Ampligen leidt tot aanzienlijke verbetering van de inspanningskapaciteit
Ampligen zal op de komende konferentie van de HHV-Foundation de (tussentijdse) resultaten van de fase 3-studies presenteren : circa 15% verbetering, onder meer bepaald aan de hand van de inspanningskapaciteit: de prestaties op de loopband. Eigenlijk is al 15 jaar bekend dat Ampligen (antiviraal middel en immuunmodulator) voor een grote groep CVS-patiënten een effektief geneesmiddel is. Vraag dat maar aan de mensen die begin jaren 90 (!!) aan de Ampligen-proefstudie mochten deelnemen. Cfr. : http://www.hetalternatief.org/Ampligen%20Fase%20III%202006%20160.htm
Ampligen komt in 2009 op de markt
Het eerste medicijn voor CVS, Ampligen, komt in 2009 in de Verenigde Staten op de markt. De fabrikant, farmaceut Hemispherx, heeft in juli 2008 het complete dossier met onderzoeksgegevens overhandigd aan de Food and Drug Administration (FDA) die nog een laatste beoordeling gaat verrichten. In februari 2009 verwacht de firma het groene licht te krijgen.
Daarmee komt een eind aan een bizar lang onderzoekstraject. In de zestiger jaren van de vorige eeuw ontdekte een farmaceut in de VS een stukje RNA dat tumorgroei tegenging en interferonproductie stimuleerde. In de zeventiger jaren werd ditzelfde stukje RNA gemodificeerd en verbeterd aan de John Hopkins University en daar gaven de onderzoekers het de naam Ampligen : een middel dat de genetische activiteit vergroot.
Klinische experimenten met de drug, noodzakelijk om het de ooit op de markt te brengen, startten eind tachtiger jaren. Omdat Hemispherx in de VS geen toestemming kreeg voor grootschalige experimenten, week de firma daarvoor uit naar andere landen, België onder andere. Na twintig jaar testen is het dan nu eindelijk zo ver dat de FDA alle informatie voor een New Drug Application binnen heeft.
De werking van Ampligen is nog niet helemaal ontrafeld. Het middel bestrijdt ziekteverwekkers in het lichaam en moduleert het immuunsysteem. In het bijzonder één bepaalde receptor op de cel, TLR-3 genaamd – een receptor die zich gedraagt als een tol (denk aan een tolhuis aan een rijksweg) – schijnt bijzonder efficiënt te zijn in het herkennen van ziekteverwekkers die langskomen, waarna het immuunsysteem in werking gesteld kan worden.
U zult begrijpen dat de aandeelhouders van Hemispherx geen miljoenen dollars in de ontwikkeling van het medicijn gestopt zouden hebben, als het sommige CVS-patiënten niet hielp. Dat doet het dan ook. Naar verluidt worden sommigen er helemaal beter van, terwijl anderen - de meesten - er aanzienlijk door opknappen.
Mary McKinney Schweitzer, en Amerikaanse CVS-patiënte die het middel jarenlang gebruikt heeft, rapporteert dat haar Karnofsky-schaal door Ampligen van 30 naar 70 is gegaan (100 = helemaal gezond). Ze krijgt het middel tweemaal in de week intraveneus in een kliniek toegediend en met die dosis zit ze op een stabiel energieniveau van 70, al jarenlang. Daardoor kan ze toch functioneren, al heeft ze haar vroegere leven niet teruggekregen. Het heeft haar de afgelopen tien jaar wel 20.000 dollar per jaar gekost, maar ze heeft het geluk een rijke echtgenoot te hebben. Eenmaal is ze gestopt, maar na een jaar kreeg ze een terugval, waarna ze opnieuw aan de Ampligen moest.
Volgens dr. Cheney, een bekende Amerikaanse CVS-arts (foto), hebben twee van de drie CVS-patiënten baat bij Ampligen. Patiënten bij wie de ziekte is getriggerd door een virale infectie – Pfeiffer bijvoorbeeld – hebben nog iets meer kans op een gunstige werking.
Ampligen for Chronic Fatigue Syndrome - Update on the Approval Process -
About.com, August 13, 2009
After what was supposed to be a short delay in May, now it looks like we won't hear yea or nay about Ampligen – cfr. : http://en.wikipedia.org/wiki/Ampligen - until this fall. The drug's manufacturer, Hemispherx Biopharma, says it doesn't expect to hear from the FDA until then on the experimental chronic fatigue syndrome treatment.
Dr. William Carter, Hemispherx' CEO, maintains that staffing problems are behind the delay. Some people speculate that something fishy is going on -- which is hard to avoid, given Ampligen's long, complicated history -- but to keep things in perspective, the FDA is late on a host of other approval decisions as well. Carter says the company is continuing to talk to potential marketing partners for Ampligen while awaiting the decision.
It's irritating, annoying, frustrating etc. to wait like this, but at least now we have a rough timeline. We can relax for another 5.5 weeks, then resume watching for this long-awaited, much-anticipated decision.
A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W et al. - School of Medicine, Hahnemann University, Philadelphia, Pennsylvania 19102 - Clin Infect Dis. 1994 Jan;18 Suppl 1:S88-95 - PMID: 8148460 Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation and impairment of cognition. In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined. Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale and exercise treadmill performance. After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05). Cfr. : - http://www.ncbi.nlm.nih.gov/pubmed/8148460 - http://www.find-health-articles.com/rec_pub_8148460-a-controlled-clinical-trial-specifically-configured-rna-drug-poly.htm
Ampligen Adrienne Dellwo, About.com, June 11, 2009 What Ampligen is Ampligen (polyu I : poly C12U) in an experimental anti-viral, immune-system modulating drug that's been in the works for more than 30 years. It's been studied as a possible treatment for multiple conditions, including chronic fatigue syndrome (CFS or ME/CFS), HIV/AIDS, certain types of cancer and, most recently, both avian flu (H5N1) and swine flu (H1N1). Ampligen's manufacturer, Hemispherx Biopharma Inc., has applied for FDA approval of Ampligen as an ME/CFS treatment and the decision is expected in June 2009. If it's approved, Ampligen will be the first approved treatment for this condition. What Ampligen does Ampligen is believed to work by jump-starting your body's natural anti-viral pathway and regulating levels of RNase L (a substance in your cells that attacks viruses), which can be high in people with ME/CFS. It's also been shown to inhibit tumor-cell growth. Ampligen for Chronic Fatigue Syndrome In clinical trials, Ampligen has been shown to improve cognition, exercise tolerance, neuropsychological health and overall function in people with ME/CFS; decrease activity of HHV-6 (a virus believed to be linked to ME/CFS); and decrease RNase L activity. According to Ampligen's manufacturer, Hemispherx Biopharma Inc., more than 40,000 doses of Ampligen were given to about 500 patients in clinical trials at more than 20 U.S. clinics. One of those clinics, the Hunter-Hopkins Center, says 80% of its patients improved on Ampligen and 50% improved significantly. Ampligen dosage Ampligen is administered intravenously (I.V.). In trials and under conditional permits by the FDA, patients typically have received 400mg of the drug twice a week. Hunter-Hopkins recommends at least 12 months of therapy and 18 months for the severely ill. Ampligen side effects Possible side effects of Ampligen include : - mild flushing - tightness of the chest - rapid heartbeat - anxiety - shortness of breath - feeling hot - sweating - nausea - liver enzyme level changes - diarrhea - itching - low blood pressure - rash - arrhythmias - low white blood cell count - dizziness - donfusion. Some patients have flu-like symptoms for a few hours after receiving a dose of the drug and the company says these effects typically went away after several months of treatment. Cfr. : http://chronicfatigue.about.com/od/treatingfmscfs/p/ampligen.htm Cfr. also : http://www.hemispherx.net/content/rnd/drug_candidates.htm
Ampligen & chronic fatigue - Townsend letter for doctors and patients Jule Klotter – BNET, August-Sept, 2005 Hemispherx Biopharma, Inc. has completed a Phase III Chronic Fatigue Syndrome (CFS) trial of Ampligen, a double-stranded RNA drug. In vitro studies indicate that Ampligen may modulate the immune system as well as act as an antiviral agent. Ampligen has been investigated as a possible therapy for HIV/AIDS and CFS since the 1980s. 'Osler's Web - Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic' (Hillary Johnson - Crown (1st edition), March 12 1996 - ISBN-10 : 051770353X – ISBN-13 : 978-0517703533 – cfr. : http://www.amazon.com/Oslers-Web-Labyrinth-Syndrome-Epidemic/dp/051770353X -) profiles some of the early pilot studies. The recent Phase III trial, which took place at 12 centers in the US, was a randomized, double-blind, placebo-controlled, crossover study of 234 subjects with 'severely debilitating CFS.' Subjects received 400 mg of Ampligen parenterally, twice each week for 40 weeks. At the end of the 40 weeks, those receiving Ampligen showed improved treadmill exercise performance : 19.4% (Ampligen group) vs. 5.1% (placebo group). The study was presented at the 17th International Conference on Antiviral Research on 3 May 2004 (Tucson, Arizona). A company press release says "there was no significant difference in the number of serious adverse events, missed dosages or dropouts (ie leaving the study prematurely) among patients receiving Ampligen vs those receiving placebo...." An increase in headaches and muscle pain were common complaints among the first test subjects in the 1980s, according to Osler's Web. Being an experimental drug, Ampligen is only available to persons who take part in a FDA-approved research program. Cfr. : http://findarticles.com/p/articles/mi_m0ISW/is_265-266/ai_n15622560/
Ampligen for chronic fatigue syndrome National Horizon Scanning Centre (part of the National Institute for Health Research), December 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. Cfr. : http://www.pcpoh.bham.ac.uk/publichealth/horizon/outputs/documents/2007/december/ Ampligen.pdf
Ampligen for Chronic Fatigue Syndrome - What's Behind the Delay ? - The FDA is already dragging their feet MySpace.com, Juin 24, 2009 The FDA's 1-2 week delay on the Ampligen decision has now stretched into nearly a month. While this kind of thing is hardly uncommon with the FDA, as time drags on with no announcement people are wondering if something more is going on. At least one Wall Street blogger thinks Ampligen's manufacturer, Hemispherx Biopharma Inc., will withdraw its application rather than have it turned down. That would save the company some embarrassment and allow it to focus its energy on studies of Ampligen for swine flu (H1N1). Then again, this particular blogger has been hammered for spreading misinformation about both the drug and the company, so it's hard to say whether his opinion carries any weight. The delay, however, doesn't necessarily mean something is wrong. Last October, when the agency was supposed to make its decision on Savella (milnacipran) for fibromyalgia, it told the manufacturer it needed more time and then we heard nothing at all until January, when the drug was approved. So what do I think is behind the delay ? Hard to say, but it's certainly not a stretch to think that the FDA just hasn't gotten its you-know-what together enough to release a decision. Cfr. : http://blogs.myspace.com/index.cfm?fuseaction=blog.view&friendId=302950400&blogId=496572575
