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The '''Vagus Nerve Infection Hypothesis''' (VNIH) proposes that the symptoms of [[Chronic Fatigue Syndrome]] are caused by an infection in or around the [[vagus nerve]], longest nerve of the autonomic nervous system in the human body.
{{Cleanup|reason="Evidence" section needs improvement (see Discussion) | date = 2021}}


In 2013, [[Michael VanElzakker]], then a graduate student at Tufts University but now a postdoctoral researcher at Harvard Medical School, published the hypothesis.<ref name="VanElzakker2013"/>
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.<ref name="medscape_vn"/> 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.<ref name="hhv6f-vnih"/>
In 2013, [[Michael VanElzakker]], then a graduate student at Tufts University and now a postdoctoral researcher at Harvard Medical School, published the hypothesis.<ref name="VanElzakker2013" />
 
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.<ref name="medscape_vn">{{Cite web | last1 = Medscape| title = Vagus Nerve Anatomy| date  = Aug 17, 2015 | url = http://emedicine.medscape.com/article/1875813-overview}}</ref> 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 [[Chronic fatigue syndrome|CFS]].<ref name="hhv6f-vnih">{{Cite web | last1 = HHV-6 Foundation| title = CFS: a herpesvirus infection of the vagus nerve? | date = Jul 13, 2013| url = http://hhv-6foundation.org/news/cfs-a-herpesvirus-infection-of-the-vagus-nerve}}</ref>s


==Theory==
==Theory==
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 cell]]s [cells that support and protect neurons] can bombard the sensory vagus nerve with proinflammatory [[cytokine]]s 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 cell]]s 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.<ref name="VanElzakker2013" />


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 cell]]s [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 cell]]s 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.<ref name="VanElzakker2013"/>
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 [[enterovirus]]es and even [[Borrelia burgdorferi|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.<ref name="lowhistchef-vnih">{{cite web | last1 = Ykelenstam | first1 = Yasmina  | authorlink1 = Yasmina Ykelenstam | last2 = VanElzakker | first2 = MB | authorlink2 = Michael VanElzakker|title  = Harvard Neuroscientist Dr. Michael VanElzakker: Chronic Fatigue Vagus Nerve Link|website = The Low Histamine Chef
| date = Dec 8, 2015 | url = http://thelowhistaminechef.com/harvard-neuroscientist-dr-michael-van-elzakker-chronic-fatigue-vagus-nerve-link }}</ref>


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 [[enterovirus]]es 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.<ref name="lowhistchef-vnih"/>
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."<ref name="lowhistchef-vnih" />
In addition, he suggests that one possibility is vagus nerve biopsy samples from CFS patients who have died prematurely from other causes.<ref name="hhv6f-vnih" /> However, given the size and highly intricate branching of the vagus nerve, direct evidence of infection would be difficult to demonstrate.


To test his hypothesis, VanElzakker is using a combined [[MRI]] and [[PET scan]] 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."<ref name="lowhistchef-vnih"/>
==Evidence==
In addition, he suggests that one possibility is vagus nerve biopsy samples from CFS patients who have died prematurely from other causes.<ref name="hhv6f-vnih"/> However, given the size and highly intricate branching of the vagus nerve, direct evidence of infection would be difficult to demonstrate.
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". https://link.springer.com/article/10.1007/s00401-023-02612-x
==Treatment==
If this theory proved correct, possible treatment approaches might include:


