Vagus nerve infection hypothesis

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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.

In 2013, Michael VanElzakker, then a graduate student at Tufts University and now a postdoctoral researcher at Harvard Medical School, published the hypothesis.[1]

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.[2] 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.[3]s

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.[1]

In 2015, VanElzakker stated he believed that any infectious agent with an affinity for nerve tissues can cause a vagus nerve infection, including Human herpesvirus 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.[4]

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."[4] In addition, he suggests that one possibility is vagus nerve biopsy samples from CFS patients who have died prematurely from other causes.[3] 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]

VNIH has been substantiated by researches at University Medical Center Hamburg Eppendorf in a 2023 study where they "performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes".

Treatment[edit | edit source]

If this theory proved correct, possible treatment approaches might include:

Antiviral treatments[edit | edit source]

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.[3] 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.[5][6] 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[edit | edit source]

Drugs such as ibudilast (brand names Ketas or Pinatos or in Japan), an anti-inflammatory drug used for over 20 years in Japan, mostly for asthma and post-stroke dizziness.[7] Ibudilast can be combined with opioids to reduce chronic nerve pain.[7] Ibudilast is also a phosphodiesterase (PDE) inhibitor, and crosses the blood-brain barrier and suppresses glial cell activation.

Vagus nerve stimulation[edit | edit source]

Vagus nerve stimulation (VNS) 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 some VNS devices have recently been approved for migraine, and is being researched as a viable treatment for many other conditions, including ME, CFS, and fibromyalgia.[8][9][10] 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[edit | edit source]

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[edit | edit source]

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).

Ampligen[edit | edit source]

Ampligen (Rintatolimod) is a drug that stimulates the production of natural interferon.

Talks and interviews[edit | edit source]

Notable studies[edit | edit source]

  • 2016, Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome[11] - (Full text)
  • 2013, Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis[1] - (Full text)

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 VanElzakker, MB (September 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.
  2. Medscape (August 17, 2015). "Vagus Nerve Anatomy".
  3. 3.0 3.1 3.2 HHV-6 Foundation (July 13, 2013). "CFS: a herpesvirus infection of the vagus nerve?".
  4. 4.0 4.1 Ykelenstam, Yasmina; VanElzakker, MB (December 8, 2015). "Harvard Neuroscientist Dr. Michael VanElzakker: Chronic Fatigue Vagus Nerve Link". The Low Histamine Chef.
  5. 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.
  6. 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.
  7. 7.0 7.1 Rolan, P; Hutchinson, MR; Johnson, KW (December 2009). "Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease". Expert Opinion on Pharmacotherapy. 10 (17): 2897–2904. doi:10.1517/14656560903426189. ISSN 1465-6566.
  8. Traianos, E.; Dibnah, B.; Lendrem, D.; Clark, Y.; Macrae, V.; Slater, V.; Wood, K.; Storey, D.; Simon, B.; Blake, J.; Tarn, J. (June 1, 2021). "Ab0051 the Effects of Non-Invasive Vagus Nerve Stimulation on Immunological Responses and Patient Reported Outcome Measures of Fatigue in Patients with Chronic Fatigue Syndrome, Fibromyalgia, and Rheumatoid Arthritis". Annals of the Rheumatic Diseases. 80 (Suppl 1): 1057–1058. doi:10.1136/annrheumdis-2021-eular.1999. ISSN 0003-4967.
  9. Molero-Chamizo, Andrés; Nitsche, Michael A.; Bolz, Armin; Andújar Barroso, Rafael Tomás; Alameda Bailén, José R.; García Palomeque, Jesús Carlos; Rivera-Urbina, Guadalupe Nathzidy (January 2022). "Non-Invasive Transcutaneous Vagus Nerve Stimulation for the Treatment of Fibromyalgia Symptoms: A Study Protocol". Brain Sciences. 12 (1): 95. doi:10.3390/brainsci12010095. ISSN 2076-3425.
  10. Kutlu, Nazlı; Özden, Ali Veysel; Alptekin, Hasan Kerem; Alptekin, Jülide Öncü (March 2, 2020). "The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome". BioMed Research International. 2020: e8656218. doi:10.1155/2020/8656218. ISSN 2314-6133.
  11. 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.