Biovail acquires Ampligen marketing rights for Canada - New treatment for Chronic Fatigue Syndrome Eugene Melnyk & Kenneth G. Howling - Biovail Corporation, Feb. 11, 2000 Biovail Corporation International (NYSE:BVF)(TSE:BVF) today announced that it has acquired under license the exclusive rights to market Ampligen(R) in Canada from Hemispherx Biopharma, Inc. (Amex:HEB) in return for an initial undertaking by Biovail to purchase approximately $2 million in Hemispherx common shares from treasury. Crystaal plans to submit to the TPP in the near future a new drug submission seeking marketing approval for Ampligen in the treatment of Chronic Fatigue Immune Deficiency Syndrome (CFIDS), also known as Myalgic Encephalomyelitis (ME). Approximately 50,000 Canadians suffer from CFIDS, which is a severely debilitating and complex disorder for which no specific and effective treatment is available in Canada. Ampligen is currently available in Canada under the Emergency Drug Release Program. Ampligen is being clinically evaluated in a confirmatory large phase III trial for CFIDS and the new drug submission will be submitted to the TPP upon completion of certain tests. Other potential uses for Ampligen include the treatment of AIDS, Hepatitis B and Renal Cell Carcinoma. Ampligen will be marketed by Crystaal, Biovail's Canadian marketing division. Crystaal, a division of Biovail, is engaged in the registration, marketing and distribution of branded pharmaceutical products developed by Biovail or acquired from third parties worldwide. Crystaal also promotes Brexidol(R), Tiazac(R), Retavase(R), Cardiac STATus(TM) and co-promotes Celexa(R) in Canada. Biovail Corporation is an international full-service pharmaceutical company, engaged in the formulation, clinical testing, registration and manufacture of drug products utilizing advanced drug delivery technologies. "Safe Harbor" statement under the Private Securities Litigation Reform Act of 1995. To the extent any statements made in this release contain information that is not historical, these statements are essentially forward looking and are subject to risks and uncertainties, including the difficulty of predicting FDA and TPP approvals, acceptance and demand for new pharmaceutical products, the impact of competitive products and pricing, new product development and launch, reliance on key strategic alliances, availability of raw materials, the regulatory environment, fluctuations in operating results and other risks detailed from time to time in the Company's filings with the U.S. Securities and Exchange Commission. Cfr. : http://www.biovail.com/english/Investor%20Relations/Latest%20News/default.asp?s=1&state=showrelease&releaseid=74228
Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE et al. - Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 - In Vivo. 1994 Jul-Aug;8(4):599-604 - PMID: 7893988 Latent 2', 5'-oligoadenylate (2-5A) synthetase activity, bioactive 2-5A and RNase L activity were measured in extracts of peripheral blood mononuclear cells (PMBC) before and during a randomized, multicenter, placebo-controlled, double-blind study of poly(I)-poly(C12U) in individuals with chronic fatigue syndrome (CFS) as defined by the Centers for Disease Control and Prevention. The mean values for bioactive 2-5A and RNase L activity were significantly elevated at baseline compared to controls (p < .0001 and p = .001, respectively). In individuals that presented with elevated RNase L activity at baseline, therapy with poly(I)-poly(C12U) resulted in a significant decrease in both bioactive 2-5A and RNase L activity (p = .09 and p = .005, respectively). Decrease in RNase L activity in individuals treated with poly(I)-poly(C12U) correlated with cognitive improvement (p = .007). Poly(I)-poly(C12U) therapy resulted in a significant decrease in bioactive 2-5A and RNase L activity in agreement with clinical and neuropsychological improvements (Strayer DR et al., Clin. Infectious Dis. 18:588-595, 1994). The results described show that poly(I)-poly(C12U) is a biologically active drug in CFS. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/7893988
Chronic Fatigue Syndrome treatment - FDA's Ampligen decision imminent Adrienne Dellwo - About.com, Friday May 22, 2009 Will the millions of people with chronic fatigue syndrome (CFS or ME/CFS) finally have an FDA-approved drug treatment ? We should know soon, as the long-awaited decision on Ampligen (poly I: poly C12U) is due on or around May 25. Ampligen has languished in the "experimental" stage for 30 years. Then, in October 2007, Hemispherex Biopharma Inc. put in a New Drug Application for Ampligen as the first ever FDA approved treatment for ME/CFS. In July 2008, the company responded to questions sent back by the FDA and the application was officially accepted. The decision was originally due in late February, but the FDA at that time announced it needed 3 more months. Now, it's just a matter of time before we hear yea or nay. Ampligen is an immume-system modulator that works by jump-starting your body's natural anti-viral pathway and regulating levels of Rnase L (a substance in your cells that attacks viruses), which can be high in people with ME/CFS. Studies show it's more effective and has far fewer side effects than other drugs in its class. Ampligen has also been studied as a possible treatment for AIDS, avian flu, and certain types of cancer. This drug has been available to certain U.S. clinics for several years, and there's a lot of evidence (both clinical and experiential) showing that it works. Some doctors claim they've seen improvement in 80% of people with ME/CFS who take Ampligen and significant improvement in about 50%. They say a lot of seriously disabled people have even been able to go back to work because of it. Side effects are reportedly mild and include flu-like symptoms, dizziness and confusion (after living with ME/CFS, would you even recognize those as side effects ?). Cfr. : http://chronicfatigue.about.com/b/2009/05/22/fdas-ampligen-decision-imminent.htm
Chronic fatigue syndrome/myalgic encephalomyelitis (or encaphalopathy) - Diagnosis and management of CFS/ME in adults and Children National Institute for Health and Clinical Excellence - Guideline 53. August 2007
Evidence based guideline for the management of CFS/ME (Chronic Fatigue Syndrome/myalgic encephalopathy) in children and young people Royal College of Paediatrics and Child Health - December 2004 Cfr. : http://www.rcpch.ac.uk/doc.aspx?id_Resource=1480
Frequently Asked Questions about Ampligen WWCoCo New Media, December 10, 1996 What is Ampligen ? Ampligen is a drug manufactured by HEMISPHERx Biopharma, Inc. (NASDAQ:HEMX), Philadelphia, Pa. It is an antiviral and immune modulatory drug under the nucleic acid class of drugs (Nas). Nucleic acid drugs are designed to mimic the body's own digitalized informational molecules (called DNA and RNA) which, in some laboratory and animal studies, reprogram certain diseased cells to enhance their intrinsic disease capabilities. To date, HEMISPHERx and its subsidiaries have received over 200 patents internationally to protect its proprietary position in NA and related drug technologies. What is the generic name of Ampligen ? Ampligen is the drug poly I: poly C12U, which is a specific form of mismatched double-stranded ribonucleic acid (dsRNA) where uridylic acid (U) substitutions in the polycytidylic acid chain create periodic regions of non-hydrogen bonding in the helical configuration. These changes, developed by HEMISPHERx, have resulted in unique double-stranded RNA s, termed mismatched double-stranded RNA s. Double-stranded RNA s act as modulators or molecules that mediate cellular immune and antiviral activities. How does Ampligen work ? Ampligen inhibits viruses and tumor-cell growth through pleiotropic or multiple interrelated, mechanisms. Ampligen up-regulates or down-regulates, as needed, two important enzyme systems; (1) the 2 ,5 oligoadenylate synthetase/RNase L (2-5A synthetase/RNase L) pathway; and (2) the P68 protein kinase pathway. Ampligen can induce the production of 2-5A synthetase independent of interferon induction. It also can activate both 2-5A and p68 protein kinase, while IFNs can only induce production, but not activate, these enzymes, an important biological distinction. Ampligen can also inhibit 2-phosphodiesterase, an enzyme which destroys the product of 2-5A synthetase, biactive 2-5A. These differences in mechanisms between IFNs and Ampligen result in clinical and biological activities in interferon intolerant or resistant states and synergistic interactions between Ampligen and interferon (once these pathways are stimulated correctly, the cell responds with the production of cytokines and lymphokines, the chemical messengers immune cells used to communicate the memory response of antigen specific CD8+ cells, the type of white blood cells thought to play the major role in cell-mediated immunity). 2-5A Synthetase/RNase L Pathway : Once 2-5A mRNA has been transcribed by the genes in the nucleus (which earlier had been stimulated by messages from the cAMP signal transition pathway), latent 2-5A synthetase is created. Ampligen then activates this latent 2-5A synthetase and activated 2-5A is created. Activated 2-5A, in turn, activates an enzyme called RNase-L, which destroys viral RNA (oragen compounds directly stimulate the production of active 2-5A). 