​ 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 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 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.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. EvidenceIndirect 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. TreatmentIf 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.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.56 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.7 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 fibromyalgia8. 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). Ampligen - a drug that stimulates the production of natural interferon. Notable studies2013, Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis.12016: Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome9 2013, CFS: a herpesvirus infection of the vagus nerve?102013, One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome112014, Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)122015, Chronic Fatigue from Vagus Nerve Infection a Psychoneuroimmunological Hypothesis13transcript of podcast142016, Vagus Nerve Infection Hypothesis and the Driscoll Theory15The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS https://www.sciencedirect.com/science/article/abs/pii/S000632230500569X Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis Michael B. VanElzakker Tufts University Psychology, Massachusetts General Hospital Psychiatric Neuroscience, 490 Boston Avenue, Medford, MA 02155, USAarticle  infoArticle history:Received 25 July 2012Accepted 23 May 2013 abstractChronic fatigue syndrome (CFS) is an often-debilitating condition of unknown origin. There is a generalconsensus among CFS researchers that the symptoms seem to reflect an ongoing immune response, per-haps due to viral infection. Thus, most CFS research has focused upon trying to uncover that putativeimmune system dysfunction or specific pathogenic agent. However, no single causative agent has beenfound. In this speculative article, I describe a new hypothesis for the etiology of CFS: infection of the vagusnerve. When immune cells of otherwise healthy individuals detect any peripheral infection, they releaseproinflammatory cytokines. Chemoreceptors of the sensory vagus nerve detect these localized proinflam-matory cytokines, and send a signal to the brain to initiate sickness behavior. Sickness behavior is aninvoluntary response that includes fatigue, fever, myalgia, depression, and other symptoms that overlapwith CFS. The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologicallyexaggerated version of normal sickness behavior that can occur when sensory vagal ganglia or paragan-glia are themselves infected with any virus or bacteria. Drawing upon relevant findings from the neuro-pathic pain literature, I explain how pathogen-activated glial cells can bombard the sensory vagus nervewith proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated andintractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagusnerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen. The vagusnerve infection hypothesis offers testable hypotheses for researchers, animal models, and specific treat-ment strategies.  Elsevier Ltd. All rights reserved.IntroductionChronic fatigue syndrome (CFS) is an often-debilitating stateof constant intense exhaustion that is unmitigated by rest or sleep. A diagnosis of CFS is given in the absence of alternativediagnoses, and the United States Center for Disease Control def-inition of this syndrome is based entirely upon subjectivesymptom self-report1,2. Prognosis is poor3. The cause ofCFS is unknown and is the source of considerable contentiousdebate. Previous studies of CFS patients have reported a diversearray of viral and even bacterial agents (e.g.4–11), as well asmany  immune  system  abnormalities  (e.g.12,13).  These findings have led most researchers to assume a role for pathogen-induced immune system activation in CFS. However, inconsistent and contradictory results between (and even within) studies have left the field at a loss to explain the causal mechanisms. No single pathogen has emerged as the common etiological agent.In this article, I describe a hypothesis that integrates many ofthe general observations in CFS and explains some of the conflicting observations. Rather than continuing the search for one specific virus or bacteria as the root cause of CFS, this hypothesis focuses on thelocationof an infection, along the sensory (affer-ent) vagus nerve. The Vagus Nerve Infection Hypothesis (VNIH) of CFS is as follows: While the sensory vagus nerve normally signals the body to rest when it senses a peripheral infection, that fatigue signal is pathologically exaggerated when an infection