Vagus nerve infection hypothesis
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"Evidence" section needs improvement (see Discussion) (unknown date)
The Vagus Nerve Infection Hypothesis (VNIH) proposes that, in some individuals, the symptoms of chronic fatigue syndrome (CFS) are caused by an infection in or around the vagus nerve, the longest nerve of the autonomic nervous system in the human body.
The vagus nerve, also called the tenth cranial nerve, starts in the brain and runs down the trunk of the body, with branches that innervate all of the major organs. It is responsible for the sickness response, an involuntary response characterized by fatigue, fever, myalgia, depression, and other symptoms that are often observed in patients with CFS.
Theory[edit | edit source]
As explained by Dr. Michael VanElzakker: "The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologically exaggerated version of normal sickness behavior that can occur when sensory vagal ganglia [structures containing a number of nerve cell bodies] or paraganglia [non-nerve cells that surround nerves] are themselves infected with any virus or bacteria.... [The] glial cells [cells that support and protect neurons] can bombard the sensory vagus nerve with proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated and intractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagus nerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen." The neuroimmune cells whose job is to protect the nerve, such as mast cells and glial cells, can sense an infectious agent and become activated, in turn signaling the vagus nerve to tell the brain there is an infection present, causing a systemic reaction.
VanElzakker believes that any infectious agent with an affinity for nerve tissues can cause a vagus nerve infection, including HHV-6, Epstein-Barr virus, Varicella zoster virus, chickenpox, certain kinds of enteroviruses and even borrelia, the bacterium that causes Lyme disease. He thinks this could explain why no single infective agent has been isolated as the cause of CFS, even though all of these agents have been associated with disease.
To test his hypothesis, VanElzakker is using a combined MRI and PET scan with radio labeled antibodies to look for "increased cellular activity in the brain stem in a place called the nucleus of the solitary tract, which is where about 80 percent of these sensory vagus nerve fibers have their cell bodies...The idea is that if we can see extra signal there, there’s more activity there in Chronic Fatigue Syndrome patients than there is in healthy people, that would be evidence that there’s an exaggerated signal coming from the vagus nerve into the brain." In addition, he suggests that one possibility is vagus nerve biopsy samples from CFS patients who have died prematurely from other causes. However, given the size and highly intricate branching of the vagus nerve, direct evidence of infection would be difficult to demonstrate.
Evidence[edit | edit source]
Indirect evidence is discussed at length in the hypothesis paper. Direct evidence of viral infection in the vagus nerve would be very difficult to obtain because the entire vagus nerve cannot be removed to be biopsied.
Treatment[edit | edit source]
If this theory proved correct, possible treatment approaches might include:
- Antiviral treatments - potential problems with antivirals are that these drugs would need to be a broad spectrum antiviral because a specific virus may not be identified and that antiviral drugs tend not to be effective on the vagal paraganglia. Dr. Jose Montoya and Dr. Martin Lerner, have published studies suggesting that IV valganciclovir therapy may be effective for the subset of CFS patients suspected of having elevated IgG for EBV. Lerner also included patients with elevated IgG for CMV. Both Montoya and Lerner have shown that longer treatment terms (>6 months) have achieved greater success than short-term antiviral therapy. Rodent studies have shown that the antiviral Famvir (famciclovir) penetrates peripheral nerve ganglia better than other antivirals (e.g., Thackray & Feld 1996 J Infect Dis 173; Thackray & Feld 1998 Antimicrob Agents & Chemother 42), which makes it an attractive option if symptoms are driven by latent or active herpesvirus infection of peripheral vagus ganglia.
- Glial cell inhibitors - such as lbudilast, an anti-inflammatory drug used mainly in Japan for asthma, stroke, and treatment of neuropathic pain as an adjunct with opioids. Ibudilast crosses the blood-brain barrier and suppresses glial cell activation.
- Vagus nerve stimulation - involves delivering electrical impulses to the vagus nerve via a medical device. Use is currently reserved as an adjunctive treatment for certain types of intractable epilepsy and treatment-resistant depression, but it is being researched as a viable treatment for many other conditions, including ME, CFS, and fibromyalgia. Vagus nerve stimulation promotes the anti-inflammatory effects of the motor (efferent) vagus nerve. In the case of the vagus nerve infection hypothesis, it may also regulate exaggerated sensory (afferent) signaling.
- Mestinon (Pyridostigmine) - a drug that blocks the enzymatic breakdown of acetylcholine, which is the primary neurotransmitter of the vagus nerve, especially the parasympathetic/ motor/ efferent branch. Mestinon is frequently prescribed for POTS, especially to improve tachycardia, and can work synergistically with vagus nerve stimulation.
