Myalgic Encyphalomyelitis

Annotations:

• http://www.medscape.com/viewarticle/837577_4

1. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease
2. CYTOKINES: Elevated levels of cytokines in ME patients, indicating that ME is indeed an inflammatory disease

   Annotations:

   • 2015 Distinct plasma immune signatures in ME/CFS are present early in the course of illness http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/ Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.
3. Significantly reduced oxygen consumption and workload for ME/CFS patients after treadmill tests

   Annotations:

   • http://ptjournal.apta.org/content/93/11/1484.full STEVEN'S PROTOCOL: Reduced functional capacity and postexertion fatigue after physical activity. These symptoms are often delayed. single exercise test is insufficient to reliably demonstrate functional impairment in people with CFS. A second test might be necessary.
4. Bilateral white matter atrophy in ME/CFS patients compared with controls,

   Annotations:

   • http://dx.doi.org/10.1148/radiol.14141079
5. THESE ARTICLES NEED TO BE ANALYZED AND KEY KEARNINGS LISTED (SEE NOTE)

   Annotations:

   • http://www.tandfonline.com/doi/full/10.1080/21641846.2014.906066 IMMUNOLOGICAL BIOMARKERS: http://www.tandfonline.com/doi/pdf/10.1080/21641846.2014.906066 http://www.medscape.com/viewarticle/837577_4

1. ABOUT
   1. Associated with: Infectious mononucleosis (glandular fever); Cancer: Hodgkin's lymphoma, Burkitt's lymphoma, nasopharyngeal carcinoma; Conditions associated with HIV: hairy leukoplakia and central nervoussystem lymphomas; higher risk of certain autoimmune diseases (dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis.

      Annotations:

      • https://en.wikipedia.org/wiki/Epstein%E2%80%93Barr_virus
   2. EBV & ME
      1. EBV in ME affects mostly B-cells

         Annotations:

         • https://www.youtube.com/watch?v=5ZWTDmhNeQ8
      2. B cells of ME patients have a poor memory of the virus - immune system is not remembering that you had mononucleosis (2 out of 3 responses are not working). The other B cells are working over time but not fast enough to deal with the virus. so virus freely explores the body, destroying mitochondria.

         Annotations:

         • https://www.youtube.com/watch?v=5ZWTDmhNeQ8
      3. TO DO: THESE STUDIES NEED TO BE ANALYZED AND KEY LEARNINGS LISTED (SEE NOTE)

         Annotations:

         • STUDY: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893202/ ARTICLE ABOUT THE STUDY: http://simmaronresearch.com/2014/03/1591/
   3. 90% of population has evidence of previous infection
   4. Viral Tropism: Affects B cells & epithelial cells

      Annotations:

      • https://en.wikipedia.org/wiki/Epstein%E2%80%93Barr_virus
      1. B CELLS: To enter B cells, viral glycoprotein gp350 binds to cellular receptor CD21 (also known as CR2). Then, viral glycoprotein gp42 interacts with cellular MHC class II molecules. This triggers fusion of the viral envelope with the cell membrane, allowing EBV to enter the B cell. Human CD35, also known as complement receptor 1 (CR1), is an additional attachment factor for gp350/220, and can provide a route for entry of EBV into CD21-negative cells, including immature B-cells. EBV infection downregulates expression of CD35.