2-5A itself also can control the growth of certain human tumor cells and inhibits reverse transcriptase, the enzyme both HIV and HBV use for reproduction. The RNase-L pathway is one of the immune system s standard response to viral infection (termed intracellular immunity ). Some viruses, however, such as HIV, herpes and HBV overcome intracellular immunity by producing substances that deactivate RNase-L, thereby releasing the virus to multiply largely unchecked within the intracellular environment and clinical deterioration occurs. Protein Kinase (p68) Pathway : The protein kinase (p68) pathway is also affected in a similar manner. Once p68 kinase mRNA is transcribed from DNA templates in the nucleus of the cell, p68 kinase is formed by translation of the RNA message. Ampligen then induces the autophosphorylation of p68 kinase (essentially an activation of p68 kinase) that leads through two other steps, elF2a and elf25-P to the inhibition of viral protein syntheses. Who invented Ampligen ? William A. Carter, M.D., the co-inventor of Ampligen, was a pioneer in the clinical development of interferon, a protein therapy now approved for more than a dozen viral diseases and commanding a market in excess of $2 billion. Where is Ampligen manufactured ? Ampligen is currently manufactured in the United States. To prepare a shipment of the drug, the Company receives certain raw materials from Pharmacia/Upjohn functioning as a subcontractor and then processes this material to develop the final finished drug using HEMISPHERx facilities in Rockville, Maryland. Dosage units are then prepared and tested for quality assurance. Also, on December 18, 1995, Bioclones Proprietary (an affiliated company of the South African Breweries Limited) as part of a strategic alliance with HEMISPHERx, successfully completed the first production runs at a larger nucleic acid manufacturing plant near Johannesburg, South Africa. It is expected that the combined facilities of the partnership will, with the passage of time, increase efficiency and thus lower the overall manufacturing costs of this drug. How much does Ampligen cost ? The cost of manufacturing Ampligen for the treatment programs in Belgium and Canada is relatively high (U.S. $12-18,000) due to the low volume. Who responds well to Ampligen ? The results of Ampligen trials in the United States and Belgium suggest that Ampligen may be an effective treatment for a certain subset of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) patients, namely those with severe debilitation. The patients who entered the Ampligen trials met the strict case study definition of ME/CFS established by the Center for Disease Control and Prevention (CDC). Where is Ampligen available ? As of this writing (December 1996), Ampligen is available to patients in Canada and Belgium under cost recovery programs. Belgium : A trial initiated in Belgium in May, 1996 by Kenny DeMeirleir, M.D., Ph.D., from the University of Brussels and by David Strayer, M.D., Professor of Medicine at Allegheny University, PA and Medical Director for HEMISPHERx, was significantly expanded in November, 1996. The expanded enrollment came at the request of the Belgian investigator, who reported that after six months of Ampligen therapy, approximately 80% of the treated patients thereafter experienced an apparent complete clinical recovery, which meant that the patient could go back to school or to work. The typical patient had been bedridden because of CFIDS for between 3 and 7 years prior to the initiation of the six-month treatment program. The results of the Belgium clinical study were reported in San Francisco, Calif., on October 14, 1996, at the scientific meeting of the American Association for Chronic Fatigue Syndrome (AACFS). The improvements observed in the two key measurements of physical performance used for the 24-week long Belgium study confirmed and extended earlier findings obtained from open-label and placebo-controlled American trials. The two measures of physical performance were Karnofsky Performance Score (KPS), used to measure activities of daily living; and exercise performance on a bicycle. KPS improved 43% from a severely debilitating level of 53 to a level of 76. A KPS score of 80 describes an individual who can perform normal activities with effort, but continues to have limited signs of the illness. On the bicycle testing, Belgium patients improved oxygen uptake significantly, from 1.16 liters/minute before the twice-weekly Ampligen administration of 200 to 400 mg, to 1.48 liters/minute after treatment. In addition to physical improvement, significant cognitive improvements were documented among patients on the three Ampligen trials, using the cognitive subscale of the SCL 90-R or neuropsychological function tests. The Ampligen treatments were generally well tolerated. By contrast, spontaneous recovery of untreated patients suffering from CFIDS is low. Earlier studies indicate that only 2% of the CFIDS population report spontaneous improvement to normal function and activity levels. Canada : On May 3, 1996 Canada's Health Protection Board made Ampligen available to sufferers of Chronic Fatigue and Immune Dysfunction Syndrome ( CFIDS ), an extremely debilitating chronic viral condition with no previously approved treatments in the U.S. and Canada. On October 1, 1996, HEMISPHERx BioPharma, Inc. announced that it began shipment of Ampligen to Rivex Pharma in Aurora, Ontario, a wholly-owned subsidiary of Helix BioPharma Corp. Ampligen is administered in Canada at the request of Canadian physicians. Cfr. : http://wwcoco.com/cfids/ampligen.html
Hemispherex files first chronic fatigue syndrome candidate Scrip News - PJB Publications. Number 3304. October 19th 2007. Page 18
Hemispherx Biopharma files new drug application for Ampligen® as treatment of Chronic Fatigue Syndrome - NDA of investigational drug includes four well-controlled trials, more than 1,200 trial subjects and 90,000 doses Hemispherx Biopharma Press Release for Thursday, October 11, 2007 Cfr. : http://www.hemispherx.net/content/investor/default.asp?goto=315
Immunological aspects of chronic fatigue syndrome Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G - Department of Neurology, Mellino Mellini Hospital, Chiari, Brescia, Italy - Autoimmun Rev. 2009 Feb;8(4):287-91. Epub 2008 Sep 16 - PMID: 18801465 Chronic fatigue syndrome (CFS) is a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months, in the absence of a medical diagnosis that would otherwise explain the clinical presentation. Other common symptoms include headaches, myalgia, arthralgia and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years. The estimated worldwide prevalence of CFS is 0.4-1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK. No physical examination signs are specific to CFS and no diagnostic tests identify this syndrome. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people. The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed. This review discusses the immunological aspects of CFS and offers an immunological hypothesis for the disease processes. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/18801465
Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome Nijs J, De Meirleir K - Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium : Jo.Nijs@vub.ac.be - In Vivo. 2005 Nov-Dec;19(6):1013-21 - PMID: 16277015 This paper provides an overview of the evidence addressing the impairments of the 2'-5' oligoadenylate (2-5 A) synthetase/RNase L pathway in Chronic Fatigue Syndrome (CFS) patients. The 2-5A synthetase/RNase L pathway in CFS patients appears to be both up-regulated (i.e. increased levels of bioactive 2-5A synthetase and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments with molecular masses of 37 and 30 kDa, respectively). The deregulation of the 2-5A synthetase/RNase L pathway in CFS accompanies decreased NK-function and deregulation of apoptotic pathways. Since various components of the pathway appear to be related to performance during a graded exercise stress test, some evidence supportive of the clinical importance of the impaired pathway in CFS patients has been provided. Studies addressing the treatment of the deregulation of the 2-5A synthetase/RNase L pathway in CFS are warranted. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/16277015
Mismatched Double-Stranded RNA - Ampligen, Oragen, Polyi:Polyc12u Drugs in R&D, Volume 3, Number 2, 1 February 2002 , pp. 132-138(7) Ampligen [polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts. It has been developed by Hemispherx Biopharma. In the USA, Ampligen has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II). Chronic fatigue syndrome Hemispherx submitted an application to the European Medicines Evaluation Agency (EMEA) for the approval of Ampligen in the treatment of chronic fatigue syndrome at the end of 1998. Ampligen has cleared the first stage of regulatory EMEA review. In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen for the treatment of chronic fatigue syndrome in the European Union. This will provide Hemispherx with 10 years of marketing exclusivity upon launching as well as potential financial research benefits for the agent. In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen in the Southern Hemisphere, UK and Ireland. In April 1999, Hemispherx received authorisation from the FDA to more than double the number of patients (to more than 200) enrolled in its phase III trial of Ampligen as a treatment for chronic fatigue syndrome (termed AMP 516) in the USA. In February 2000, Crystaal Corporation (Biovail) acquired exclusive marketing rights to Ampligen in Canada and has submitted a new drug submission for the agent in the treatment of chronic fatigue syndrome in Canada. In the meantime Ampligen is available to be administered under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma). Bioclones has initiated clinical studies with Ampligen for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen is manufactured by F.H.Faulding Ltd. Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa. Hemispherx has developed a `ready-to-use' liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen), which is undergoing preclinical evaluation. HIV-infections Hemispherx announced at the end of January 2001 that it had made a major amendment to the original trial protocol, with the intention of accelerating immunological effects in patients. Under the new protocol, patients receive Ampligen constantly, with antivirals (HAART) administered periodically. This `Strategic Treatment Intervention' (STI) has the ultimate endpoint of induction of chronic immune control of HIV, with elimination of the need for lifelong use of HAART. According to data presented at the DART 2000 HIV conference in Puerto Rico in December 2000, 60 years of HAART therapy may be required to eliminate HIV from patients if immune support is not given; cumulative liver toxicity has been reported with long term use of HAART. In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen in the treatment of late stage, multidrug resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options. In July 2001, Hemispherx stated that Ampligen was being evaluated in phase IIb trials in patients with HIV in the USA. The studies, REARMI and REARMII (Research/Evaluation of Ampligen for Retroviral Mutations I and II) will evaluate the ability of Ampligen to prevent the emergence of mutated, drug-resistant strains of the virus. `Several hundred' patients currently on anti-retroviral therapy and at risk of viral relapse will be enrolled at centres in Conneticut, New York, Florida and California. In July 2001, Hemispherx Biopharma also announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections. Hepatitis B and C Hemispherx has conducted phase I/II trials in patients with chronic hepatitis B, patients with severe thermal injury and patients with metastatic melanoma. Bioclones plans to undertake clinical trials in hepatitis B and C in South Africa and Australia. Cfr. : http://www.ingentaconnect.com/content/adis/rdd/2002/00000003/00000002/art00016
