Elsevier

Medical Hypotheses

Volume 73, Issue 5, November 2009, Pages 728-734
Medical Hypotheses

Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?

https://doi.org/10.1016/j.mehy.2009.04.043Get rights and content

Summary

This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS. Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS. A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia. The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.

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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