is located on the vagus nerve itself. More specifically: Immune cells, including neuroimmune cells called glial cells ,sense infection and launch the same basic neuroexcitatory response regardless of infection type. When the glial cells that envelop the sensitive vagus nerve are activated by any viral or bacterial  infection,  their  neuroexcitatory  secretions  escalate afferent vagus nerve signaling, which is misinterpreted by the brain as evidence of a severe peripheral infection. The brain then initiates sickness behavior, which includes fatigue and many other CFS symptoms (see Key Terms Table). Because of the way that glial cell activation may persist in a pathological positive feedback loop (as it does in neuropathic pain conditions), these CFS symptoms can persist for many years. Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.mehy.2013.05.034⇑Tel.: +1 617 627 2526; fax: +1 617 627 3181.E-mail address:[email protected]Medical Hypotheses 81 (2013) 414–423Contents lists available atSciVerse ScienceDirectMedical Hypothesesjournal homepage: www.elsevier.com/locate/mehy Key Terms TableGlial cell: Neuroimmune cells that include astrocytes andoligodendrocytes in the central nervous system or satellite glial cells, Schwann cells, and enteric glial cells in the peripheral nervous system. Glial cells are in close proximity to nerve cells and release neuroexcitatory substances when they encounter a foreign pathogen. These substances include proinflammatory cytokines, glutamate, nerve growth factor, prostaglandin, nitric oxide, and reactive oxygen species Neurotropic virus: A virus that has particular affinity for nerve tissue. Herpes viruses are neurotropic, frequently associated with CFS, and are characterized by their tendency to lay latent in nerve tissue until reactivated by stress or illness. CFS symptoms often begin following a period of stress or illness Paraganglia: Ganglia of the sensory vagus nerve that are embedded in or near most trunk organs. These immunoprivileged and glia rich sites are potential sites for viral infection to cause glial signaling of the vagus nerve Proinflammatory cytokine: A class of neuroexcitatory innateimmune system proteins that includes IL-1beta, IL-6 andTNF-alpha. Proinflammatory cytokines are released locally by immune cells, including glial cells, when these cells encounter a pathogen Sensory vagus nerve: The afferent division of the tenth cranial nerve. The sensory vagus nerve innervates every majortrunk organ, especially tissues that are likely to contact pathogens. It is sensitive to proinflammatory cytokines, and upon contact signals the brain to begin sickness behavior Sickness behavior: Involuntary behavioral changes, such as fatigue, that are triggered by innate immune system activation. Sickness behavior is brain-based and triggeredby cytokine signaling of the vagus nerve. The vagus nerve infection of hypothesis states that CFS is a pathological version of normal sickness behavior (seeTable 1) The study of phenomena – such as sickness behavior – that sit at the intersection of behavior, brain biology, and immunology, is a relatively new field of study known as psychoneuroimmunology14. Because psychoneuroimmunology spans several scientific domains, and readers may not be familiar with them all, I will give ample background for each. To understand the VNIH, one mustunderstand each part of the connection among behavior (‘‘psy-cho-’’), the nervous system (‘‘-neuro-’’) and the innate immune sys-tem (‘‘-immunology’’). In this speculative article, I will begin with a discussion of neurotropic viruses as a model pathogen for CFS, and explain how an active virus can trigger a localized immune re-sponse. I will then describe how one class of molecules, proinflammatory cytokines, turns this local immune response into an organism-wide immune response, which includes involuntary behaviors such as fatigue. I will explain the vagus nerve’s vital role in this process, which is the crux of the VNIH. I will then use existing neuropathic pain literature as a template for explaining how aninfection on the vagus nerve could lead to ongoing CFS symptoms. Finally, I will suggest how the VNIH of CFS might be empirically evaluated with patient studies and animal models, and I will also describe potential treatment strategies. A caveat: Because fatigue and many other symptoms associated with CFS are part of the general innate immune response to infection, and because there are currently no definitive diagnostic tests for CFS, it is unlikely that all CFS cases have the same etiology. Thus, the VNIH is not intended to be an all-inclusive explanation for every case of intractable fatigue. Rather, I merely intend to hypothesize a mechanism by which