Review of Ampligen® clinical trials in Chronic Fatigue Syndrome W. Mitchell – Chronic Fatigue Syndrome Clinical Consortium, Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA; Hemispherx Biopharma, Philadelphia, PA, USA : firstname.lastname@example.org - ProHealth, January 17, 2007 - Journal of Clinical Virology, Vol. 37, Supplement I, December 2006, pg. S113. [Sponsored by HHV-6 Foundation. E-Publication Jan 2007 - Full text available for a fee at : http://www.sciencedirect.com/science/journal/13866532 -] Objectives Ampligen is a double-stranded (ds) RNA with well established broad antiviral and immunomodulatory properties that has been studied extensively in the treatment of Chronic Fatigue Syndrome (CFS). A total of five open-label and two double-blind, placebo-controlled trials have enrolled over 750 subjects. Primary endpoints have been achieved with statistical significance. No serious safety issues have resulted from the administration of ~75,000 doses IV (most commonly 400 mg) twice weekly for up to one year periods or greater. Animal toxicity studies support this observation in humans with primates demonstrating the greatest margin of safety. In the recently completed Phase 3 trial, patients receiving Ampligen for 40 weeks improved exercise treadmill performance 14.8% compared to the placebo group (p = 0.025) and 12.9% by intent to treat analysis (p = 0.052) and this improvement represents twice the minimum considered medically significant (6.5%). The Ampligen cohort with Baseline exercise duration >9 min improved oxygen utilization compared to a decrease in the placebo group (p < 0.05). Increased oxygen utilization correlated significantly with improved treadmill exercise duration (p < 0.001). The KPS, as a function of general physical capacity, was similarly significantly correlated (p = 0.01) with the improvement in exercise tolerance of the Ampligen study arm. Summary - Patients with CFS use large quantities of drugs to alleviate the symptoms associated with CFS. The concomitant use of drugs to treat symptoms of CFS was significantly less in the Ampligen arms of both the Phase 2 and Phase 3 controlled trials. - Ampligen treatment in chronically debilitated CFS populations has demonstrated significant improvement in physical well being and quality of life that can be linked with dysregulation of gene expression associated with energy metabolism. - The improvement in exercise duration is significantly correlated to improvement in oxygen utilization and physical performance. Cfr. : http://www.prohealth.com/library/showarticle.cfm?id=7638&t=CFIDS_FM
RNase L - Definition Adrienne Dellwo, About.com, (updated) December 05, 2008 A cellular enzyme that is part of the body’s immune defense. RNases are extremely common in the body and act to break up ribonucleic acid (RNA). Studies of CFS patients have shown that RNase levels may be higher than normal. While the reason for this is not clear, some speculate that it could be related to a viral attack. In the case of CFS patients, the RNase destroys all of the RNA within the cell, whether cellular or viral. Chronic fatigue syndrome sufferers frequently have elevated levels of RNase L, which supports the theory that the onset of CFS could be linked to a virus. Some studies have looked into whether RNase L levels could be used for diagnosing CFS. Cfr. : http://chronicfatigue.about.com/od/cfsglossary/g/RNaseL.htm
Treating Chronic Fatigue Syndrome (ME/CFS) - Ampligen Part II - Twisted History About ME-CFS A twisted history Ampligen and chronic fatigue syndrome (ME/CFS) have had a twisted history. Twenty years ago advocates were lobbying for ‘fast-track’ status for the new wonder drug they hoped would cure the disease. Ampligen never had a chance of being fast-tracked given the patient population wasn’t dying in large numbers but the road to approval has nevertheless been an uncommonly slow one. Hemispherx Biopharma has been seeking FDA approval on and off since 1988 but twenty years later the only patients currently able to use the drug are patients in the drug trials or very ill patients who have been able to use it on a ‘cost-recovery basis’. Ampligen has been available for use in both Belgium and Canada (under its emergency drug release program) since 1996. With friends like this… Hemispherx Biopharma, the small company that produces the drug, and it’s founder, Dr. William Carter, have Ampligen (poly I:poly C12U) have been embroiled in lawsuits throughout much of its existence. Throughout his career Dr. Carter has been a lightning rod for controversy with dismissals, accusations and lawsuits dotting his time with different companies. Some of the allegations have been remarkable; one sick chronic fatigue syndrome (ME/CFS) patient sued Carter claiming he required him to buy $1,000,000 in Hemispherx stock to order to participate in a study (he later dropped the lawsuit). Dr. Carter has twice sued former employers (once successfully) to get his job back. Patients in the chronic fatigue syndrome drug trials successfully sued after Hemispherx denied them the drug after the trial ended (for a hilarious and often heartrending 'fictional' account of the early Ampligen trials read Patient 002 by Floyd Skloot). With a 30 million dollar infusion from DuPont, Dr. Carter and Hemispherx began clinical trials in Ampligen in chronic fatigue syndrome (ME/CFS) in 1988. Trouble ensued and in 1990 Dupont settled (what else) a lawsuit with Hemispherx and gave up all claims to the drug. Possibly hemorrhaging money after a major financier died, Hemispherx cut back a 48 week trial to 24 weeks and, according to one report, applied for fast-track limited drug approval at the FDA. As the media spread accounts of a wonder drug that significantly helped many patients, the FDA, citing toxicity concerns and calling the data before them ‘incomplete and inadequate’ (and not happy at all about the media attention) nixed the fast track status. Hemispherx then turned its attention away from getting approval for the drug in the U.S. It would be almost 20 years before Ampligen would finally near the end of the treatment trial road at the FDA. Despite producing a drug that has substantially helped some chronic fatigue syndrome (ME/CFS) patients, Hemispherx has gathered few friends in the past 20 years. In the early 1990s Kim Kenney (McCleary), now the President of the CFIDS Association of America , said : “Ampligen is a good drug in the wrong hands". Daniel Hoth, then head of the National Institutes of Health's AIDS drug program, went further when he told the Wall Street journal that "no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM." Indeed the drug trial has been going on for so long that Hemispherx is reportedly tied to an obsolete definition for the disease (Holmes) and an out of date statistical package. Advocates and physicians have questioned what kinds of patients are in the studies, the markers Hemispherx is using to chart the patients' progress and the overall competence of the company. Whatever mistakes have been made, Hemispherx has its advocates as well. Ampligen is still the only drug that has undergone clinical trials for this controversial disease. While many fervently wish a different company had taken over the drug years ago, others applaud Dr. Carter’s tenacity for sticking with it through thick and thin for over 30 years. That the drug is still alive and may, in fact, be on the edge of approval, may be something of a miracle given its history, the disease it treats, and the high failure rate of drugs in general. The Present. Hemispherx appears to have gotten its financing and legal house in order. Dr. Carter recently reported that all legal issues have been settled leaving the company free to focus on the drug itself. Ampligen has completed Phase II and III clinical trials. After having missed the deadlines in 2005 and earlier in 2007, Hemispherx filed its ‘New Drug Application’ (NDA) with the FDA in October, 2007. The FDA bounced back the application with questions in early 2008. Hemispherx replied and after both the drug and the company went under further reviews the FDA passed the drug onto the final review; we’ll probably know by spring 2009 whether Ampligen will become the first FDA-approved drug for chronic fatigue syndrome (ME/CFS). Cfr. : http://aboutmecfs.org/Trt/AmpHist.aspx
Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Müller WE, Schröder HC, Carter WA et al. - Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 - Clin Infect Dis. 1994 Jan;18 Suppl 1:S96-104 - PMID: 8148461 Levels of 2',5'-oligoadenylate (2-5A) synthetase, bioactive 2-5A and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls. Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002) and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/8148461
Using antidepressants to treat Chronic Fatigue Syndrome Charles Lapp, MD - Dr. Lapp practices internal medicine at the Hunter-Hopkins Center in Charlotte, NC. He is also a Clinical Associate Professor of Family and Community Medicine at Duke University Antidepressants have proven to be useful in treating chronic fatigue syndrome (CFS). They can help improve sleep, energy levels and cognitive impairment and alleviate pain.1,2,3 It needs to be emphasized that these drugs are helpful not because patients are primarily depressed (although depression may occur as a result of the illness), but because they often have low levels of the neurotransmitters serotonin and dopamine.4 I find that almost all of my patients benefit from treatment with antidepressants. The chart at this link is not intended to be comprehensive, but rather to represent classes of drugs that may be helpful. Following is a brief discussion of research on the benefits of antidepressants and the process that I use when deciding which drug to try with a patient. Review of research A small number of trials have been conducted to assess the possible value of antidepressants for CFS and for the most part have provided evidence of their usefulness in treating specific symptoms. A minority of patients in a six-week treatment study of Nardil (phenelzine), a monoamine oxidase inhibitor (MAOI), reported significant improvement, although some had to drop out of the trial due to side effects.1 Trials of Manerix (moclobemide), another MAOI, with CFS patients have showed significant reductions in fatigue.3,4 Unfortunately, moclobemide is not available in the United States. Pamelor (nortriptyline), a tricyclic antidepressant (TCA), was tested in a single-case, double-blind study for CFS. A 60 mg-per day dose significantly reduced CFS symptom scores.5 In controlled trials, TCAs have also proven beneficial in the treatment of fibro-myalgia (FM), an illness that shares many clinical features with CFS.6 Despite encouraging results from earlier case studies, a trial of Prozac (fluoxetine) conducted in the Netherlands with 44 CFS patients with concomitant depression and 52 with CFS but no evidence of depression