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Neurology Today:
doi: 10.1097/01.NT.0000363232.20200.c9
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Human T‐Lymphotropic Virus May Trigger More Neurologic Problems Than Previously Thought

FITZGERALD, SUSAN

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New research indicates that both HTLV-I and II can cause leg weakness, gait abnormalities, and urinary incontinence in isolation or together.

While human T-lymphotropic virus (HTLV) type I is known to cause a debilitating myelopathy, the retrovirus and the type II counterpart can also trigger more subtle motor problems that may go undiagnosed, according to a Sept. 8 paper in Neurology.

It is well recognized that HTLV-I is responsible for a progressive disorder known as HAM (HTLV-associated myelopathy), also called tropical spastic paraparesis. Now the new research indicates that both HTLV-I and II can also cause leg weakness, gait abnormalities, and urinary incontinence in isolation or together.

“Further investigation of the clinical course and etiology of these abnormalities is warranted,” concluded a team headed by Edward L. Murphy MD, MPH, professor of laboratory medicine, epidemiology, and biostatistics at the University of California-San Francisco, and senior investigator at the Blood Research Institute in the same city.

The finding that HTLV has a much broader reach than generally assumed could lead to identification of patients who may be experiencing neurologic problems that are either overlooked or blamed on some other causes, Dr. Murphy told Neurology Today.

“As with many neurologic disorders, it makes sense that you would have a milder form of the classical HAM syndrome,” said Dr. Murphy, who has been studying HTLV for 25 years.

HTLV — which also can cause T-cell leukemia or lymphoma — targets the CNS and may cause severe neurologic problems many years after a person becomes infected. According to background information in the paper, approximately 4 percent of persons infected with HTLV-I will develop full-blown myelopathy, or HAM, over the course of a lifetime, with symptoms and signs that include leg weakness, hyper-reflexia, clonus, loss of vibration sense, and bladder dysfunction. Patients with HAM have progressive paraplegia and most eventually require wheelchair support.

The role of HTLV-II in the development of HAM is not as clear, though there is some evidence to suggest a connection. There also has been some research, mostly from case studies and cross-sectional reports, to suggest that HTLV infection may result in a broader spectrum of symptoms that do not meet the clinical definition of HAM.

“A better understanding of the neurologic abnormalities associated with HTLV infection is important for the clinical care of infected patients,” the researchers wrote. “The etiology and pathogenesis of these abnormalities are poorly defined, and it is unclear where they are a precursor to the development of HAM or part of a broader spectrum of HTLV-associated morbidity.”

To gain some clarity on the issue, the researchers analyzed data collected for the HTLV Outcomes Study, a prospective study made up of people who attempted to donate blood at one of five blood banks, located in Baltimore and Washington, DC; Detroit; Oklahoma City; San Francisco; and Los Angeles. The researchers compared three groups: 153 people infected with HTLV-I; 388 people with HTLV-II; and 810 people who tested negative for the virus. HTLV patients who had HAM were excluded from the study.

After being enrolled in the study from 1990–1992, participants were followed up every two years. Those visits included a standardized symptom questionnaire; blood tests; and a neurologic exam that evaluated heel, toe, and tandem gait, biceps reflex, patellar reflex, Babinski sign, and vibration sensation. To check for leg muscle weakness, the participants were asked to rise from a chair without using their hands. Later in the study, participants were also tested for sensory neuropathy in their legs.

Nearly 12 percent of the HTLV-I patients and nearly 15 percent of the HTLV-II patients in the study had leg weakness, compared to 6 percent of the controls (who were blood donors at the clinics). Likewise, nearly 22 percent of type I patients and about 28 percent of type II patients reported incontinence, compared to 13 percent of controls. Impaired tandem gait was identified in 28 percent of HTLV-I patients and nearly 35 percent of HTLV-II, but just over 19 percent of the controls had the problem.

“Although the role of HTLV-II in the development of neurologic disorders has been less clear than HTLV-I in the literature, our findings show similar odds of neurologic abnormalities across both groups of infected subjects,” the investigators wrote.

Hope Biswas, a research scientist at the Blood Systems Research Institute, who was a co-author for the study, told Neurology Today that her group's finding that HTLV-II could be as worrisome as HTLV-I was particularly key since “less is known about the disease outcomes of HTLV-II infection.”

Joseph R. Berger, MD, chairman and professor of neurology at the University of Kentucky, told Neurology Today the study results are fascinating. “We always thought 2 to 5 percent of persons with HTLV had myelopathy over the course of their lifetime, but the frequency of clinical disease seems to be much, much higher,” he said.

“This paper is very well done and the results are believable,” Dr. Berger said. “It may serve as an impetus for the medical community to develop more effective treatments for the virus if we realize this is a significant public health risk.”

Whether the more subtle cases identified in the study will worsen over time into full-blown HAM is not clear, Dr. Murphy said. “We don't have enough data to say whether these people will progress or stay at a mild level.” His team hopes to continue to track the patients in the study.

Both HTLV-I and II are uncommon viral infections in the US — though injection drug users are at high risk of HTLV-II — but are more frequent elsewhere in the world, including Jamaica, southern Japan, and parts of Central and West Africa and South America, affecting between an estimated 10 million to 20 million people depending on the estimate.

“HAM is kind of an orphan disease. The treatments for HAM are not ideal,” said Dr. Murphy, noting that the use of steroids, interferon, and antiretroviral drugs has met with mixed and often disappointing results.

Dr. Murphy said that now that the physical manifestations of HTLV infection are better identified, his team plans to focus in detail on viral and immunologic factors to see how they eventually play out in spinal cord damage. That work could lead to the development of new and better therapies.

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Reference

• Biswas H, Engstrom J, Murphy EL, et al., for the HTLV Outcomes Study (HOST). Neurologic abnormalities in HTLV-I– and HTLV-II–infected individuals without overt myelopathy. Neurology 2009;73:781–789.

©2009 American Academy of Neurology

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