many – and possibly most – cases of CFS may arise. Neurotropic virusesThe association of many different types of infection with CFS is currently an inconsistency in the literature. These seemingly conflicting findings may instead provide evidence a of chronic neuro-immune activation (described in more detail in later sections) that can be caused by any pathogen, including viruses or bacteria. The suggestion that the location of infection matters more than thespecific infection type is at the core of the VNIH of CFS. However, neurotropic viruses are the type of pathogen most commonly associated with CFS. Because the VNIH of CFS is based upon the infection of nerve tissue, this is likely not a coincidence: neurotropic viruses are characterized by their affinity for invading neural tissue, especially afferent sensory nerves15. As a large and widely permeating afferent sensory nerve that highly innervates the organs that are most likely to come into contact with foreign pathogens, the afferent vagus nerve and associated glial cells are prominent targets for neurotropic virus infection and the subsequent general immune response. I will briefly review some relevant  information  about  neurotropic  viruses,  however  it  is important to point out that those viruses and bacteria which are not classically considered to be particularly neurotropic could actually be the cause of CFS if they infect the vagus nerve. Neurotropic viruses implicated in CFS include the eight human herpesvirus types16, especially human herpesvirus type 6 (HHV-6)4,7,10,17, and HHV-5 (cytomegalovirus)5. Although it is immunotropic more often than neurotropic (it can be both, and the vagus nerve directly synapses with immune cells), HHV-4 (Epstein–Barr virus) is also commonly associated with CFS10,18,19. Herpesviruses are characterized by their ability to become latent, especially in the ganglia of nervous and lymphoid tissues20. Even though initial infection may have occurred within the first 10 years of life15, neurotropic viruses such as herpesvirus can be reactivated even in the healthiest adults21. As these viruses tend to remain latent until reactivation during stress or illness, it follows that CFS patients usually report that their symptoms began during a period of stress or with a normal cold or flu22. While latency tends to occur within nerve tissue, upon reactivation, the viral infection spreads to the extracellular space. There, satellite glial cells envelop the viral particles15. These satellite glial cells proliferate and activate, releasing neuroexcitatory mediators such as immune proteins called proinflammatory cytokines, and other substances which are described below23,24. The release of proinflammatory cytokines is a general response by glia and other immune cells like interleukin-producing cells (white blood cells) to encountering any virus or bacteria anywhere in the body. These locally-released cytokines are detected by the nearest sensory vagus nerve chemoreceptors, causing an afferent signal to the brain. The brain then initiates fatigue and several other symptoms that overlap with CFS (seeTable 1). The premise of the VNIH of CFS is that when a neurotropic virus or any other pathogen infects the vagus nerve itself, cytokines are released directly onto sensitive vagus nerve receptors and this normal immune response becomes pathologically intense. Here, I will provide some background and detail to the general immune response and how it relates to CFS symptoms.Proinflammatory cytokines, the innate immune system, and sickness behaviorOver one hundred years ago, Kuniomi Ishimori, a Japanesephysiologist, made an important discovery about the biological M.B. VanElzakker /Medical Hypotheses 81 (2013) 414–423415 From: 'Vagus nerve infection hypothesis' http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis The Vagus Nerve Infection Hypothesis (VNIH) proposes that the symptoms of Chronic Fatigue Syndrome http://me-pedia.org/wiki/Chronic_Fatigue_Syndrome "Chronic Fatigue Syndrome" are caused by an infection in or around the vagus nerve http://me-pedia.org/wiki/Vagus_nerve "Vagus nerve", the longest nerve of the autonomic nervous system in the human body. In 2013, Michael VanElzakker http://me-pedia.org/wiki/Michael_VanElzakker "Michael VanElzakker", then a graduate student at Tufts University but now a postdoctoral researcher at Harvard Medical School, published the hypothesis.1 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-VanElzakker2013-1 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 http://me-pedia.org/wiki Vagus_nerve_infection_hypothesis #cite_note-medscape_vn-2 It is responsible for the sickness response http://me-pedia.org/wiki Sickness response "Sickness response", an