failed to show significant beneficial effects. The researchers suggested that the fact that even the depressed group failed to improve indicates chemical changes in the brain in CFS that are very dissimilar to depression.7 In an uncontrolled trial, 79 patients with CFS who showed no signs of depression reported seeing major improvement (particularly regarding levels of fatigue, muscle pain and sleep disturbance) after treatment with Zoloft (sertraline).8 Antidepressants may also benefit the immune system in CFS. Dr. Nancy Klimas at the University of Miami has studied the effect of selective serotonin reuptake inhibitors (SSRIs) on the immune system. She has reported that CFS patients given Prozac for three months showed moderate to marked improvement in the number of natural killer cells present.9 Choosing the right drug The first question I ask when deciding which antidepressant to prescribe for a CFS patient is whether the individual is having difficulty sleeping. Three drugs listedin the chart at this link, Desyrel (trazadone), Remeron (mirtazapine) and Serzone (nefazadone) are more sedating and may be useful in assisting sleep. Desyrel in particular increases stage 3 and 4 (or "deep") sleep. Wellbutrin (bupropion), Prozac and Zoloft are more activating drugs in terms of increasing CFS patients' perceived energy levels, but they may actually interfere with deep sleep. Some stimulating drugs may also increase the risk of seizure activity by causing hyperexcitability in the central nervous system. Pain control is another factor that I consider. TCAs increase levels of norepinephrine in the central nervous system, which will increase the patient's pain threshold. This is why Elavil (amitriptyline) is often used to treat FM and CFS. However, while Elavil has a soporific effect, it reduces deep sleep and in the long run may not be the best choice for patients having trouble sleeping. Effexor (venlafaxine) is a serotonin and norepinephrine reuptake inhibitor that mayalso increase the pain threshold. Wellbutrin is the first antidepressant on the market to increase levels of the neurotransmitter dopamine, which is typically "balanced" with serotonin in the brain. If a patient has tried serotonin agonists and does not tolerate them well, then Wellbutrin may be a good choice. Wellbutrin may be taken alone or with other antidepressants. Remeron is another unique drug in that it affects alpha 2 receptors and histamine receptors in the brain. At lower doses (7.5 to 30 mg), the histaminic effect can induce sleep. Starting at 30 mg, the alpha 2 effect appears, which can give patients increased energy levels. Clinicians should be aware that 30 mg is the highest recommended dose according to the manufacturer, although psychiatrists occasionally prescribe 45 or 60 mg doses. The histaminic effect of Remeron can stimulate appetite, so patients on low-dose therapy with this drug usually gain weight rapidly. Clinicians may want to use Remeron only with individuals who are low weight or losing weight. If the patient has neurally mediated hypotension or orthostatic intolerance, which can cause fluctuations in blood pressure and heart rate, clinicians may want to choose an antidepressant that can improve those symptoms as well. Prozac, Zoloft and Paxil (paroxetine) have been shown in controlled, blinded studies to improve autonomic function. Antidepressant drugs have been associated with numerous side effects. Wellbutrin, Desyrel, Remeron and Serzone show the least incidence of sexual dysfunction as a side effect, while Prozac, Zoloft and Paxil are most likely to suppress libido. The drugs with the highest anitcholinergic effect, Paxil, Elavil and Desyrel, can lead to dry eyes and mouth and blurred vision. Some antidepressants can also affect the cytochrome P450 system, which detoxifies the liver. If that system is blocked by the drug, other medications cannot be metabolized and build up in the body, leading to a higher risk of adverse effects. Additional clinical suggestions Selecting the most efficacious agent depends upon taking a good patient history and tailoring drug therapy to the patient's specific symptoms. Clinicians should be aware that CFS patients often have sensitivities and idiosyncratic reactions to medication. They also may show a therapeutic response at much lower doses than individuals suffering from major depression. I start low and go slow, using one-half to one-third of the usual dose at first (see chart for specific dose suggestions). Some patients require even lower doses. Using medications that are available in the liquid form, such as Sinequan (doxepin), may be helpful, since the dose is infinitely adjustable. References 1/ Natelson BH et al. - Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome - Psychopharmacol. 1996; 124: 226-30 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/8740043 2/ Goodnick PJ - Treatment of CFS with venlafaxine - Am J Psychiatry. 1996; 153: 294 Cfr. : http://ajp.psychiatryonline.org/cgi/reprint/153/2/294a 3/ White PD and Cleary KJ - An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome - Int Clin Psychopharmacol. 1997; 12: 47-52 Cfr. : http://cat.inist.fr/?aModele=afficheN&cpsidt=2661461 4/ Hickie IB et al. - A randomized, double-blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome - J Clin Psych. 2000; 61: 643-8 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/11030484 5/ Goodnick PJ and Sandoval R - Psychotropic treatment of chronic fatigue syndrome and related disorders - J Clin Psych. 1993; 54: 13-20 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/8428892 6/ Blondel-Hill E and Shafran SD - Treatment of chronic fatigue syndrome - A review and practical guide - Drugs. 1993; 46: 639-51 Cfr. : http://www3.interscience.wiley.com/journal/119283190/abstract?CRETRY=1&SRETRY=0 7/ Vercoulen J et al. - Randomized, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome - Lancet. 1996; 347: 858-61 and 1770-2 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/8622391 8/ Behan P et al. - A pilot study of sertraline for the treatment of chronic fatigue syndrome - Clin Infect Dis. 1994; 18 (suppl 1): S111 9 / Information presented by Nancy Klimas at The CFIDS Association of America's 1990 research conference in Charlotte, NC. Cfr. : http://chronicfatigue.about.com/gi/dynamic/offsite.htm?zi=1/XJ&sdn=chronicfatigue&cdn=health&tm=11&gps=331_153_1020_483&f=00&su= p736.8.336.ip_&tt=2&bt=1&bts=1&zu=http%3A//www.cfids.org/archives/2001rr/2001-rr3-article01.asp
Het CVS/ME Centrum te Amsterdam - de enige locatie in Nederland waar ME/CVS-patiënten terecht kunnen voor enkele gerichte diagnostische testen zoals een inspanningsproef (fietstest) en een kanteltest (tilt-table) - heeft vanwege de sterk opgelopen wachttijd per 24 juli 2009 een patiëntenstop ingesteld. Nieuwe patiënten zouden pas in april 2010 aan de beurt zijn.
Volgens arts Ruud Vermeulen van het centrum, is de opening van een tweede centrum in Nederland wenselijk.
Onlangs is het centrum begonnen met het uitproberen van apparatuur voor het meten van zuurstofverzadiging, de mate waarin de capaciteit van rode bloedlichaampjes om zuurstof te vervoeren wordt gebruikt.
Volgens wetenschappelijk onderzoek ligt hier bij ME een probleem :
Impaired oxygen delivery to muscle in chronic fatigue syndrome McCully KK, Natelson BH - Department of Medicine, Medical College of Pennsylvania and Hahnemann University, Philadelphia, PA 19129, USA : email@example.com - Clin Sci (Lond). 1999 Nov;97(5):603-8; discussion 611-3 - PMID: 10545311 The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced oxygen delivery to muscles. Patients with CFS according to CDC (Center for Disease Control) criteria (n=20) were compared with normal sedentary subjects (n=12). Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous-wavelength near-IR spectroscopy. Phosphocreatine resynthesis was measured simultaneously using (31)P magnetic resonance spectroscopy. The time constant of oxygen delivery was significantly reduced in CFS patients after exercise (46.5+/-16 s; mean+/-S.D.) compared with that in controls (29.4+/-6.9 s). The time constant of oxygen delivery was also reduced (20.0+/-12 s) compared with controls (12.0+/-2.8 s) after cuff ischaemia. Oxidative metabolism was also reduced by 20% in CFS patients and a significant correlation was found between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced in CFS patients compared with that in sedentary controls. This result is consistent with previous studies showing abnormal autonomic control of blood flow. Reduced oxidative delivery in CFS patients could be specifically related to CFS or could be a non-specific effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result in reduced oxidative metabolism and muscle fatigue, further studies will be needed to address this issue. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/10545311
Also read the comment on this article : Chronic fatigue syndrome - The physiology of people on the low end of the spectrum of physical activity ? Wagenmakers AJ - Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands - PMID: 10545313 - Clin Sci (Lond). 1999 Nov;97(5):611-3 Cfr. : http://www.clinsci.org/cs/097/0611/0970611.pdf
De hele nacht slapen, maar toch hondsmoe wakker worden ? Een mogelijke oorzaak is een stokkende ademhaling ’s nachts. Deze aandoening heet het OSAS.
De oorzaak van het OSAS ('obstructief slaapapneu syndroom') is het ontspannen van de spieren in de slaap. De tong en weke delen in de keel blokkeren de ademhaling meerdere malen per nacht. Er komt niet genoeg zuurstof in het bloed en het lichaam vecht om weer lucht te krijgen. Op de langere termijn kan OSAS tot ernstige hart- en vaatproblemen leiden, zoals hartinfarcten en hartfalen.
De patiënt heeft vooral last van concentratieproblemen, vermoeidheid en slaperigheid overdag, maar´s nachts merkt hij vaak niets. De partner merkt het wel, vooral omdat OSAS meestal gepaard gaat met snurken. Voor hem of haar is het behoorlijk beangstigend dat de patiënt soms een minuut lang geen adem haalt.
KNO- en longarts
De huisarts kan deze patiënt doorverwijzen naar de afdeling KNO van een ziekenhuis. Aan de hand van een vragenlijst en vervolgens een slaaponderzoek bij de afdeling Longziekten bepalen de KNO-arts en de longarts samen of de patiënt het OSAS heeft. Binnen twee weken heeft de patiënt uitsluitsel en kan de behandeling beginnen.
Naast obstructief slaap apneu syndroom (OSAS) is er nog een tweede vorm, nl. het centraal slaapapneu. Bij centraal slaapapneu worden de onderbrekingen in de ademhaling niet veroorzaakt door een blokkering van de luchtwegen, maar door een slechte werking van de signalen die worden uitgewisseld tussen het ademhalingscentrum in de hersenen en de spieren die de ademhaling regelen. Centraal slaapapneu treedt het meest op bij oudere mensen, in combinatie met hartfalen of na een beroerte, als resultaat van beschadiging van de hersenen of zenuwcircuits.
