Extraordinary claims require extraordinary evidence

Chronic fatigue syndrome (CFS) (Table) has probably been with us for at least 3 centuries, traveling under various names including the vapors, neurasthenia, effort syndrome, hyperventilation syndrome, chronic brucellosis, epidemic neuromyasthenia, myalgic encephalomyelitis, hypoglycemia, multiple chemical sensitivity syndrome, chronic candidiasis, chronic mononucleosis, chronic Epstein-Barr virus infection, and post-viral fatigue syndrome. Related conditions with overlapping symptoms include chronic Lyme infection and also Gulf War Illness, a problem affecting approximately 30% of veterans of the first Gulf War in 1990-1991, and perhaps equal numbers of soldiers in the current Middle East conflict. Many others who suffer from chronic, medically unexplained symptoms not satisfying full criteria for CFS may be labeled as having nonspecific chronic fatigue, chronic musculoskeletal pain, fibromyalgia, or other ailments. The cause of CFS is unknown. Because persistent fatigue can follow some viral infections, and is associated with various inflammatory (especially autoimmune) conditions, the focus of research into CFS has been to investigate possible viral or immune causes. Numerous reports of viruses (most prominently HTLV-II) or immune biomarkers have been advanced over the years, yet none have withstood the test of replication. In October 2009, a new virus claim appeared: xenotropic murine leukemia virus-related virus or XMRV. This retrovirus, a relative of the murine leukemia virus (MLV) family, had first been identified in a small number of human prostate cancers. In the journal Science, Lombardi and colleagues reported successful PCR amplification of XMRV gag sequences from peripheral blood mononuclear cells in 68/101 CFS patients and only 8/218 controls. Furthermore, in some positive cases anti-XMRV antibodies could be detected in the serum, and cell-cell transfer of XMRV could also be demonstrated by co-culture. In September 2010, a second report by Lo and colleagues that appeared in the Proceedings of the National Academy of Sciences USA provided support for a role for a retrovirus by identifying MRV-like gag sequences in 32/37 CFS patients and only 3/44 controls. However, the identical XMRV-specific gag primers used by Lombardi tested negative in CFS in the study of Lo, thus on closer inspection this by no means could be considered a replication. In addition to the high prestige of the journals in which these reports were published, the authors themselves included well known scientists from the Food and Drug Administration, Harvard Medical School, and National Institutes of Health. This all served to add gravitas to the claim. For many sufferers of CFS, the concept that a new retrovirus was the culprit was extremely attractive. It offered a simple, clear and reasonable explanation for their symptoms; provided reassurance that they had a true illness and not a psychological condition; and generated new hope that effective therapy could be quickly found. Indeed, anecdotal reports of success with antiretrovirals have recently appeared in such places as the Wall Street Journal. In this issue of the Annals of Neurology, Schutzer and colleagues searched for evidence of XMRV in the cerebrospinal fluid of 43 patients with CFS, based on the reasonable hypothesis that, if a retrovirus is responsible for CNS infection, it might be revealed more easily in cerebrospinal fluid than in peripheral blood. The study was well-performed, employing the identical primers used by Lombardi and also co-culture, but results were dramatically negative. As this issue of the Annals goes to press, at least seven other reports from various regions in the US, Europe, and Asia have now been unable to find any evidence for XMRV or MLV involvement in CFS (summarized by Satterfield, et al.). Perhaps not surprisingly, these negative reports attracted less attention in the lay media than did the earlier positive claims. Although it is possible that subtle technical differences in the protocols permitted detection of pathogenic retroviruses by a few groups but not by many others, or that CFS is caused by a retrovirus only in a few isolated locations, a far more likely explanation is that the original positive findings represented false-positives, perhaps due to laboratory contamination. The confluence of the Internet, the hope for a simple and correctible answer to a common, mysterious and