been used to approximate population prevalence. A study of more than 1.7 million blood donors from five major U.S. cities between 1991 and 1995 found a seroprevalence of 0.01% for HTLV-I and 0.02% for HTLV-II.1 In endemic areas, which include Japan, the Caribbean, parts of Africa, and Central and South America, the prevalence ranges from 1–5% for HTLV-I. 2 HTLV-II is highly prevalent among Amerindians (5–10%)3, 4 and US injection drug users (10–20%).5, 6

HTLV-I and -II can be transmitted via mother-to-child, sexual, and parenteral routes. In the US, due to the epidemiologic features associated with each type, vertical and sexual transmission are predominant in HTLV-I, and parenteral transmission via injection drug use is predominant in HTLV-II. Sexual transmission has been documented for both HTLV types at a rate of about one per 100 person-years among discordant couples.7

AAN.com: What are the features of HTLV-I associated myelopathy (HAM), and can HTLV-II also cause myelopathy?

Authors: HAM is a progressive neurologic disorder characterized by pyramidal tract signs including leg weakness, diffuse hyperreflexia, clonus, loss of vibration sense, and detrusor insufficiency leading to bladder dysfunction. The differential diagnosis includes other causes of spastic paraplegia or neuropathy (spinal cord injury, tumor or vascular malformation, atypical presentation of multiple sclerosis, neurosyphilis, diabetic neuropathy, and B12 and folate deficiency). HAM is a clinical diagnosis based on the presence of a characteristic clinical syndrome, the exclusion of other differential diagnoses by imaging and laboratory studies, and the demonstration of HTLV infection by serology or PCR.

There is strong evidence for the association between HTLV-I and HAM, although the pathogenesis is still under investigation. There have been fewer cases of HTLV-II HAM, so it is difficult to prove causality from an epidemiological viewpoint. However, there is a growing consensus that HTLV-II also causes HAM.8

AAN.com: What is the pathogenesis of HAM and the isolated neurologic features?

Authors: The mechanism through which HTLVs cause HAM (and, we speculate, the isolated neurological deficits) has not been settled. Histologic examination of affected spinal cord tissue shows perivascular infiltration of HTLV-infected lymphocytes. Viral genes and proteins or, more likely, the cytotoxic T-lymphocyte response to HTLV infection, are the cause of the spinal cord damage. HTLV infected individuals with higher proviral loads and/or stronger CD8 + cytotoxic T-lymphocyte response are at higher risk of HAM. Specific HLA subtypes are associated with different risks of neurologic dysfunction, supporting the immunologic hypothesis. These parallels to the pathogenesis of multiple sclerosis make HAM a worthy topic of research.

AAN.com: From your findings, can you comment on temporal course of isolated neurological deficits and the rate of conversion to HAM?

Authors: In our cohort, we had only four incident cases of HAM. The four participants had at least some leg weakness, impaired gait, impaired vibration sense, or urinary tract abnormality before HAM was diagnosed.HAM is a slowly progressive disorder that develops over many decades. Further follow-up of our cohort is needed to determine whether other participants with isolated neurologic abnormalities will progress to HAM.

AAN.com: What are the implications of your findings for clinical neurologists?

Authors: This study suggests that in addition to well-defined HAM, both HTLV-I and HTLV-II are associated with a spectrum of predominantly pyramidal track and sensory findings including leg weakness, impaired tandem gait, Babinski sign, impaired vibration sense, and urinary incontinence. Practicing neurologists should be aware of this when they examine patients known to be infected with HTLV-I or HTLV-II. In addition, they ought to consider HTLV testing in patients with these clinical findings who have risk factors for HTLV-I or HTLV-II such as familial origin (Japan, Africa, Caribbean, or Amerindian) or a history of injection drug use, or sexual contact with someone from these groups. They should be aware that currently licensed enzyme immunoassay (EIA) screening tests are associated with moderate levels of false positivity and require confirmatory testing with an immunoblot or immunofluorescence. Also, EIAs do not distinguish between HTLV-I and HTLV-II because of cross-reactivity. Type-specific confirmatory testing is recommended because of the different prognoses of the two viruses: HTLV-I but not HTLV-II causes adult T-cell leukemia lymphoma, and HTLV-I appears to have higher penetrance of neurologic abnormalities than HTLV-II.

Notes

  1. Murphy EL, Watanabe K, Nass CC, Ownby H, Williams A, Nemo G. Evidence among blood donors for a 30-year-old epidemic of human T lymphotropic virus type II infection in the United States. J Infect Dis. Dec 1999;180(6):1777-1783.
  2. Murphy EL, Biswas HH. Human T-Cell Lymphotropic Virus Types I and II. Chapter 168. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases. 7 ed. Philadelphia: Churchill Livingston / Elsevier; 2009 (in press).
  3. Maloney EM, Biggar RJ, Neel JV, et al. Endemic human T cell lymphotropic virus type II infection among isolated Brazilian Amerindians. J Infect Dis. 1992;166:100-107.
  4. Vitek CR, Gracia FI, Giusti R, et al. Evidence for sexual and mother-to-child transmission of human T lymphotropic virus type II among Guaymi Indians, Panama. J Infect Dis. Apr 1995;171(4):1022-1026.
  5. Feigal E, Murphy E, Vranizan K, et al. Human T cell lymphotropic virus type I and II in intravenous drug users in San Francisco: Risk factors associated with seropositivity. J Infect Dis. 1991;164:36-42.
  6. Khabbaz RF, Onorato IM, Cannon RO, et al. Seroprevalence of HTLV-1 and HTLV-2 among intravenous drug users and persons in clinics for sexually transmitted diseases. N Engl J Med 1992;326(6):375-380.
  7. Roucoux DF, Wang B, Smith D, et al. A prospective study of sexual transmission of human T lymphotropic virus (HTLV)-I and HTLV-II. J Infect Dis. 2005;191(9):1490-1497. Link to
  8. Araujo A, Hall WW. Human T-lymphotropic virus type II and neurological disease. Ann Neurol. 2004;56(1):10-19.

Author Disclosures

Dr. Murphy has received research support from a National Heart, Lung, and Blood Institute grant.

Ms. Biswas has nothing to disclose.

Dr. Merino performed a one time consultation with staff from Bell, Falla and Associates.