New perspective on chronic fatigue syndrome - Lessons from developmental neuroscience - Part I
New perspective on chronic fatigue syndrome - Lessons from developmental neuroscience -
Christine Heim, Associate Professor, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, WRMB, Suite 4000, Atlanta, GA 30322, USA : firstname.lastname@example.org - Future Neurology, July 2009, Vol. 4, No. 4, Pages 377-381
Hardly ever has a somatic disorder been surrounded with as much controversy as chronic fatigue syndrome (CFS). Some people believe that the disorder does not even exist and consider CFS a classic manifestation of Freud’s concept of hysteria, which implies the unconscious simulation of organic disorders, in the context of emotional excitability, high anxiety and sensory and motor disturbances . Of note, Freud thought that hysteria is brought about by an infantile traumatic experience . At the other end of the spectrum, patient representative groups often vividly advocate CFS as a true medical disease with a sole physiologic cause that, once pinned down, may hopefully be reversible using standard medical techniques in the future.
In an effort to promote CFS as a legitimate medical condition, a nationwide public awareness campaign has recently been launched in the USA, with the aim to dissolve existing myths that surround CFS and educate the public regarding CFS facts .
What are some of these facts ? First and foremost, the condition is very common with up to 2.5% of the population suffering from CFS in the USA. CFS affects four-times more women than men and most cases are middle-aged individuals. The average duration of CFS in cases identified from the population is 5–7 years, but less than 20% have been diagnosed with CFS by a physician. A quarter of affected individuals are unemployed or receive disability benefit and the average household forgoes US $20,000 in lost earnings and wages as a result of CFS. The total economic cost of CFS in the USA is an estimated $9.1 billion per year. Without doubt, CFS is a debilitating condition that is associated with considerable personal suffering and decreased quality of life for affected individuals [2,102].
Despite the magnitude of the public health problem, the causes of CFS remain unknown and specific targets for prevention and treatment remain elusive. To date, more than 4000 research studies have failed to identify a unanimous cause of CFS and there is evidence that both biological and psychological factors contribute to CFS. Reported biological abnormalities in CFS mostly affect the brain’s regulatory outflow systems, namely, the endocrine, autonomic and immune systems. Psychological or behavioral factors contributing to the development or maintenance of CFS include inactivity, avoidance behavior, anxiety sensitivity and stress. High rates of psychiatric comorbidity have been reported for cases with CFS. Behavioral interventions, such as cognitive-behavioral therapy and graded exercise, are among the most effective treatments for CFS, perhaps providing the strongest support for the importance of psychological factors in CFS [3–4].
Patients and clinicians often point out that physical, emotional or chemical stressors trigger the onset of CFS symptoms, an impression also supported by research . As early as in the 1930s, Hans Selye, who first coined the term ‘stress’, proposed that psychological stress elicits a physiologic response, which he recognized to be adaptive, but that failure of physiological adaptation to stress or exhaustion of the system, could result in disease . Nowadays, we know that stress exerts multiple effects on the central nervous, neuroendocrine, autonomic and immune systems that help an organism adapt to challenge. However, much less is known regarding why some individuals fail to adapt, resulting in functional changes that lead to symptoms, such as fatigue, pain, cognitive impairment and sleep disruption, combined with emotional problems. In order to understand CFS, it is of critical importance to understand sources of individual differences in the vulnerability to the pathogenic effects of stress.
This article discusses results from two recent studies emphasizing the role of childhood trauma in CFS [7–8]. Childhood trauma might be a vulnerability factor that interferes with successful adaptation to stress, thereby conveying a risk to developing CFS. Indeed, there is substantial plasticity of the developing CNS as a function of experience. During such critical periods, certain brain regions are also particularly sensitive to adverse experiences, which may then lead to major, sometimes irreversible, changes . Animal studies, pioneered by the late Seymour Levine , provide direct evidence that early adversity permanently programs neural circuits that are involved in regulating the adaptation of physiologic systems and behavioral responses to the environment, by inducing functional, structural and even epigenetic changes in these circuits [11–12]. Among the consequences of early-life stress in animal models and human studies, are many changes that resemble key features of CFS, including decreased basal cortisol secretion, increased immune activation, pain sensitivity, impaired cognition and altered sleep [11–12]. Most recently, it has been ascertained in human post-mortem brain tissue obtained from suicide victims that early adversity associates with epigenetic modulation of a neuron-specific promoter region of the hippocampal glucocorticoid receptor gene, a key regulator of the hypothalamic–pituitary–adrenal (HPA) axis, leading to silencing of the gene by interfering with transcription, which in turn modifies endocrine stress reactivity and behavior .
Applying the general principle to CFS, it may be proposed that CFS indeed has an identifiable biological basis, which, albeit unknown, is most likely located at the brain level. At least in some affected individuals, this neurobiological basis may have been shaped by early experience, perhaps in interaction with other factors. As a consequence, the vulnerable brain may inadequately process and/or fail to adapt to emotional, physical or even chemical challenges, thereby producing the often described physiological and behavioral characteristics that form the clinical phenotype of CFS. Clearly, considered from a developmental neuroscience perspective, supported by basic research, it becomes evident that the seemingly disparate points of view regarding the nature of CFS, that is to say psychological versus biological, are not mutually exclusive and that the diverse findings produced by CFS research may well be integrated in a developmental pathway model. Indeed, this perspective offers a new opportunity to reconcile some of the controversy surrounding CFS.
In order to start testing this assumption, it must be demonstrated that; first, early adverse experience is a risk factor for CFS and; second, that this risk factor is associated with a cardinal biological feature of CFS. Towards that end, the CDC (Atlanta, GA, USA) in collaboration with Emory University (Atlanta, GA, USA) recently conducted two population-based studies of CFS cases and controls.
The first study employed a sample of 43 clinically confirmed cases with current CFS and 60 controls identified from a general population sample of 56,146 adult residents in Wichita, KS, USA. CFS cases reported significantly higher levels of childhood sexual, physical and emotional abuse, as well as emotional and physical neglect compared with controls. Exposure to childhood trauma was associated with a three- to eight-fold increased risk for CFS, depending on trauma type. Emotional neglect and sexual abuse were the best predictors of CFS. There was a graded relationship between degree of exposure and CFS risk. Childhood trauma was further associated with CFS symptom severity and with depression, anxiety and post-traumatic stress disorder (PTSD) symptoms. While childhood trauma was ascertained as an independent risk factor for CFS, even in the absence of significant psychopathology, the risk of CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology. These results provided support for childhood trauma as an important risk factor of CFS, partly mediated through an altered emotional state . These results, which can be generalized to the population, confirmed and extended similar observations in tertiary clinical samples [14–15].
In a second study , our group closely replicated the above findings in an independent sample of CFS cases and controls identified from the general population in Georgia, USA. Results of this second study confirmed that emotional maltreatment and sexual abuse in particular, are potent risk factors of CFS. The risk of having CFS increased to ninefold in the presence of concurrent PTSD symptoms. We then tested whether childhood trauma is associated with a cardinal biological feature of CFS in this sample. One of the hallmark features of CFS is dysfunction of the HPA axis, characterized by lower-than-normal cortisol secretion. Relative hypocortisolism has been observed as a correlate of early-life stress in nonhuman primates and humans and is also a prominent feature of post-traumatic stress disorder (PTSD). In our study, the CFS group, as a whole, had flattened cortisol levels in response to awakening, in accordance with the general CFS literature. Only when stratifying groups by childhood trauma, it emerged that decreased cortisol secretion in CFS, in fact, was associated with childhood trauma, whereas CFS cases with no childhood trauma, exhibited normal cortisol levels. These results suggested that relative hypocortisolism in CFS, frequently described in the literature, may reflect a biological marker of risk of developing CFS, secondary to childhood trauma, rather than reflecting a correlate of the disorder itself. Similar associations appear to exist with other biological changes in CFS – for example, altered autonomic function.
Although unequivocal evidence for the importance of developmental factors in CFS must come from longitudinal studies, the current data provide important cues regarding potential disease mechanisms and the nature of comorbidity, resilience factors, illness subtypes and intervention strategies related to CFS. Regarding mechanisms, a reduced effect of cortisol as a potential consequence of childhood trauma, may be directly and causally linked to several of the key features of CFS; cortisol secreted during stress mobilizes metabolic resources, by inducing gluconeogenesis, mobilizing free fatty acids and reducing the use of amino acids for protein synthesis. Thus, reduced cortisol effects may decrease the organism’s energy resources during stress, leading to exhaustion and fatigue. Cortisol further exerts regulatory effects on the immune system and helps reduce inflammatory responses to challenge. A lack of these cortisol functions may induce an inflammation-like state, promoting fatigue, pain and cognitive problems. Lastly, cortisol has inhibitory effects on stress and emotion systems in the brain. Reduced cortisol effects may thus promote sensitization to stress and anxiety. The combined effects of relative cortisol deficiency might thus promote the symptom complex of CFS and might also explain comorbidity with emotional disorders, based on overlapping pathways [16–17].
Consequently, in terms of resilience factors, maintaining normal cortisol function after childhood trauma may protect against CFS and other disorders. To emphasize this point, in our study, the average risk of CFS associated with any childhood trauma exposure was increased sixfold . When computing risk ratios depending on childhood trauma exposure and cortisol status, we found that the risk for CFS increased by tenfold for persons who had both a history of childhood trauma and low cortisol secretion. For persons, who had childhood trauma but maintainance of normal cortisol levels, the risk of having CFS ameliorated and was increased approximately threefold [Heim C, Emory University, USA; Maloney M & Reeves W, CDC, USA, Unpublished Observations]. Thus, maintaining normal cortisol function appears to be a resilience factor that, at least partially, protects against CFS. As a consequence, interventions that normalize the HPA axis and restore cortisol funtion may be effective in the prevention or treatment of CFS in children or adults who have experienced early trauma.
A final implication of the above results is that CFS is clearly a heterogeneous disorder. There appears to be subgroups of CFS as a function of childhood trauma that are biologically distinguishable. Approximately 60% of our sample reported at least one form of childhood adversity, while 40% did not. Changes in neuroendocrine function were limited to the subgroup of CFS cases with childhood trauma histories. The other 40% had normal cortisol levels, but still suffered from CFS. Perhaps, in analogy to historic approaches to depression classification, the latter group suffers from a more ‘endogenous’ form of CFS that did not develop in reaction to an environmental event and, therefore, is not associated with altered stress hormone secretion. In fact, there might be even further subgroups not captured by our study design. Thus, an important area for future research is to better define subgroups of CFS and scrutinize diverse mechanisms that may lead to the same clinical picture.
