Medical Hypotheses Vol. 71, #2, pp 270-274 August 2008
http://www.sciencedirect.com/science/journal/03069877
Is chronic fatigue syndrome caused by a rare brain infection of a common,
normally benign virus?
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Bjorn Grinde(*)
* National Institute of Public Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway
Tel.: +47 22042420; fax: +47 22042447. E-mail address: bjgr@fhi.no
Received 15 February 2008; accepted 10 March 2008
Summary
Chronic fatigue syndrome (CFS) is a disabling disease of unknown aetiology. A
variety of factors have been suggested as possible causes. Although the
symptoms and clinical findings are heterogeneous, the syndrome is
sufficiently distinct, at least in relation to the more obvious cases, that a
common explanation seems likely. In this paper, it is proposed that the
disease is caused by a ubiquitous, but normally benign virus, e.g., one of
the circoviruses. Circoviruses are chronically present in a majority of
people, but are rarely tested for diagnostically. Normally these viruses do
not penetrate the blood-brain barrier, but exceptions have been reported, and
related viruses cause disease in the central nervous system of animals. The
flu-like illness that often precedes the onset of CFS may either suppress
immune function, causing an increased viremia, and/or lower the blood-brain
barrier. In both cases the result may be that a virus already present in the
blood enters the brain. It is well known that zoonotic viruses typically are
more malignant than viruses with a long history of host-virus evolution.
Similarly, a virus reaching an unfamiliar organ may cause particular
problems.
Introduction
Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis
(ME), is characterised by a severe debilitating fatigue lasting for at least
6 months (reviewed in [1-4]). The worldwide prevalence may be as high as
0.5%. The pathological findings include immune system abnormalities such as
chronic immune activation, dysfunction of the hypothalamic-pituitary-adrenal
(HPA) axis, brain abnormalities, emotional stress, and evidence of infectious
agents.
The cause of CFS has been attributed to a variety of factors. Although an
infection of the central nervous system (CNS) would seem likely, the lack of
affirmative findings has led to a preference for other theories, including:
psychological stress, disturbances of immunity, endocrine control, oxidative
stress, cardiovascular homeostasis, and systemic infections. Not
surprisingly, genetic constitution also appears to be important [5,6].
A majority of cases report that the onset of CFS was preceded by a
'flu-like' illness. A popular theory is that the infectious agent causing
this illness triggers a chronic activation of the immune system, which
subsequently leads to CFS. Thus, the condition may be caused by a virus in
the absence of any actual infection of the CNS.
Emotional stress may be relevant as it reduces the efficiency of the immune
system, and because it leads to activation of the HPA-axis. In fact, some
practitioners suggest that the condition is solely due to psychosomatic
factors and thus should be labelled as a psychiatric disorder. Although
mental problems are highly relevant in connection with fatigue, it seems
likely that the extreme state observed in many CFS patients have a more
distinct cause; particularly as many of the patients were highly active and
well-adjusted prior to the onset of disease.
With a condition such as CFS, it is inherently difficult to distinguish
between cause and consequences. Yet, an actual infection of the CNS offers a
parsimonious theory. The remaining pathology can convincingly be ascribed as
secondary effects. For example, if the virus causes damage in the
hypothalamus, an effect on the HPA-axis would be expected, as well as a
subsequent impact on immune parameters.
In order to support the present hypothesis one should ideally detect one (or
a few) infectious agents in the spinal fluid in a substantial number of
patients. So far this has not been possible. The present article suggests a
theory that would explain the various observations relating to CFS, including
the epidemiological data and the fact that no convincing agent has yet been
described. Moreover, a strategy for testing the hypothesis is indicated.
Evidence for CNS infection by a common virus
A variety of microbes have been implicated in CFS, including Epstein-Barr
virus, cytomegalovirus, enteroviruses, parvovirus B19, Coxiella burnetii and
Chlamydia pneumoniae [1]. Some of these agents are found in the spinal fluid,
and could exert their effect there, while others are typically found
elsewhere in the patients and might affect the CNS indirectly. Several
outbreaks of CFS (or CFS-related disorders) have been described, and in some
cases particular infectious agents, such as C. burnetii and enteroviruses,
were assumed to be responsible [1,7,8]. Yet, the idea of a CNS infection
causing CFS is not advocate in recent reviews [14]. The problem is lack of
consistent finding, and lack of obvious markers, or symptoms, of infection in
the brain.
