Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?
Introduction
Chronic Fatigue Syndrome (CFS), a debilitating disorder that affects over one million people in the US alone [1], has stumped researchers for decades. Some researchers have found immunological [2], [3], [4] and endocrine [4], [5] abnormalities in CFS patients, providing evidence that CFS is a physiological illness, rather than a psychiatric problem. However, research in these areas has produced inconsistent results, and no current laboratory tests can diagnose CFS [4]. Many researchers have focused on the possibility that a viral infection causes the disease, but no one virus has been found to be both present in CFS patients and absent in normal individuals [4]. As a result, CFS has been without a unifying theory that could explain the illness, greatly hampering research and slowing progress on potential treatments.
This article sets forth a model of CFS that unifies most of the previous findings on CFS. It proposes that CFS results when a neurotropic (tending to attack the nervous system) herpesvirus reactivates in the peripheral ganglia without spreading to other organs, such as the skin, where the infection can be more easily diagnosed. Numerous forms of neurotropic herpes without skin involvement have been previously documented in the medical literature but can be extremely difficult to diagnose [6], potentially explaining why a viral cause of CFS has been elusive. Dysfunction of the peripheral nervous system (PNS) can take a wide variety of forms, which could explain why CFS presents with a diversity of symptoms. As explained later in this article, infection of the PNS could also explain the chronic nature of CFS, as well as why CFS is almost never fatal.
The article begins by briefly reviewing evidence that viral infections are the cause of CFS, and then discusses the reasons why a neurotropic herpesvirus, probably varicella-zoster virus (VZV), is likely to be the most frequent cause of CFS. It then gives reasons to think that the PNS is the site of infection in most cases of CFS. Treatments for herpes infections are already available, and these are briefly discussed, as are implications of this theory for research.
Section snippets
Herpesviruses as the cause of CFS
There are a number of reasons why viral infection has long been suspected as the cause of CFS. The large majority of patients report that their symptoms started suddenly with a flu-like illness [7]. It is also known that some viruses, especially polio, can produce a syndrome of permanent post-infective fatigue [8], [9]. Many people with CFS also have unusual immunological activity, such as altered forms of the antiviral enzyme RNase L [2] and low levels of natural killer cells [3]; these
Which herpesvirus causes CFS?
Initially, researchers suspected that CFS was caused by chronic infection with EBV since mononucleosis also causes prolonged fatigue. Furthermore, many CFS sufferers had antibodies suggestive of an active EBV infection [12]. However, the theory that Epstein-Barr causes CFS fell out of favor when it was learned that some healthy people had EBV antibody profiles similar to those seen in CFS patients [19]. Research then focused on the possibility that a new virus caused CFS. A newly discovered
Properties of VZV infection
VZV infections are typically acquired in childhood in the form of chickenpox. After a chickenpox infection, VZV establishes latent infections in the peripheral ganglia [25], [26], where, as explained later in this article, viral particles are partially shielded from the immune system and therefore cannot be totally eradicated. The large majority of adults are carrying such latent VZV infections [27]. In about 15–30% of unimmunized adults, VZV eventually reactivates in the sensory ganglia and
The peripheral nervous system (PNS) as the site of infection in CFS
The peripheral ganglia are clusters of nerve cell bodies located outside the spinal cord and near major organs. Divisions of the PNS that contain peripheral ganglia include the autonomic nervous system (ANS) and the sensory nervous system. As with other parts of the nervous system, the peripheral ganglia are “immunoprivileged” – that is, shielded from many of the components of the immune system. As a protection against infection, the nervous system relies heavily (although not exclusively) on
Possible relationships between CFS and fibromyalgia
Many patients diagnosed with CFS are also diagnosed with fibromyalgia, a condition involving muscle pain. A theory has recently been put forth in which fibromyalgia results from trauma or infection of the sensory ganglia [57]. I speculate that the muscle pains seen in fibromyalgia may be caused, at least in some cases, by VZV infection of the sensory nerves enervating the muscles. In this model, patients whose infection was primarily in the ANS would have the severe fatigue seen in CFS,
Potential treatments for CFS
If VZV does indeed cause CFS, this would suggest several treatments for CFS, as well as ways of possibly preventing CFS. Antivirals of the acyclovir class, including valacyclovir, show some efficacy against VZV if given in high doses, and as noted previously, have shown utility against CFS in preliminary studies.
In CFS patients who show high levels of antibodies to cytomegalovirus, an immunotropic herpesvirus, improvement has not been shown with acyclovir class drugs, but has been shown with a
Putting the pieces together: a model of CFS
To summarize, the theory being set forth here is that CFS begins when a neurotropic herpesvirus, most likely VZV, reactivates in the ganglia of the PNS. Co-infection with other herpesviruses might contribute to this reactivation of VZV. Some people might clear the infection easily and never seek medical attention; others would develop easily identifiable symptoms such as facial paralysis or blistering rash, and receive diagnoses such as Bell’s palsy or shingles, respectively. Whether specific
Implications of this theory for research
Testing the theory that VZV causes CFS will pose challenges. As noted previously, serologic tests for herpesvirus antibodies often produce confusing results, because virtually all adults have been infected with these viruses in the past. Finding definitive evidence of herpes infection is especially difficult when the infection is confined to the nervous system, since signs of such infection are often not present in the blood, and biopsies of the nervous system are generally too damaging to
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