         Annotations:

         • https://en.wikipedia.org/wiki/Epstein%E2%80%93Barr_virus
   5. The site of persistence of EBV may be bone marrow. EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after transplantation

      Annotations:

      • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282526/
   6. LATENCY (TO DO)
2. TREATMENTS
   1. Cyclophosphamide

      Annotations:

      • https://clinicaltrials.gov/ct2/show/study/NCT02444091?term=cyclophosphamide+chronic+fatigue+syndrome&rank=1 http://www.prohealth.com/library/showarticle.cfm?libid=20460
      1. Led by senior consultant Dr Øystein Fluge and Prof Olav Mella, the team is focusing on non-responders and those patients who have relapsed after treatment with rituximab, a B-cell depleting drug. Six intravenous infusions of cyclophosphamide will be administered at four-week intervals with the first at 600 mg/m2 and subsequent infusions at 700 mg/m2. Scheduled for completion by September 2016.
   2. Rituximab
      1. Nitric oxide
         1. Makes Rituximab more effective - Fluge and Mella filed a European Patent Application for the use of a nitric oxide donor in combination with a B-cell depleting agent (RUTIXIMAB) to treat ME

            Annotations:

            • https://data.epo.org/publication-server/pdf-document/EP13168487NWA1.pdf?PN=EP2805730%20EP%202805730&iDocId=7868378&iepatch=.pdf http://www.prohealth.com/library/showarticle.cfm?libid=20460Recent  findings by Fluge and Mella have supported anecdotal evidence of ME patients receiving immediate relief after treatment with nitric oxide. In 2014 Fluge and Mella filed a European Patent Application for the use of a nitric oxide donor in combination with a B-cell depleting agent to treat ME. The application details a case where an ME patient experienced immediate relief from symptoms after treatment with an NO donor. Nitric oxide donor: the administration of a NO donor surprisingly allow a treatment of CFS patients for immediate relief of symptoms without any delay as described for e.g. a B-cell depleting agent, like Rituximab. Recommended use of a B-cell depleting agent, such as rituximab, together with relatively high doses of L-Arginine 5 g twice daily and -Citrulline 200 mg twice daily. ...
         2. Over the years there have quite a number of proposed disease mechanisms relating to nitric oxide (NO) problems of patients suffering with ME/CFS. Studies have however, over the years, proven somewhat inconclusive in the past.

            Annotations:

            • http://phoenixrising.me/archives/18836
         3. ME patients have high levels of nitric oxide and its oxidant product peroxynitrite.

            Annotations:

            • http://www.prohealth.com/library/showarticle.cfm?libid=12896
      2. TO DO: THESE STUDIES NEED TO BE ANALYZED AND KEY LEARNINGS LISTED (SEE NOTE)

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198463/ 2009 http://www.ncbi.nlm.nih.gov/pubmed/19566965
      3. It circulates in the lymphatic system and tissue. It binds specifically to the CD20 antigen, a molecule present on the surface of the normal and malignant pre-B and mature B cells. This binding can be imagined as a lock fitting a key. More than 90 percent of B-cell NHL express CD20. Once bound to B-cells, Rituxan induces lysis (destruction of the cell)

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848172/ http://www.lymphomation.org/rituxan.htm#how-it-works
         1. It affercts the "CD20" antigen, or "CD20," an about 35-kDa, non-glycosylated phosphoprotein

            Annotations:

            • C20 is found on the surface of greater than 90% of B cells from peripheral blood or lymphoid organs in humans. CD20 is present on both normal B cells as well as malignant B cells, but is not expressed on stem cells. Other names for CD20 in the literature include "B- lymphocyte- restricted antigen" and "Bp35".
   3. Methotrexate
   4. Valganciclovir
      1. Patrients in trials before got better, experienced initial worsening

         Annotations:

         • http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/epdf Patients in the VGCV and placebo arms experienced an initial worsening of their symptoms that has been previously reported by the Stanford CFS group and in a recent clinical trial [Kogelnik et al., 2006; Fluge et al., 2011]. It is possible that the worsening in the placebo arm was due to placebo effect and/or the additional physical/emotional load of frequent visits to the clinical research center. In the VGCV arm, in addition to the factors present in the placebo group, a drug effect may have taken place as well. The pathogenesis of this initial worsening is unclear but it may resemble a Jarisch Herxheimer-like reaction that has been observed during the initial treatment of certain infections and may be mediated by an immune response to transiently increased circulating microbial antigen(s) [Bryceson, 1976].
      2. TO DO: THESE STUDIES NEED TO BE ANALYZED AND KEY LEARNINGS LISTED (SEE NOTE)