involuntary response characterized by fatigue, fever, myalgia, depression, and other symptoms that are often observed in patients with CFS.3 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-hhv6f-vnih-3 As explained by Dr. Michael VanElzakker http://me-pedia.org/wiki/Michael_VanElzakker "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 http://me-pedia.org/wiki/Glial_cell "Glial cell" 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(http://me-pedia.org/wiki/Mast_cell "Mast cell") 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\(http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-VanElzakker2013-1) VanElzakker believes that any infectious agent with an affinity for nerve tissues can cause a vagus nerve infection, including HHV-6 http://me-pedia.org/wiki/HHV-6 "HHV-6", Epstein-Barr virus http://me-pedia.org/wiki/Epstein-Barr_virus "Epstein-Barr virus", Varicella zoster virus http://me-pedia.org/wiki/Varicella_zoster_virus "Varicella zoster virus", Chickenpox http://me-pedia.org/wiki/Chickenpox "Chickenpox", certain kinds of enteroviruses http://me-pedia.org/wiki/Enterovirus "Enterovirus" and even Borrelia http://me-pedia.org/wiki/Borrelia "Borrelia", the bacterium that causes Lyme disease http://me-pedia.org/wiki/Lyme_disease "Lyme disease". He thinks this could explain why no single infective agent has been isolated as the cause of CFS http://me-pedia.org/wiki/CFS "CFS", even though all of these agents have been associated with disease.4 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-lowhistchef-vnih-4 To test his hypothesis, VanElzakker is using a combined MRI http://me-pedia.org/index.php?title=MRI&action=edit&redlink=1  and PET scan http://me-pedia.org/index.php?title=PET_scan&action=edit&redlink=1  with radiolabeled 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 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-lowhistchef-vnih-4 In addition, he suggests that one possibility is vagus nerve biopsy samples from CFS   However, given the size and highly intricate branching of the vagus nerve, direct evidence of infection would be difficult to demonstrate. 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. Notable studiesedit http://me-pedia.org/index.php?title=Vagus_nerve_infection_hypothesis&action=edit&section=4 * 2016: Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome http://www.sciencedirect.com/science/article/pii/S2213158216300584http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-Barnden2016-9 * 2013, Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis http://www.ncbi.nlm.nih.gov/pubmed/23790471http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-VanElzakker2013-1 * 2016, CFS Remission blog - Vagus Nerve Infection Hypothesis and the Driscoll Theory https://cfsremission.wordpress.com/2016/03/13/vagus-nerve-infection-hypothesis * 2015, The Low Histamine Chef podcast - Chronic Fatigue from Vagus Nerve Infection a Psychoneuroimmunological Hypothesis http://thelowhistaminechefpodcast.libsyn.com/chronic-fatigue-from-vagus-nerve-infection-a-psychoneuroimmunological-hypothesis transcript of podcast http://thelowhistaminechef.com/harvard-neuroscientist-dr-michael-van-elzakker-chronic-fatigue-vagus-nerve-link * 2015, The Low Histamine Chef blog - The Vagus Nerve Inflammation Connection http://c7c.37f.myftpupload.com/the-vagus-nerve-inflammation-connection * 2014, Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS) http://simmaronresearch.com/2014/02/michael-vanelzakker-ph-d-talks-vagus-nerve-infection-hypothesis-chronic-fatigue-syndrome-mecfs, by Cort Johnson http://me-pedia.org/wiki/Cort_Johnson "Cort Johnson" * 2013, HHV-6 Foundation Website - CFS: a herpesvirus infection of the vagus nerve? http://hhv-6foundation.org/news/cfs-a-herpesvirus-infection-of-the-vagus-nerve * 2013, One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome http://simmaronresearch.com/2013/12/one-theory-explain-vagus-nerve-infection-chronic-fatigue-syndrome, by Cort Johnson* Vagus nerve stimulation http://me-pedia.org/wiki/Vagus_nerve_stimulation "Vagus nerve stimulation"* Twitter #VNIH https://twitter.com/search?f=tweets&vertical=default&q=%23VNIH&src=typd * The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS http://me-pedia.org/wik/The_spread_of_EBV_to_ectopic_lymphoid_aggregates_may_be_the_final_common_pathway_in_the_pathogenesis_of_ME/CFS  by Dr. Willy Eriksen http://me-pedia.org/wiki/Willy_Eriksen General Causes of Chronic Fatigue SyndromeFrom: 'CFS Epstein Barr Virus Connection, Key To A Cure?' http://alifewellred.com/cfs-epstein-barr-virus-connection/ Van Elzakker proposes that herpesviruses like Epstein Barr (HHV-4) can latently hang around the vagus nerve