==Treatment==
=== [[Antiviral]] treatments ===
Potential treatments include:
Potential problems with [[antiviral]]s 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.<ref name="hhv6f-vnih" /> 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 [[Epstein-Barr virus|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.<ref name="Lerner2010">{{Cite journal | last1 = Lerner | first1 = AM | authorlink1 = A Martin Lerner | last2 = Beqaj | first2 = S | authorlink2 = Safedin Beqaj| last3 = Fitzgerald | first3 = JT | authorlink3 = James T Fitzgerald | last4 = Gill | first4 = K | authorlink4 = Ken Gill | last5 = Gill | first5 = C | authorlink5 = Carol Gil | last6 = Edington | first6 = J | authorlink6 = James Edington| title = Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome| journal = Virus adaptation and treatment| volume = 2 | pages = 47-57 | date = 2010| url = https://www.dovepress.com/subset-directed-antiviral-treatment-of-142-herpesvirus-patients-with-c-peer-reviewed-article-VAAT}}</ref><ref name="Montoya2013">{{Cite journal | last1 = Montoya | first1 = JG  | authorlink1 = Jose Montoya | last2 = Kogelnik | first2 = AM  | authorlink2 = Andreas Kogelnik | last3 = Bhangoo | first3 = M  | authorlink3 = | last4 = Lunn |first4 = MR  | authorlink4 = | last5 = Flamand |first5 = L | author-link5 = |last6 = Merrihew |first6 = LE | author-link6 = |last7 = Watt |first7 = T | author-link7 =|last8 = Kubo |first8 = JT | author-link8 =|last9 = Paik |first9 = J | author-link9 = | last10 = Desai | first10 = M  | authorlink10 =| title =  Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.| journal = Journal of Medical Virology| volume = 85 | pages = 2101-9| date = 2013| doi = 10.1002/jmv.23713| url=http://www.ncbi.nlm.nih.gov/pubmed/23959519}}</ref>  Rodent studies have shown that the antiviral [[Famciclovir|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 [[Herpesviruses|herpesvirus]] infection of peripheral vagus ganglia.
*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.<ref name="hhv6f-vnih"/> 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.<ref name="Lerner2010"/><ref name="Montoya2013"/>  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.<ref>https://en.wikipedia.org/wiki/Ibudilast</ref> Ibudilast crosses the blood-brain barrier and suppresses [[glial cell]] activation.  
=== [[Glial cell]] inhibitors ===
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]].<ref name="Rolan2009" /> Ibudilast can be combined with [[opioid]]s to reduce chronic [[nerve pain]].<ref name="Rolan2009">{{Cite journal | title = Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease | date = Dec 2009|url=https://www.researchgate.net/publication/40023191_Ibudilast_A_review_of_its_pharmacology_efficacy_and_safety_in_respiratory_and_neurological_disease|journal=Expert Opinion on Pharmacotherapy|volume=10|issue=17|pages=2897–2904 | last =Rolan | first=P | authorlink = | last2 = Hutchinson |  first2 = MR|author-link2 = | last3 = Johnson | first3=KW | authorlink3 = |language=en|doi=10.1517/14656560903426189|pmc=|pmid=|access-date=|issn=1465-6566|quote=|via=}}</ref> Ibudilast is also a phosphodiesterase (PDE) inhibitor, and 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]]<ref name="prohealth_vns"/>. 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.
=== Vagus nerve stimulation ===
[[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 [[myalgic encephalomyelitis|ME]], CFS, and [[fibromyalgia]].<ref name="Traianos2021">{{Cite journal | title = 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 | date = 2021-06-01|url=https://ard.bmj.com/content/80/Suppl_1/1057.3|journal=Annals of the Rheumatic Diseases|volume=80|issue=Suppl 1|pages=1057–1058 | last = Traianos | first = E. | last2 = Dibnah | first2 = B. | last3 = Lendrem | first3 =  D. | last4 = Clark | first4 = Y. | last5 = Macrae | first5 = V. | last6 = Slater | first6 = V. | last7 = Wood | first7 = K. | last8 = Storey | first8 = D. | last9 = Simon | first9 = B. | last10 = Blake | first10 = J. | last11 = Tarn | first11 = J.|language=en|doi=10.1136/annrheumdis-2021-eular.1999|issn=0003-4967}}</ref><ref name="Chamizo2022">{{Cite journal | title = Non-Invasive Transcutaneous Vagus Nerve Stimulation for the Treatment of Fibromyalgia Symptoms: A Study Protocol | date = Jan 2022|url=https://www.mdpi.com/2076-3425/12/1/95/htm|journal=Brain Sciences|volume=12|issue=1 | pages = 95 | last =Molero-Chamizo | first = Andrés | last2 = Nitsche | first2 = Michael A. | last3 = Bolz | first3 = Armin | last4 = Andújar Barroso | first4 = Rafael Tomás | last5 = Alameda Bailén | first5 = José R. | last6 = García Palomeque | first6 = Jesús Carlos | last7 = Rivera-Urbina | first7 = Guadalupe Nathzidy|language=en|doi=10.3390/brainsci12010095|issn=2076-3425}}</ref><ref name="Kutlu2020">{{Cite journal | title = The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome | date = 2020-03-02|url=https://www.hindawi.com/journals/bmri/2020/8656218/|journal=BioMed Research International|volume=2020| pages = e8656218 | last = Kutlu | first = Nazlı | last2 = Özden | first2=Ali Veysel | last3 = Alptekin | first3=Hasan Kerem | last4 = Alptekin | first4=Jülide Öncü|language=en|doi=10.1155/2020/8656218|issn=2314-6133}}</ref> 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.
{{See also|Vagus nerve stimulation}}