- Celebrex - Celebrex is a COX2 inhibitor, which blocks an enzyme that is part of the production of prostaglandins. When glial cells become activated, they produce neuroexcitatory mediators - molecules that turn on nerve cells. According to the vagus nerve infection hypothesis, infection of vagus nerve ganglia causes activation of associated glial cells, which in turn overly-excite the vagus nerve via these mediators. Prostaglandins are one of these neuroexcitatory mediators, along with proinflammatory cytokines, nitric oxide, reactive oxygen species, glutamate, and nerve growth factor. Beside the antiinflammatory mechanism of COX2 inhibition, herpesviruses upregulate COX2 to aid with its own replication (e.g., Reynolds & Enquist 2006 Rev Med Virol 16).
Notable studies[edit | edit source]
- 2013, Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis.
- 2016: Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome
See also[edit | edit source]
Learn more[edit | edit source]
- 2013, CFS: a herpesvirus infection of the vagus nerve?
- 2013, One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome
- 2014, Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)
- 2015, Chronic Fatigue from Vagus Nerve Infection a Psychoneuroimmunological Hypothesistranscript of podcast
- 2016, Vagus Nerve Infection Hypothesis and the Driscoll Theory
- The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS
- Twitter #VNIH
References[edit | edit source]
- Van Elzakker, MB (Sep 2013), "Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis" (PDF), Medical Hypotheses, 81 (3): 414-423, doi:10.1016/j.mehy.2013.05.034, PMID 23790471
- Medscape (Aug 17, 2015), Vagus Nerve Anatomy
- HHV-6 Foundation (Jul 13, 2013), CFS: a herpesvirus infection of the vagus nerve?
- Ykelenstam, Yasmina; Van ElZakker, MB (Dec 8, 2015), "Harvard Neuroscientist Dr. Michael Van ElZakker: Chronic Fatigue Vagus Nerve Link", The Low Histamine Chef (interview)
- Lerner, AM; Beqaj, S; Fitzgerald, JT; Gill, K; Gill, C; Edington, J (2010), "Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome", Virus adaptation and treatment, 2: 47-57
- Montoya, JG; Kogelnik, AM; Bhangoo, M; Lunn, MR; Flamand, L; Merrihew, LE; Watt, T; Kubo, JT; Paik, J; Desai, M (2013), "Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.", Journal of Medical Virology, 85: 2101-9, doi:10.1002/jmv.23713
- "Ibudilast". Wikipedia. Sep 24, 2018.
- ProHealth Website (Feb 16, 2016), Vagus Nerve Stimulation, Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)
- Barnden, LR; Kwiatek, R; Crouch, B; Burnet, R; Del Fante, P (2016), "Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome", NeuroImage: Clinical, 11: 530-537, doi:10.1016/j.nicl.2016.03.017
- "CFS: a herpesvirus infection of the vagus nerve? | HHV-6 Foundation | HHV-6 Disease Information for Patients, Clinicians, and Researchers | Apply for a Grant". hhv-6foundation.org. Jul 23, 2013. Retrieved Oct 14, 2018.
- Johnson, Cort (Dec 28, 2013). "One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome - Simmaron Research". Simmaron Research. Retrieved Oct 14, 2018.
- Johnson, Cort (Feb 14, 2014). "Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS) - Simmaron Research". Simmaron Research. Retrieved Oct 14, 2018.
- Ykelenstam, Yasmina (Dec 7, 2015). "Yasmina Ykelenstam's Healing Histamine Podcast: Chronic Fatigue from Vagus Nerve Infection: A Psychoneuroimmunological Hypothesis". thelowhistaminechefpodcast.libsyn.com. Retrieved Oct 14, 2018.
- "Harvard neuroscientist Dr. Michael Van ElZakker: chronic fatigue vagus nerve link | Healing Histamine". Healing Histamine. Dec 8, 2015. Retrieved Oct 14, 2018.
- lassesen (Mar 13, 2016). "Vagus Nerve infection hypothesis and the Driscoll Theory". CFS Remission. Retrieved Oct 14, 2018.
chronic fatigue syndrome (CFS) - A controversial term, invented by the U.S. Centers for Disease Control, that generally refers to a collection of symptoms as “fatigue”. There have been multiple attempts to come up with a set of diagnostic criteria to define this term, but few of those diagnostic criteria are currently in use. Previous attempts to define this term include the Fukuda criteria and the Oxford criteria. Some view the term as a useful diagnostic category for people with long-term fatigue of unexplained origin. Others view the term as a derogatory term borne out of animus towards patients. Some view the term as a synonym of myalgic encephalomyelitis, while others view myalgic encephalomyelitis as a distinct disease.
antibody - Antibodies or immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.