         Annotations:

         • Montoya 2013: http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/epdf Lerner 2011: http://www.treatmentcenterforcfs.com/pdf/VAAT-15105-herpesvirus-immediate-early-gene-expression-induces-host-cel_022111.pdf Montoya 2006: http://www.journalofclinicalvirology.com/article/S1386-6532%2806%2970009-9/pdf
      3. In a controlled pilot study (random and blinded) the antiviral drug valacyclovir (Valtrex) is shown effective in reducing the fatigue of single virus EBV CFS. A blinded trial of valacyclovir has been completed and confirms the original study. Initial studies involving subsets including HCMV and HHV6, utilizing the antiviral drug valgancyclovir (Valcyte), are also successful and exciting. When patients are treated with appropriate antiviral medicines after specific proof of EBV, HCMV and/or HHV6 virus active infection (subset classification), research has shown significant improvement in cardiac and CFS symptoms.

         Annotations:

         • http://www.treatmentcenterforcfs.com/FAQ/index.html
      4. It is used to treat infection with a virus called cytomegalovirus

         Annotations:

         • http://www.netdoctor.co.uk/infections/medicines/valcyte.html
      5. By blocking the action of DNA polymerase and disrupting viral DNA, ganciclovir prevents CMV from multiplying. This controls the infection and helps the immune system to deal with it.

         Annotations:

         • http://www.netdoctor.co.uk/infections/medicines/valcyte.html
   5. Rintatolimod
      1. TO DO: THESE STUDIES NEED TO BE ANALYZED AND KEY LEARNINGS LISTED

Annotations:

• http://onlinelibrary.wiley.com/doi/10.1002/art.34508/full

Annotations:

• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

1. Stanford University
   1. Anthony L. Komaroff

      Annotations:

      • Simcox-Clifford-Higby Professor of Medicine, Harvard Medical School Senior Physician, GIM, Department of Medicine, Brigham & Woen's Hospital chief editor of Harvard Healt
      1. PRESENTATION: 2014 The Biology of Chronic Fatigue Syndrome

         Annotations:

         • https://www.youtube.com/watch?v=VCowKm4N2Ow
      2. PRESENTATION: 2013 Chronic Fatigue Syndrome: The Challenges in Primary Care

         Annotations:

         • http://www.medscape.org/viewarticle/759095_transcript
   2. Jose G. Montoya

      Annotations:

      • Professor of Medicine (Infectious Diseases and Geographic Medicine) at the Stanford University Medical Center FOCUS: Infectious Disease Toxoplasmosis Infection in the setting of solid organ transplantation Infection as a trigger of chronic diseases Chronic Fatigue Syndrome
      1. ONGOING CLINICAL TRIAL: 2014 The Synergy Trial: Methylphenidate Plus a CFS-Specific Nutrient Formula as a Treatment for Chronic Fatigue Syndrome - (ADHD medicine)

         Annotations:

