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Extraordinary claims require extraordinary evidence.

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MESSAGE FROM THE EDITOR
Extraordinary Claims Require
Extraordinary Evidence
C
hronic 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.1 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.2 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-II3) 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.4 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.5 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.6
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.7 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.).8 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.9
The confluence of the Internet, the hope for a simple and correctible answer to a common, mysterious and
C 2011 American Neurological Association
V
A9
ANNALS
of Neurology
TABLE: CDC Criteria for Diagnosis of Chronic
Fatigue Syndrome
A case of chronic fatigue syndrome is defined
by the presence of:
1. Clinically evaluated, unexplained, persistent or
relapsing fatigue that is of new or definite onset;
is not the result of ongoing exertion; is not
alleviated by rest; and results in substantial
reduction of previous levels of occupational,
educational, social, or personal activities; and
2. Four or more of the following symptoms that
persist or recur during six or more consecutive
months of illness and that do not predate the fatigue:
their peers, either in peer-reviewed publications or at
platform presentations at meetings. The lay media also
needs to be equally cautious, and strive not to disseminate false hope that ultimately frustrates vulnerable people searching for answers to terrible problems.14 It is not
possible, or even desirable, to police scientific ideas and
theories, but as journal editors we have a responsibility
to do everything possible to insure that data appearing in
our pages will stand the test of time.
Stephen L. Hauser, MD
S. Claiborne Johnston, MD PhD
Editors
Self-reported impairment in short-term
memory or concentration
Sore throat
Tender cervical or axillary nodes
Muscle pain
Multijoint pain without redness or swelling
Headaches of a new pattern or severity
Unrefreshing sleep
References
1.
Straus SE. Chronic Fatigue Syndrome. In Harrison’s Principles of
Internal Medicine 17th Ed. New York: McGraw Hill, 2008.
2.
Institute of Medicine: Committee on Gulf War and Health: Health
Effects of Serving in the Gulf War. Update 2009. The National
Academies Press, Washington DC.
3.
DeFreitas E, Hilliard B, Cheney PR, et al. Retrovral sequences
related to human T-lymphotropic virus type II in patient with
chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci
USA 1991;88:2922–2926.
4.
Lombardi VC, Rscetti FW, Gupta JD, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic
fatigue syndrome. Science 2009;326:585.
5.
Lo S-C, Pripuzova N, Li B, et al. Detection of MLV-related virus
gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci USA 2010;
107:15874.
6.
Marcus AD. The Puzzle of Chronic Fatigue. The Wall Street Journal. March 5, 2011. See also Marcus AD: New Hope in Fatigue
Fight. The Wall Street Journal August 24, 2010.
7.
chutzer SE, et al: CSF probe of chronic fatigue patients for multiple ubiquitous viruses and XMRV. Ann Neurol 2011;69:735–738.
8.
Satterfield BC, Garcia RA, Jia H, et al. Serologic and PCR testing
of persons with chronic fatigue syndrome in the united States
shows no association with xenotropic or polytropic murine leukemia virus-related viruses. Retrovirol 2011;8:12.
9.
Kaiser J. Chronic fatigue syndrome. Studies point to possible contamination in XMRV findings. Science 2011;331:17.
10.
Khan O, Filippi M, Freedman MS, et al. Chronic cerebrospinal
venous insufficiency and multiple sclerosis Ann Neurol 2010;67:
286–90.
11.
Doepp F, Paul F, Valdueza JM, et al. No cerebrocervical venous
congestion in patients with multiple sclerosis Ann Neurol 2010;68:
173–83.
12.
Baracchini C, Perini P, Calabrese M, et al. No evidence of chronic
cerebrospinal venous insufficiency at multiple sclerosis onset. Ann
Neurol 2011;69:90–9.
13.
Johnston SC, Hauser SL. Diagnosis and prognosis unclear for
scientific manuscripts. Ann Neurol 2011;69:A9–A10.
14.
Johnston SC, Hauser SL. The challenge of publishing newsworthy
epidemiology. Ann Neurol 2010;68:A8–A10.
Postexertional malaise lasting 24 h
CDC, US Centers for Disease Control and Prevention.
untreatable problem, and well-organized patient advocacy
groups, can create a ‘‘perfect storm’’ in which preliminary
or uncertain claims are rapidly disseminated and acquire
momentum well beyond that justified by the strength of
evidence. A similar situation, discussed earlier in these
pages, followed preliminary reports that potentially correctible venous abnormalities (chronic cerebro-spinal
venous insufficiency or CCSVI) might underlie multiple sclerosis (MS). Sadly, repeated failures to replicate
these original claims using carefully designed methodologies have not yet reduced the considerable attention
and public interest in CCSVI, nor eliminated unsound
and dangerous attempts to ‘‘repair’’ abnormal veins
in MS patients (outrageously called ‘‘the liberation
procedure’’).10–12
A few simple steps can go a long way towards
reducing the number of scientific claims that are not ultimately validated. Replications should be carried out prior
to publication.13 Reports of failures to replicate should
be published expeditiously, and when possible by the
same journal that published the original claim. Scientists
should not introduce new results to the press before the
underlying data can be reviewed in adequate detail by
A10
Volume 69, No. 4
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