Neurologists not convinced by study linking XMRV to CFS

January 5, 2010

From Neurology Today, 3 December 2009 (Story by Dan Hurley)

Neurologists who specialize in infectious disease questioned the reported association between a xenotropic murine leukemia virus-related virus and chronic fatigue syndrome, saying more data are needed to confirm the association.

The latest study in a prominent journal seeking to cut through the fog surrounding chronic fatigue syndrome (CFS) with the light of objective test data has met with remarkable skepticism among neurologists.

In an article published in the Oct. 23 Science, investigators – past and current staff of the National Cancer Institute (NCI) and the Cleveland Clinic – reported that the retrovirus, xenotropic murine leukemia virus-related virus (XMRV), could be detected in 67 percent of 101 patients with CFS, compared to just 3.7 percent of 218 healthy controls. The researchers also showed that the patient-derived XMRV was infectious in cell cultures.

The retrovirus was first described three years ago in a handful of patients with prostate cancer, and has since been detected in nearly one in four prostate cancer biopsies.


But neurologists emphasized the poor track record of other agents proposed to play a causative role in the disease. More fundamentally, they questioned whether CFS, still controversial after decades of study, is a real disease entity with any organic cause at all.

Chronic fatigue syndrome has been previously associated with a large number of microbial agents, thyroid disease, heavy metal exposure, and organophosphate exposure, said Joseph R. Berger, MD, professor and chairman of neurology at the University of Kentucky College of Medicine in Lexington. This isn't the first time that a virus has been correlated with the disease – if it is truly a disease.

Initially linked to Epstein-Barr virus in the 1980s, CFS has since been associated at one time or another to human herpes virus 6, enteroviruses, parvovirus, and human T-lymphotropic virus type 2.

Although the Centers for Disease Control and Prevention (CDC) estimates that 4 million Americans have CFS (of whom only 20 percent have been diagnosed by a physician), according to its Web site no diagnostic laboratory test or biomarker has yet been conclusively linked to it. (See The CDC Diagnostic Criteria for CFS.)

It's been one virus after another, said Thomas D. Sabin, MD, professor of neurology at Tufts Medical Center and co-editor of a 1993 book Chronic Fatigue Syndrome (Lippincott Williams & Wilkins). Each time, there's been great excitement, and then it's faded. Right now we should await confirmatory evidence from other laboratories.

An editorial accompanying the new study in Science stated that in addition to laboratory studies, epidemiological studies are now needed to determine whether this virus has a causative role, not only in this disease, but perhaps in others as well. While acknowledging the many uncertainties regarding both CFS and XMRV, the editorial – by John M. Coffin, PhD, who heads a laboratory in the department of molecular microbiology at Tufts University, and Jonathan P. Stoye, PhD, head of the division of virology at the Institute of Medical Research in London – noted that even the 3.7

percent infection rate seen in controls would add up to 10 million Americans if confirmed in future studies, a concern underscored by the senior author of the paper in an interview with Neurology Today.

The importance of the study is that it showed a new human retrovirus infection, and that 10 million Americans could be affected with it, said Judy A Mikovits, PhD, research director of the Whittemore Peterson Institute for Neuro-Immune Disease, a privately funded institution affiliated with the University of Nevada-Reno. We have no idea how this agent might cause disease. But retroviruses are never benign and they're not ubiquitous.

Should the link between XMRV and CFS be confirmed, she said, clinical trials could test whether treatment with antiretroviral therapy might prove beneficial. We're talking with drug companies about screening existing antiretrovirals, she said. We could have some rational clinical trials soon.


But neurologists said such speculation is as yet unjustified by the single paper.

The authors did not describe the characteristics of the patients or controls, said Karen Roos, MD, the John and Nancy Nelson Professor of Neurology at Indiana University, where she specializes in the study of CNS infections. I am surprised that Science published it. It is far too premature to comment on the significance of this.

Even the association of XMRV with prostate cancer has been put in doubt by an Oct. 16 paper published in the journal Retrovirology, in which researchers at the Robert Koch Institute in Berlin, Germany, were unable to detect XMRV antibodies in 146 serum samples from prostate tumor patients.

But Dr. Mikovits, who spent more than 20 years at the NCI before joining the Whittemore Institute, strongly defended the integrity of her study, noting that all patients defined as having CFS had been diagnosed with it by a physician and met the CDC criteria.

For all his doubts, Dr. Berger pointed out that the recent history of medicine has been studded with examples of diseases thought by doctors to be primarily psychosomatic or caused by stress, until evidence established an organic cause.

I'm not ready to sign onto the bandwagon yet, he said. But they seem to be onto something. Remember, we viewed Helicobacter pylori as a cause of peptic ulcers with great skepticism, until it turned out to be irrefutable.


Despite the lack of objective measures, the CDC list of diagnostic criteria for CFS is careful both in what it requires and excludes.

The clinical diagnosis includes:

* unexplained persistent or relapsing chronic fatigue that is of new or definite onset (that is, not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

* Four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post- exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.

A full description of the CDC's definition, diagnostic criteria, treatment options and research updates for healthcare professionals can be found on its Web site at


– Lombardi VC, Ruscetti FW, Gupta JD, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009; 326:585-589.

– Coffin JM, Stoye JP. A new virus for old diseases? Science 2009; 326:530-531.

– Hohn O, Krause H, Barbarotto P, et al. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology 2009;6:92.

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