         • https://clinicaltrials.gov/ct2/show/NCT01966276 The Synergy Trial will evaluate the safety and efficacy of a currently available medication (methylphenidate) combined with a CFS-specific dietary supplement (CFS Nutrient Formula) to treat Chronic Fatigue Syndrome (CFS). The CFS Nutrient Formula to be used in this trial is a broad-spectrum micronutrient supplement that provides CFS patients with vitamins, minerals, and other cofactors (amino acids, antioxidants, and mitochondrial cofactors) to complement the low-dose Central Nervous System (CNS) stimulant (methylphenidate). In other words, therapeutic dosages of micronutrients are provided to support the functioning of the nervous, endocrine, and immune systems to a level at which a lower than customary dosage of methylphenidate can produce positive clinical effects on CFS symptoms and also be well tolerated. Methylphenidate is the generic form of Ritalin®. The dose being tested in this study is relatively low (5-10mg twice daily). This drug has been in clinical use for over 50 years for the treatment of Narcolepsy and Attention Deficit Disorder and has a well-described safety profile when used as recommended. Methylphenidate alone has been studied as a treatment for CFS in the past and has been shown to produce mild benefits and be well-tolerated. When provided as innovative therapy, methylphenidate plus this CFS Nutrient Formula has produced substantial improvements in CFS symptoms in a limited number of patients, and demonstrated excellent tolerability. Use of low dose methylphenidate hydrochloride coadministered with a CFS Nutrient Formula has not been previously evaluated in a controlled clinical study. The risk to patients using this combination is believed to be low, especially in the context of a well-controlled clinical study. Furthermore, this combination is not expected to increase the incidence or severity of adverse events associated with methylphenidate hydrochloride.
      2. CLINICAL TRIAL: 2013 Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pubmed/23959519?dopt=Abstract
      3. CLINICAL TRIAL: 2006 Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein—Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue

         Annotations:

         • http://www.journalofclinicalvirology.com/article/S1386-6532%2806%2970009-9/abstract Results Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients. Conclusion These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.
      4. PRESENTATION: 2011 Stanford's Dr. Jose Montoya on Chronic Fatigue Syndrome

         Annotations:

         • https://www.youtube.com/watch?v=Riybtt6SChU
      5. ORIGINAL RESEARCH: 2015 Right arcuate fasciculus abnormality in chronic fatigue syndrome.

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pubmed/25353054
      6. ORIGINAL RESEARCH: 2015 Distinct plasma immune signatures in ME/CFS are present early in the course of illness.

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/
2. Department of Health and Human Services
   1. Staci R. Stevens

      Annotations:

      • http://iacfsme.org/Organization/Leadership-of-the-IACFS-ME/Staci-Stevens.aspx Staci Stevens holds a bachelor's degree in Sports Medicine from the University of the Pacific and a master's degree from Pacific in Exercise Physiology. Ms. Stevens has served on the Department of Health and Human Services Chronic Fatigue Syndrome Advisory Committee and developed continuing education curricula for CFS in conjunction with the CDC for physical therapists and other allied healthcare professionals. She has directed several research projects and supervised testing for clinical trials. Her clinical experience is in disability evaluation, cardiopulmonary exercise testing and prescribing activity management programs for patients with CFS/ME. Her primary research interest is in functionally characterizing CFS/ME and improving quality of life for patients with the illness.
      1. ORIGINAL RESEARCH: 2013 Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome (Steven's protocol)

         Annotations:

         • http://ptjournal.apta.org/content/93/11/1484.full
      2. CLINICAL TRIAL: 2012 A Double-Blind, Placebo-Controlled, Randomized, Clinical Trial of the TLR-3 Agonist Rintatolimod in Severe Cases of Chronic Fatigue Syndrome

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/
3. William Beaumont Hospital
   1. Martin Lerner
      1. CLINICAL TRIAL: 2011 A paradigm linking herpesvirus immediate-early gene expression apoptosis and myalgic encephalomyelitis chronic fatigue syndrome

         Annotations:

         • http://www.treatmentcenterforcfs.com/pdf/VAAT-15105-herpesvirus-immediate-early-gene-expression-induces-host-cel_022111.pdf

1. Haukeland University Hospital

   Annotations:

   • http://helse-bergen.no/en/Sider/default.aspx
   1. Øystein Fluge

      Annotations:

      • oystein.fluge@helse-bergen.no
      1. CLINICAL TRIAL: 2011 Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

         Annotations:

         • http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026358
      2. CLINICAL TRIAL: 2009 Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series.

         Annotations:

         • http://www.ncbi.nlm.nih.gov/pubmed/19566965
   2. Olav Mella
   3. Mella and Fluge believe that ME is a form of autoimmune illness where the body comes under attack from its own defence system.