The recognition that there are different subgroups of CFS with different pathophysiologic pathways also helps explain inconsistent findings regarding mechanisms and treatment efficacy in the field. For example, disregarding childhood trauma histories alone likely has significantly confounded previous research on neuroendocrine function in CFS, as demonstrated above. Defining CFS subgroups might also allow for selecting optimal targets for intervention, depending on the individual pathways that led to the disorder. For example, for patients with chronic depression and irritable bowel syndrome, it has been demonstrated that those with childhood trauma experiences benefitted from different treatments than those without such experiences [18–19].
In conclusion, adopting a developmental neuroscience perspective has significant potential to advance our understanding of CFS. Insights from this line of research may help to overcome the prevailing rejection of the idea that psychological factors may play a role in CFS, at least for a proportion of cases. Perhaps patients and advocacy groups fear to be labeled with the stigma of ‘simulating’ symptoms, as initially suggested by Freud. However, modern neuroscience clearly demonstrates that experience shapes biology (and vice versa) and, in this way, can create ‘real’ organic symptoms. Freud’s legacy is that he was remarkably correct in recognizing that early-life trauma is a major risk factor for a variety of functional disorders. However, it was Hans Selye who realized that successful biological adaptation to stress is critical to maintain health. The key to CFS might lie in the combination of both points of view, based on indisputable advances from modern developmental neuroscience.
Financial & competing interests disclosure The work discussed in this editorial was supported by the CDC (Atlanta, GA, USA). Christine Heim has received/receives funding or fees from National Institute of Mental Health, National Alliance for Research in Schizophrenia and Depression, Anxiety Disorders Association of America, Eli Lilly, Novartis and CeNeRx. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Prevalence of chronic fatigue syndrome in metropolitan, urban and rural Georgia Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R - Chronic Viral Diseases Branch, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA : email@example.com - Popul Health Metr. 2007 Jun 8;5:5 - PMID: 17559660 Background - Chronic fatigue syndrome (CFS) is a debilitating illness with no known cause or effective therapy. Population-based epidemiologic data on CFS prevalence are critical to put CFS in a realistic context for public health officials and others responsible for allocating resources. Methods - Based on a random-digit dialing survey we ascertained CFS cases and controls to estimate the prevalence of CFS in metropolitan, urban and rural populations of Georgia. This report focuses on the 5,623 of 19,381 respondents ages 18 to 59 years old. Fatigued (2,438), randomly selected unwell not fatigued (1,429) and randomly selected well (1,756) respondents completed telephone questionnaires concerning fatigue, other symptoms and medical history. Subsets of those identified by interview as having CFS-like illness (292), chronic unwellness which was not CFS-like (268 - randomly selected) and well subjects (223, matched to those with CFS-like illness on sex, race, and age) completed a clinical evaluation. Results - We estimated that 2.54% of persons 18 to 59 years of age suffered from CFS. There were no significant differences in prevalence of CFS between metropolitan, urban or rural populations or between white and black residents of the three regions. However, there were significant differences in female-to-male ratios of prevalence across the strata (metropolitan female : male 11.2 : 1, urban 1.7 : 1, rural 0.8 : 1). Conclusion - We estimated that 2.54% of the Georgia population suffers from CFS, which is 6- to 10-fold higher than previous population-based estimates in other geographic areas. These differences may reflect broader screening criteria and differences in the application of the case definition. However, we cannot exclude the possibility that CFS prevalence may be higher in Georgia than other areas where it has been measured. Although the study did not identify differences in overall prevalence between metropolitan, urban and rural Georgia populations, it did suggest the need for additional stratified analyses by geographic strata. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/17559660?dopt=Abstract Also read the comment on this article : 'How common is chronic fatigue syndrome - How long is a piece of string ?' - White PD - PMID: 17559661 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/17559661?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract
Chronic fatigue syndrome Prins JB, van der Meer JW, Bleijenberg G - Department of Medical Psychology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands : firstname.lastname@example.org - Lancet. 2006 Jan 28;367(9507):346-55 - PMID: 16443043 During the past two decades, there has been heated debate about chronic fatigue syndrome (CFS) among researchers, practitioners and patients. Few illnesses have been discussed so extensively. The existence of the disorder has been questioned, its underlying pathophysiology debated and an effective treatment opposed; patients' organisations have participated in scientific discussions. In this review, we look back on several controversies over CFS with respect to its definition, diagnosis, pathophysiology and treatment. We review issues of epidemiology and clinical manifestations, focusing on the scientific status of CFS. Modern neuroscience and genetics research offer interesting findings for new hypotheses on the aetiology and pathogenesis of the illness. We also discuss promising future issues, such as psychopathophysiology and mechanisms of improvement and suggest multidisciplinary prospective studies of CFS and fatigue in the general population. These studies should pay particular attention to similarities to and differences from functional somatic syndromes and other fatiguing conditions. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/16443043?dopt=Abstract Also read the comments on this article : - 'Chronic fatigue syndrome' - Hyland ME, Whalley B - Lancet. 2006 May 13;367(9522):1573-4; author reply 1575 - PMID: 16698404 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/16698406?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract - 'Chronic fatigue syndrome' - Abbot NC, Spence V - Lancet. 2006 May 13;367(9522):1574; author reply 1575 - PMID: 16698406 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/16698404?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract
Chronic fatigue syndrome - A review Afari N, Buchwald D - Department of Psychiatry, University of Washington, Seattle, USA : email@example.com - Am J Psychiatry. 2003 Feb;160(2):221-36 - PMID: 12562565 Objective - Chronic fatigue syndrome is an illness characterized by disabling fatigue of at least 6 months, accompanied by several other symptoms. This review summarizes the current state of knowledge about chronic fatigue syndrome. Method - The case definition, prevalence, clinical presentation, evaluation and prognosis of chronic fatigue syndrome are discussed. Research on the pathophysiology and treatment of chronic fatigue syndrome is reviewed. Results - Chronic fatigue syndrome is diagnosed on the basis of symptoms. Patients with chronic fatigue syndrome experience significant functional impairment. Pathophysiological abnormalities exist across many domains, suggesting that chronic fatigue syndrome is a heterogeneous condition of complex and multifactorial etiology. Evidence also is beginning to emerge that chronic fatigue syndrome may be familial. Although chronic fatigue syndrome has significant symptom overlap and comorbidity with psychiatric disorders, several lines of research suggest that the illness may be distinct from psychiatric disorders. Patients' perceptions, attributions and coping skills, however, may help perpetuate the illness. Treatment for chronic fatigue syndrome is symptom-based and includes pharmacological and behavioral strategies. Cognitive behavior therapy and graded exercise can be effective in treating the fatigue and associated symptoms and disability. Conclusions - Chronic fatigue syndrome is unlikely to be caused or maintained by a single agent. Findings to date suggest that physiological and psychological factors work together to predispose an individual to the illness and to precipitate and perpetuate the illness. The assessment and treatment of chronic fatigue syndrome should be multidimensional and tailored to the needs of the individual patient. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/12562565?dopt=Abstract Also read the comments on this article : - 'On chronic fatigue syndrome' - Bobo WV, Hall WC - Am J Psychiatry. 2004 Jun;161(6):1132-3; author reply 1133-4 - PMID: 15169716 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/15169716?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract - 'On chronic fatigue syndrome' - Berger J - Am J Psychiatry. 2004 Jun;161(6):1133; author reply 1133-4 - PMID: 15169718 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/15169718?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract
Precipitating factors for the chronic fatigue syndrome Salit IE - Division of Infectious Diseases, Toronto Hospital, Ontario, Canada : firstname.lastname@example.org - J Psychiatr Res. 1997 Jan-Feb;31(1):59-65 - PMID: 9201648 The etiology of the Chronic Fatigue Syndrome (CFS) is unknown but it is usually considered to be postinfectious or postviral. Many infecting agents have been suspected as causative but none has been proven. We investigated precipitating factors in 134 CFS patients through the use of a questionnaire, interview, clinical examination and serology for infecting agents; 35 healthy controls completed a similar questionnaire. CFS started with an apparently infectious illness in 96 (72%) but a definite infection was only found in seven of these 96 (7%). Thirty-eight (28%) had no apparent infectious onset: 15/38 (40%) had noninfectious precipitants (trauma, allergy, surgery). There was no apparent precipitating event in 23/38 (61%). Immunization was not a significant precipitant. Stressful events were very common in the year preceding the onset of CFS (114/134, 85%) but these occurred in only 2/35 (6%) of the controls (p < .0001). The onset of CFS may be associated with preceding stressful events and multiple other precipitants. An infectious illness is not uniformly present at the onset and no single infectious agent has been found; CFS is most likely multifactorial in origin. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/9201648?dopt=Abstract
Early adverse experience and risk for chronic fatigue syndrome - Results from a population-based study Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC - Viral Exanthems and Herpesvirus Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30322, USA : email@example.com - Arch Gen Psychiatry. 2006 Nov;63(11):1258-66 - PMID: 17088506 Context - Chronic fatigue syndrome (CFS) is an important public health problem. The causes of CFS are unknown and effective prevention strategies remain elusive. A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention. Objective - To examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and nonfatigued control subjects. Design, setting and participants - A case-control study of 43 cases with current CFS and 60 nonfatigued controls identified from a general population sample of 56 146 adult residents from Wichita, Kan. Main outcome measures - Self-reported childhood trauma (sexual, physical and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety and posttraumatic stress disorder) by CFS status. Results - The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety and posttraumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology. Conclusions - This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/17088506?dopt=Abstract
