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Vagus nerve infection hypothesis
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==Treatment== If this theory proved correct, possible treatment approaches might include: === [[Antiviral]] treatments === 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. === [[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 === [[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]] === [[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]]. === [[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 === [[Ampligen]] (Rintatolimod) is a drug that stimulates the production of natural [[interferon]].
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