ME/CFS rare brain infection from normally benign virus

Discussion in 'Fibromyalgia Main Forum' started by tansy, Aug 13, 2008.

  1. tansy

    tansy New Member

    Is chronic fatigue syndrome caused by a rare brain infection of a common, normally benign virus?

    Bjorn Grinde(*)
    * National Institute of Public Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway
    Tel.: +47 22042420; fax: +47 22042447.


    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


    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

    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 ob- served 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
    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

    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

    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

    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 obtain- ing
    older samples from the odd patient that at some time had spinal fluid tapped.


    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

    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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