http://alifewellred.com/gambling-on-vagus-3-easy-steps-to-speed-up-slow-digestion-with-fibromyalgia. These can become reactivated when trauma or undo stress is present. The vagus nerve is the largest in the body with tentacles that reach out to most of the organs. It is the direct conduit of thenervous system to the brain. Surrounding and protecting the vagus nerve are ‘glial cells’. When the virus re-activates, it runs into these cells causing them to send signals to the brain that an active infection is present. The brain then goes into “Oh no, we’re sick! Time to shut down and isolate!” mode. Hence, the severe fatigue and flu-like symptoms of CFS. Around 90% of the population will test positive for the EBV virus, however only a small percentage will develop chronic problems with re-activation. Interestingly, these glial cells could also be the leading culprits in Fibromyalgia. The cells will produce pro-inflammatory and neuroexcitatory compounds, called cytokines, as they sense the presence of infection. If this happens around the dorsal horn of the spinal cord, it causes the body to produce an exaggerated pain response. When this goes on long enough, the pain response becomes permanently ‘turned on’ instead of shutting down as it normally would. Thus validating the theory of activated glial cells being a possible cause of FMS. So, providing that funding for research is met and Van Elzakker’s theories are proven, what does this mean for those of us who suffer from CFS? Here are a few possibilities: * Glial cell inhibitors which stop the immune system activation (fatigue/flu symptoms, ect.) could be used in treatment~* Antiviral medication that attack the pathogens (things that are the cause of disease) may be implemented~* Possible vagus nerve stimulation or even surgery on the vagus nerve could be a future scenario~ Epidural Dorsal or spinal injection of Antiviral medicine?Glial cell inhibitors which stop the immune system activation (fatigue/flu symptoms, ect.) could be used in treatment~Antiviral medication that attack the pathogens (things that are the cause of disease) may be implemented~Possible vagus nerve stimulation or even surgery on the vagus nerve could be a future scenario~ From: 'Vagus nerve infection hypothesis' http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis Potential treatments include Antiviral medicines, Vagus Nerve Stimulation, Famvir (famciclovir), Ampligen (Rintatolimod), Celebrex, Glial Cell Inhibitors, Mestinon (Pyridostigmine), 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.\3\(http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-hhv6f-vnih-3) Dr. Jose Montoya(http://me-pedia.org/wiki/Jose_Montoya "Jose Montoya") and Dr. Martin Lerner(http://me-pedia.org/wiki/Martin_Lerner "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(http://me-pedia.org/wiki/EBV "EBV"). Lerner also included patients with elevated IgG for CMV(http://me-pedia.org/wiki/CMV "CMV"). Both Montoya and Lerner have shown that longer treatment terms (>6 months) have achieved greater success than short-term antiviral therapy.\5\(http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-Lerner2010-5)\6\(http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-Montoya2013-6) 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 7), 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.7 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-7 Ibudilast crosses the blood-brain barrier and suppresses glial cell http://me-pedia.org/wiki/Glial_cell "Glial cell" activation. Vagus nerve stimulation http://me-pedia.org/wiki/Vagus_nerve_stimulation "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 http://me-pedia.org/wiki/ME "ME", CFS http://me-pedia.org/wiki/CFS "CFS", and fibromyalgia http://me-pedia.org/wiki/Fibromyalgia "Fibromyalgia"8 http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis#cite_note-prohealth_vns-8. 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 http://me-pedia.org/wiki/Mestinon "Mestinon" (Pyridostigmine) - a drug that blocks the enzymatic breakdown of acetylcholine http://me-pedia.org/wiki/Acetylcholine "Acetylcholine", which is the primary neurotransmitter of the vagus nerve http://me-pedia.org/wiki/Vagus_nerve "Vagus nerve", especially the parasympathetic/ motor/ efferent branch. Mestinon is frequently prescribed for POTS http://me-pedia.org/wiki/POTS "POTS", especially to improve tachycardia, and can work synergistically with vagus nerve stimulation. Celebrex http://me-pedia.org/index.php?title=Celebrex&action=edit&redlink=1 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 http://me-pedia.org/wiki/Ampligen "Ampligen" a drug that stimulates the production of natural interferon(http://me-pedia.org/wiki/Interferon "Interferon" 

Close window by clicking in grey area >