*[[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.
=== [[Mestinon]] ===
[[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 [[Postural orthostatic tachycardia syndrome|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).
=== [[Celecoxib|Celebrex]] ===
[[Celecoxib|Celebrex]] is a [[COX-2 inhibitors|COX2 inhibitor]], which blocks an enzyme that is part of the production of [[Prostaglandin|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 [[cytokine]]s, [[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]].
=== Ampligen ===
[[Ampligen]] (Rintatolimod) is a drug that stimulates the production of natural [[interferon]].


==Evidence==
==Talks and interviews ==
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.
*[http://thelowhistaminechef.com/harvard-neuroscientist-dr-michael-van-elzakker-chronic-fatigue-vagus-nerve-link Harvard Neuroscientist Dr. Michael VanElzakker: Chronic Fatigue Vagus Nerve Link] - The Low Histamine Chef


==Notable studies==
==Notable studies==
*2016: [http://www.sciencedirect.com/science/article/pii/S2213158216300584 Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome]<ref name="Barnden2016"/>
*2016, Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome<ref name="Barnden2016">{{Cite journal | last1 =  Barnden | first1 = LR  | authorlink1 = Leighton Barnden | last2 = Kwiatek | first2 = R  | authorlink2 = Richard Kwiatek | last3 = Crouch | first3 = B | authorlink3 = Benjamin Crouch | last4 = Burnet | first4 = R | authorlink4 = Richard Burnet | last5 = Del Fante | first5 = P | authorlink5 = Peter Del Fante | title =  Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome
*2013, [http://www.ncbi.nlm.nih.gov/pubmed/23790471 Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis.]<ref name="VanElzakker2013"/>
|journal = NeuroImage: Clinical| volume = 11 | pages = 530-537 | date = 2016|doi = 10.1016/j.nicl.2016.03.017 | url = http://www.sciencedirect.com/science/article/pii/S2213158216300584}}</ref> - [http://www.sciencedirect.com/science/article/pii/S2213158216300584 (Full text)]
 