The present hypothesis suggests that CFS is caused by an infection of the
CNS. The lack of substantial proof indicates that the putative agent is more
likely to be a virus than a bacteria. The hypothesis furthermore suggests
that the culprit is commonly present in humans, but only rarely penetrates
into the brain.
Below are listed observations that are congruent with this theory, and thus
may be considered as evidence in favour.
1. The disease is associated with a disturbance
of brain function. It is well known that virus
infections of the brain can cause various
behavioural changes.
2. Several viruses that normally infect other
organs, occasionally penetrate into the brain.
At least two, hepatitis C virus [9,10] and
Nipah virus [11], have been reported as the
causative agents in chronic or disabling fati-
gue of select patients. It is possible that dif-
ferent viruses can cause fatigue, however, it
is also conceivable that the actual cause in
these patients was an unknown virus that
crossed the blood-brain barrier along with
the observed virus. Hepatitis C is rare in
young people except for drug abusers, and
Nipah virus is a rare zoonotic virus. These
viruses are therefore unlikely to be responsi-
ble for more than a few CFS cases.
3. If CFS had been a normal consequence of the
infection of one or a few rare viruses, one
would expect a different epidemiological pat-
tern. That is, the cases should cluster along
possible infectious pathways. Most cases do
not. The epidemiology fits better with the
notion that the event leading to the disease
is an unexpected crossing of the blood-brain
barrier of a virus present in most people.
4. Several outbreaks of CFS-like disease have
been described [8]. These outbreaks could be
explained by the introduction of a particularly
pathogenic strain of an otherwise common and
mostly benign virus. It is interesting to note
that most of the reported epidemics date back
50 years or more. It seems likely that several
viral strains of common viruses, which previ-
ously were endemic to particular regions, at
some time started to spread worldwide. In
the case of circoviruses, for example, the
genetic variability within a local population is
close to the variability observed worldwide
[12,13]. Presumably, the genetic diversity
was originally due to independent viral prolif-
eration in different regions. Thus the present
local variability is best explained by a recent
worldwide mix of viral strains.
5. If present in the majority of the population, it
implies that the causative virus is normally
benign. However, even if the virus does not
cause overt symptoms when circulating in the
blood, it may very well do so upon entering an
organ for which it is less adapted. The situa-
tion would be a parallel to the observation
that the more severe viral diseases (e.g.,
HIV, Ebola, SARS and bird-flu) are caused by
zoonotic viruses. Viruses with a long term
relationship with a host, or in this case cer-
tain organs, generally develop a more benev-
olent profile.
6. A number of viruses fit the description of high
prevalence, continuous replication and nor-
mally benign nature; including members of
the Anellovirus genus of circoviruses (TTV,
TTMV and TTMLV) and the polyomaviruses
(BK and JC). Circoviruses and polyomaviruses
are normally associated with other organs,
yet can penetrate the brain and replicate
there [14,15]. Polyomaviruses are known to
cause clinical symptoms in the brain [15]. Cir-
coviruses have no know pathogenicity in
humans, but animal circoviruses can infect
the brain and cause disease, e.g., post-
weaning multisystemic wasting syndrome in
pigs, a condition with certain similarities to
CFS [16].
7. CFS is typically preceded by an acute systemic
infection, or by severe stress. These condi-
tions may cause a virus present in the blood
to enter the CNS, either by suppressing
immune function, and thus increasing the
viral titre, or by weakening the blood-brain
barrier. It has been shown that immune sup-
pression causes an increase in the serum con-
centration of circoviruses [17].
8. Viruses affecting the CNS are reputedly diffi-
cult to diagnose. Even in cases of encephalitis
or meningitis where there is reasonable evi-
dence to suggest a viral aetiology, positive
findings are obtained only in a fraction of
cases. The problem may be partly related to
not testing for the right virus, but most likely
it also reflects that the relevant viruses may
cause clinical symptoms in the brain even if
their replication is low, and thus less likely
to be detected. In the case of CFS, spinal fluid
is not routinely tested for any virus; and even
in cases where standard viral diagnostics are
attempted, it is unlikely to yield positive
results.