      Annotations:

      • http://www.prohealth.com/library/showarticle.cfm?libid=20460

1. Universitätsmedizin Berlin

   Annotations:

   • Institute for Medical Immunology https://www.bsrt.de/index.php?option=com_content&view=article&id=406&Itemid=474
   1. Madlen Löbel
      1. ORIGINAL RESEARCH: 2014 Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.

         Annotations:

         • RESEARCH: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893202/ ARTICLE ABOUT THE RESEARCH: http://simmaronresearch.com/2014/03/1591/

1. Sarah Myhill
   1. Original Research: 2012 Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

      Annotations:

      • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403556/
   2. Original research: 2009 Chronic fatigue syndrome and mitochondrial dysfunction.

      Annotations:

      • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

1. Carmen Vaamonde-García
   1. ORIGINAL RESEARCH: 2012 Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes.

      Annotations:

      • http://onlinelibrary.wiley.com/doi/10.1002/art.34508/full

1. Action for ME

   Annotations:

   • http://www.actionforme.org.uk Action for M.E. is the UK's leading charity for people affected by M.E. We offer invaluable information and support - and we have been at the forefront of the campaign for more research, more effective treatments and better services since 1987.
   1. Research Conference, Newcastle 12-13 October 2015

      Annotations:

      • http://cmrc2015.eventzilla.net/web/event?eventid=2139069963 http://www.actionforme.org.uk/get-informed/news/our-news/cmrc-conference-2015-places-now-available
   2. Quite active, focused on research and finding a cure
2. ME Association

   Annotations:

   • http://www.meassociation.org.uk/

1. Phoenix rising

   Annotations:

   • Phoenix Rising publishes articles, a blog and a newsletter, maintains the largest ME/CFS Forum (forums.phoenixrising.me) and contains the largest database of articles and posts on ME/CFS on the web. Non profit, created by CFS patient http://phoenixrising.me/about
   1. Active blog, newsletter and forum
2. IACFS/ME

   Annotations:

   • http://iacfsme.org/Home.aspx The IACFS/ME shall at all times be organized and operated exclusively for charitable, scientific, literary or educational purposes as a qualified exempt organization described under section 501 (c) (3) of the Internal Revenue code of 1986 and the regulations promulgated thereunder as they may now exist or as they may be hereafter amended.   TAX ID: 73-1416680 IACFS/ME
   1. Not very active. Bi annual conferences, next one in 2016.

      Annotations:

      • http://iacfsme.org/Conferences.aspxhttp://iacfsme.org/Home.aspx

Annotations:

• https://data.epo.org/publication-server/pdf-document/EP13168487NWA1.pdf?PN=EP2805730%20EP%202805730&iDocId=7868378&iepatch=.pdf Furthermore, several gene expression studies have been performed in CFS, indicating that there are specific but complex gene alterations in accordance with the dysfunction in immune response and in defence mechanisms. For example, Kaushik N., et al., 2005, J. Clin Pathol 58:826-32 describe a microarray study showing differential expression of 16 genes in CFS suggesting T-cell activation and a disturbance of neuronal and mitochondrial function. Other micro- array studies concluded that several genes affected mitochondrial function and cell cycle deregulation. Moreover, alter- ations in membrane transport and ion channels were described. Based on the numerous studies, the gene expression data are not conclusive but suggest that there are disturbances in CFS representing various cellular functions.

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• https://www.youtube.com/watch?v=VCowKm4N2Ow

Annotations:

• http://www.medscape.com/viewarticle/837577_4 login: j.u.rogowska@gmail.com password: Freewolf123 http://www.ncbi.nlm.nih.gov/pubmed/26079000

Annotations:

• 2015: Right arcuate fasciculus abnormality in chronic fatigue syndrome. http://www.ncbi.nlm.nih.gov/pubmed/25353054