* 2013, Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis<ref name="VanElzakker2013">{{Cite journal | last1 = VanElzakker | first1 = MB | authorlink1 = Michael VanElzakker| title  = Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis| journal = Medical Hypotheses | volume = 81 | issue = 3 | pages = 414-423 | date = Sep 2013 | pmid = 23790471  | doi = 10.1016/j.mehy.2013.05.034 | url = http://www.pdf-archive.com/2013/06/23/vanelzakker-vnih-cfs-in-press/vanelzakker-vnih-cfs-in-press.pdf}}</ref> -  [http://www.ncbi.nlm.nih.gov/pubmed/23790471 (Full text)]
==Learn more==
*2016, [https://cfsremission.wordpress.com/2016/03/13/vagus-nerve-infection-hypothesis/ CFS Remission blog - ''Vagus Nerve Infection Hypothesis and the Driscoll Theory'']
*2015, [http://thelowhistaminechefpodcast.libsyn.com/chronic-fatigue-from-vagus-nerve-infection-a-psychoneuroimmunological-hypothesis The Low Histamine Chef podcast - ''Chronic Fatigue from Vagus Nerve Infection a Psychoneuroimmunological Hypothesis''] [http://thelowhistaminechef.com/harvard-neuroscientist-dr-michael-van-elzakker-chronic-fatigue-vagus-nerve-link/ transcript of podcast]
*2015, [http://c7c.37f.myftpupload.com/the-vagus-nerve-inflammation-connection/ The Low Histamine Chef blog - ''The Vagus Nerve Inflammation Connection'']
*2014, [http://simmaronresearch.com/2014/02/michael-vanelzakker-ph-d-talks-vagus-nerve-infection-hypothesis-chronic-fatigue-syndrome-mecfs/ ''Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)''], by [[Cort Johnson]]
*2013, [http://hhv-6foundation.org/news/cfs-a-herpesvirus-infection-of-the-vagus-nerve HHV-6 Foundation Website - ''CFS: a herpesvirus infection of the vagus nerve?'']
*2013, [http://simmaronresearch.com/2013/12/one-theory-explain-vagus-nerve-infection-chronic-fatigue-syndrome/ ''One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome''], by [[Cort Johnson]]


==See also==
==See also==
*[[Vagus nerve stimulation]]
*[[Vagus nerve stimulation]]
*[https://twitter.com/search?f=tweets&vertical=default&q=%23VNIH&src=typd Twitter #VNIH]
*[[The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS]]
==Learn more==
* 2013, [https://hhv-6foundation.org/chronic-fatigue-syndrome/cfs-a-herpesvirus-infection-of-the-vagus-nerve CFS: a herpesvirus infection of the vagus nerve?] - HHV-6 Foundation
*2013, [http://simmaronresearch.com/2013/12/one-theory-explain-vagus-nerve-infection-chronic-fatigue-syndrome/ One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome] - Simmaron research
*2014, [http://simmaronresearch.com/2014/02/michael-vanelzakker-ph-d-talks-vagus-nerve-infection-hypothesis-chronic-fatigue-syndrome-mecfs/ Michael VanElzakker Ph.D Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)] - Simmaron research


==References==
==References==
<references>
{{Reflist}}
 
<ref name="Barnden2016">{{citation
| last1  = Barnden          | first1 = LR                | authorlink1 = Leighton Barnden
| last2  = Kwiatek          | first2 = R                  | authorlink2 = Richard Kwiatek
| last3  = Crouch          | first3 = B                  | authorlink3 = Benjamin Crouch
| last4  = Burnet          | first4 = R                  | authorlink4 = Richard Burnet
| last5  = Del Fante        | first5 = P                  | authorlink5 = Peter Del Fante
| title  = Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome
| journal = NeuroImage: Clinical| volume = 11 | page = 530-537
| date    = 2016
| doi    = 10.1016/j.nicl.2016.03.017
| url    = http://www.sciencedirect.com/science/article/pii/S2213158216300584
}}</ref>
 
<ref name="VanElzakker2013">{{citation
| last1  = Van Elzakker    | first1 = MB                | authorlink1 = Michael Van ElZakker
| title  = Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis
| journal = Medical Hypotheses | volume = 81 | issue = 3 | page = 414-423
| date    = Sep 2013
| pmid    = 23790471        | doi = 10.1016/j.mehy.2013.05.034
| url    = http://www.pdf-archive.com/2013/06/23/vanelzakker-vnih-cfs-in-press/vanelzakker-vnih-cfs-in-press.pdf
}}</ref>
 