9. Circoviruses or polyomaviruses have, to the
author's knowledge, never been tested in
connection with CFS. These viruses are tuned
to keep a low profile towards the immune sys-
tem. If present in the brain, they are likely to
have a low copy number and not cause overt
signs of infection. Moreover, the brain is less
likely to initiate an obvious immunological
response than are other organs [18]. Yet,
when carefully examined, some markers sug-
gestive of infection are found in the spinal
fluid of CFS patients [19].
10. Mothers of adolescents with CFS more often
display related symptoms than do the fathers
[20]. This could be explained by the transfer
of certain strains of virus during pregnancy
or birth, which presumably happens in the
case of circoviruses and polyomaviruses.
11. Treatment with the broad-spectrum antiviral
agents interferon and Ribavirin have been
reported to improve the condition of CFS
patients [7].
12. Although full recovery from CFS is rare,
improvement can be sufficient to suggest an
average duration of 57 years [21]. The per-
sistent nature of the disease would be in line
with the observation that viruses, such as cir-
coviruses and polyomaviruses, typically are
chronically replicating in the host. Yet, these
viruses are partly controlled by the immune
system, thus a reduction or clearance of virus
in the brain is possible.
Relevant viruses
Circoviruses and polyomaviruses fit with the above observations, but the
condition may equally well be caused by a range of other viruses.
Picornaviridae, which includes enteroviruses, is a large family of viruses
commonly present in the healthy population [22]; enteroviruses have been
implicated in CFS [7], and several subtypes are known to occasionally infect
the brain. Members of the herpes family and the parvovirus B19 have a similar
profile [1,23]. Over the last few years, several novel viruses have been
discovered. It seems likely that additional unknown viruses are commonly
present in humans. In other words, the fact that no common viral cause has so
far been described for CFS may very well be due to a lack of testing.
Most of the observations listed are also compatible with alternative
explanations as to the pathology of CFS. Taken together, however, the author
considers the evidence sufficiently indicative to warrant further
examination.
Testing the hypothesis
An obvious first possibility is to look for the specifically mentioned
viruses in spinal fluid using a sensitive PCR. A blood sample alone have
minimal value if, as hypothesized, one is dealing with a common virus.
Ideally a blood sample taken at the same time should be available in order to
evaluate whether a positive finding in the spinal fluid could reflect
contamination from blood.
Preferably one should analyse samples taken soon after the initiation of
disease. It is conceivable that the virus cause damage, and is subsequently
cleared from the brain. The damage may heal only slowly. It is, however,
likely that the virus is continuously present. In the latter case, there
should be hope of finding the virus regardless of when the sample is
obtained.
The next step, as to testing the hypothesis, would be to broaden the scope of
virus search. Recent developments with microarrays allows for the screening
of all known vertebrate-related viruses, as well as other microbes,
simultaneously in clinical samples [24]. The method relies on unspecific
amplification of RNA/DNA and subsequent probing of the obtained nuclei acids
onto microarrays containing single stranded DNA probes that capture viral
sequences.
In order to stand an even better chance of finding novel viruses of limited
homology to known viruses, it is possible to run the amplified nucleic acids
on a pyrosequencing machine. Pyrosequencing allows for up to 400 000 sequence
fragments of some 300 basepairs to be obtained from one sample in a single
operation. The obtained sequences would subsequently be examined by a
computer to look for possible homologies with known viral sequences. Even
viruses that have never been described are expected to have some genomic
regions with homology to known viral sequences.
Hopefully, it shall be possible to test the hypothesis in the near future.
The difficult part appears to be obtaining relevant samples. This is partly
because spinal punctuation is not carried out routinely in connection with
CFS patients, partly because of the bureaucratic difficulties in obtaining
older samples from the odd patient that at some time had spinal fluid tapped.
Discussion
The presence of certain virus(es) within the spinal fluid of CFS patients is
not sufficient to prove causality. If, however, the relevant virus is rare or
absent in samples from other patient groups, it would appear to be a likely
trigger. A more direct proof would be to develop antiviral treatment that
both remove the virus and improves the is sufficiently common for the
pharmaceutical industry to invest in developing novel therapy, or possibly a
vaccine.
Even in the absence of treatment, it is of great interest to establish a
causality. Besides the comfort for the patient of knowing what the problem
is, a viral connection would offer improved diagnostic opportunities.
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