<ref name="lowhistchef-vnih">{{citation
| last1  = Ykelenstam      | first1 = Yasmina            | authorlink1 = Yasmina Ykelenstam
| last2  = Van ElZakker    | first2 = MB                | authorlink2 = Michael Van ElZakker
| title  = Harvard Neuroscientist Dr. Michael Van ElZakker: Chronic Fatigue Vagus Nerve Link
| type    = interview
| journal = The Low Histamine Chef
| date    = 8 Dec 2015
| url    = http://thelowhistaminechef.com/harvard-neuroscientist-dr-michael-van-elzakker-chronic-fatigue-vagus-nerve-link
}}</ref>
 
<ref name="hhv6f-vnih">{{citation                               
| last1  = HHV-6 Foundation
| title  = CFS: a herpesvirus infection of the vagus nerve?
| date    = 13 Jul 2013
| url    = http://hhv-6foundation.org/news/cfs-a-herpesvirus-infection-of-the-vagus-nerve
}}</ref>
 
<ref name="prohealth_vns">{{citation
| last1  = ProHealth Website
| title  = Vagus Nerve Stimulation, Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)
| date    = 16 Feb 2016
| url    = http://www.prohealth.com/library/showarticle.cfm?libid=24164
}}</ref>
 
<ref name="medscape_vn">{{citation
| last1  = Medscape
| title  = Vagus Nerve Anatomy
| date  = 17 Aug 2015
| url    = http://emedicine.medscape.com/article/1875813-overview
}}</ref>
 
<ref name="Lerner2010">{{citation
| last1  = Lerner          | first1 = AM                | authorlink1 = A Martin Lerner
| last2  = Beqaj            | first2 = S                  | authorlink2 = Safedin Beqaj
| last3  = Fitzgerald      | first3 = JT                | authorlink3 = James T Fitzgerald
| last4  = Gill            | first4 = K                  | authorlink4 = Ken Gill
| last5  = Gill            | first5 = C                  | authorlink5 = Carol Gill
| last6  = Edington        | first6 = J                  | authorlink6 = James Edington
| title  = Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome
| journal = Virus adaptation and treatment| volume = 2 | page = 47-57
| date    = 2010
| url    = https://www.dovepress.com/subset-directed-antiviral-treatment-of-142-herpesvirus-patients-with-c-peer-reviewed-article-VAAT
}}</ref>
 
<ref name="Montoya2013">{{citation
| last1  = Montoya          | first1 = JG                | authorlink1 = Jose Montoya
| last2  = Kogelnik        | first2 = AM                | authorlink2 = Andreas Kogelnik
| last3  = Bhangoo          | first3 = M                  | authorlink3 =
| last4  = Lunn            | first4 = MR                | authorlink4 =
| last5  = Flamand          | first5 = L                  | authorlink5 =
| last6  = Merrihew        | first6 = LE                | authorlink6 =
| last7  = Watt            | first7 = T                  | authorlink7 =
| last8  = Kubo            | first8 = JT                | authorlink8 =
| last9  = Paik            | first9 = J                  | authorlink9 =
| last10  = Desai            | first10= M                  | authorlink10 =
| title  = Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.
| journal = Journal of Medical Virology| volume = 85 | page = 2101-9
| date    = 2013
| doi    = 10.1002/jmv.23713
| url    = http://www.ncbi.nlm.nih.gov/pubmed/23959519
}}</ref>


</references>
[[Category:Medical hypotheses]]
[[Category:Medical hypotheses]]

Latest revision as of 17:39, November 22, 2023

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". https://link.springer.com/article/10.1007/s00401-023-02612-x

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.

See also
Vagus nerve stimulation.

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.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

ganglion A ganglion is a group of neuron cell bodies in the peripheral nervous system. Plural: ganglia / ganglions

tachycardia An unusually rapid heart beat. Can be caused by exercise or illness. A symptom of postural orthostatic tachycardia syndrome (POTS). (Learn more: www.heart.org)

enzyme a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.

brainstem Region of the midbrain in adults, includes midbrain, pons, and medulla oblongata and develops.

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