Childhood trauma and risk for chronic fatigue syndrome - Association with neuroendocrine dysfunction Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC - Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Woodruff Memorial Research Bldg, Ste 4311, Atlanta, GA 30322, USA : firstname.lastname@example.org - Arch Gen Psychiatry. 2009 Jan;66(1):72-80 - PMID: 19124690 Context - Childhood trauma appears to be a potent risk factor for chronic fatigue syndrome (CFS). Evidence from developmental neuroscience suggests that early experience programs the development of regulatory systems that are implicated in the pathophysiology of CFS, including the hypothalamic-pituitary-adrenal axis. However, the contribution of childhood trauma to neuroendocrine dysfunction in CFS remains obscure. Objectives - To replicate findings on the relationship between childhood trauma and risk for CFS and to evaluate the association between childhood trauma and neuroendocrine dysfunction in CFS. Design, setting and participants - A case-control study of 113 persons with CFS and 124 well control subjects identified from a general population sample of 19 381 adult residents of Georgia. Main outcome measures - Self-reported childhood trauma (sexual, physical and emotional abuse; emotional and physical neglect), psychopathology (depression, anxiety and posttraumatic stress disorder) and salivary cortisol response to awakening. Results - Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS. Sexual abuse, emotional abuse and emotional neglect were most effective in discriminating CFS cases from controls. There was a graded relationship between exposure level and CFS risk. The risk of CFS conveyed by childhood trauma further increased with the presence of posttraumatic stress disorder symptoms. Only individuals with CFS and with childhood trauma exposure, but not individuals with CFS without exposure, exhibited decreased salivary cortisol concentrations after awakening compared with control subjects. Conclusions - Our results confirm childhood trauma as an important risk factor of CFS. In addition, neuroendocrine dysfunction, a hallmark feature of CFS, appears to be associated with childhood trauma. This possibly reflects a biological correlate of vulnerability due to early developmental insults. Our findings are critical to inform pathophysiological research and to devise targets for the prevention of CFS. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/19124690?dopt=Abstract
What explains the negative consequences of adverse childhood experiences on adult health ? - Insights from cognitive and neuroscience research Weiss MJ, Wagner SH - Behavioral Pediatrics and Family Development, Inc., Brookline, Massachusetts 02146, USA - Am J Prev Med. 1998 May;14(4):356-60 - PMID: 9635084 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/9635084?dopt=Abstract This article is a comment on : 'Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults - The Adverse Childhood Experiences (ACE) Study' - Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS - Department of Preventive Medicine, Southern California Permanente Medical Group (Kaiser Permanente), San Diego 92111, USA - Am J Prev Med. 1998 May;14(4):245-58 - PMID: 9635069 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/9635069?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract
Maternal and environmental influences on the adrenocortical response to stress in weanling rats Levine S - Science. 1967 Apr 14;156(772):258-60 - PMID: 6021047 Handling rat pups either for 10 or 20 days after birth resulted in a reduction of adrenocortical steroids in the plasma at weaning after the pups were exposed to novel stimuli as compared with controls that were not handled. Nonhandled offspring of mothers which had been handled in infancy also show a reduction in plasma steroids in response to novel stimuli when compared to nonhandled weanling rats of nonhandled mothers. Handling of the offspring when they are infants appears to counteract the influence of the experience of the mother during her infancy. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/6021047?dopt=Abstract
Maternal care, gene expression and the transmission of individual differences in stress reactivity across generations Meaney MJ - Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, Department of Psychiatry and McGill Centre for the Study of Behavior, Genes and Environment, McGill University, Montréal, Canada : email@example.com - Annu Rev Neurosci. 2001;24:1161-92 - PMID: 11520931 Naturally occurring variations in maternal care alter the expression of genes that regulate behavioral and endocrine responses to stress, as well as hippocampal synaptic development. These effects form the basis for the development of stable, individual differences in stress reactivity and certain forms of cognition. Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression and which forms the basis for the intergenerational transmission of individual differences in stress reactivity. Patterns of maternal care that increase stress reactivity in offspring are enhanced by stressors imposed on the mother. These findings provide evidence for the importance of parental care as a mediator of the effects of environmental adversity on neural development. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/11520931?dopt=Abstract
Understanding the potency of stressful early life experiences on brain and body function McEwen BS - Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA : firstname.lastname@example.org - Metabolism. 2008 Oct;57 Suppl 2:S11-5 - PMID: 18803958 Early life experiences have powerful effects on the brain and body lasting throughout the entire life span and influencing brain function, behavior and the risk for a number of systemic and mental disorders. Animal models of early life adversity are providing mechanistic insights, including glimpses into the fascinating world that is now called "epigenetics" as well as the role of naturally occurring alleles of a number of genes. These studies also provide insights into the adaptive value as well as the negative consequences, of early life stress, exposure to novelty and poor-quality vs good-quality maternal care. Animal models begin to provide a mechanistic basis for understanding how brain development and physiological functioning is affected in children exposed to early life abuse and neglect, where there is a burgeoning literature on the consequences for physical health and emotional and cognitive development. An important goal is to identify interventions that are likely to be most effective in early life and some guidelines are provided. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/18803958?dopt=Abstract
Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ - Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montreal, Quebec, H4H 1R3, Canada - Nat Neurosci. 2009 Mar;12(3):342-8 - PMID: 19234457 Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/19234457?dopt=Abstract Also read the comment ons this article : 'How adversity gets under the skin' Hyman SE - Nat Neurosci. 2009 Mar;12(3):241-3 - PMID: 19238182 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/19238182?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV Abstract
Victimization in chronic fatigue syndrome and fibromyalgia in tertiary care - A controlled study on prevalence and characteristics Van Houdenhove B, Neerinckx E, Lysens R, Vertommen H, Van Houdenhove L, Onghena P, Westhovens R, D'Hooghe MB - Department of Psychosomatic Rehabilitation, Katholieke Universiteit Leuven, Belgium : dewijn.VanHoudenhove@uz.kuleuven.ac.be - Psychosomatics. 2001 Jan-Feb;42(1):21-8 - PMID: 11161117 The authors studied the prevalence and characteristics of different forms of victimization in 95 patients suffering from chronic fatigue syndrome (CFS) or fibromyalgia (FM) compared with a chronic disease group, including rheumatoid arthritis (RA) and multiple sclerosis (MS) patients and a matched healthy control group. The authors assessed prevalence rates, nature of victimization (emotional, physical, sexual), life period of occurrence, emotional impact and relationship with the perpetrator by a self-report questionnaire on burdening experiences. CFS and FM patients showed significantly higher prevalences of emotional neglect and abuse and of physical abuse, with a considerable subgroup experiencing lifelong victimization. The family of origin and the partner were the most frequent perpetrators. With the exception of sexual abuse, victimization was more severely experienced by the CFS/FM group. No differences were found between healthy control subjects or RA/MS patients, and between CFS and FM patients. These findings support etiological hypotheses suggesting a pivotal role for chronic stress in CFS and FM and may have important therapeutic implications. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/11161117?dopt=Abstract
Childhood experiences of illness and parenting in adults with chronic fatigue syndrome Fisher L, Chalder T - Guy's, King's and St. Thomas' School of Medicine, Chronic Fatigue Syndrome Research Unit, King's Denmark Hill Campus, New Medical School Building, London SE5 9PJ, UK : email@example.com - J Psychosom Res. 2003 May;54(5):439-43 - PMID: 12726900 Objective - There are many similarities between chronic fatigue syndrome (CFS), the somatoform disorders and problems otherwise known as "medically unexplained symptoms". There is some evidence to suggest that a combination of inadequate parenting and early illness experience may predispose the individual to develop medically unexplained symptoms in adult life. The aim of this investigation was to compare the contributions of childhood experiences of illness and parenting in adults with CFS with a fracture clinic control group. Method - A retrospective case control design was used. Thirty patients with a diagnosis of CFS and 30 patients attending a fracture clinic in an inner London teaching hospital completed questionnaires measuring parental care and protection and were interviewed about childhood experiences of illness. Results - There were no differences in childhood experience of illness in the two groups. However, logistic regression revealed that maternal overprotection and depression were associated with the diagnosis of CFS. Conclusion - The findings may represent risk factors for the development of CFS in adult life. It is possible that maternal overprotection in particular is related to the formation of belief systems about avoiding activity that operate to adversely influence behaviour in patients with CFS. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/12726900?dopt=Abstract
The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders Heim C, Ehlert U, Hellhammer DH - Center for Psychobiological and Psychosomatic Research, University of Trier, Germany - Psychoneuroendocrinology. 2000 Jan;25(1):1-35 - PMID: 10633533 Representing a challenge for current concepts of stress research, a number of studies have now provided convincing evidence that the adrenal gland is hypoactive in some stress-related states. The phenomenon of hypocortisolism has mainly been described for patients, who experienced a traumatic event and subsequently developed post-traumatic stress disorder (PTSD). However, as presented in this review, hypocortisolism does not merely represent a specific correlate of PTSD, since similar findings have been reported for healthy individuals living under conditions of chronic stress as well as for patients with several bodily disorders. These include chronic fatigue syndrome, fibromyalgia, other somatoform disorders, rheumatoid arthritis and asthma and many of these disorders have been related to stress. Although hypocortisolism appears to be a frequent and widespread phenomenon, the nature of the underlying mechanisms and the homology of these mechanisms within and across clinical groups remain speculative. Potential mechanisms include dysregulations on several levels of the hypothalamic-pituitary adrenal axis. In addition, factors such as genetic vulnerability, previous stress experience, coping and personality styles may determine the manifestation of this neuroendocrine abnormality. Several authors proposed theoretical concepts on the development or physiological meaning of hypocortisolism. Based on the reviewed findings, we propose that a persistent lack of cortisol availability in traumatized or chronically stressed individuals may promote an increased vulnerability for the development of stress-related bodily disorders. This pathophysiological model may have important implications for the prevention, diagnosis and treatment of the classical psychosomatic disorders. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/10633533?dopt=Abstract
When not enough is too much - The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Raison CL, Miller AH - Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA - Am J Psychiatry. 2003 Sep;160(9):1554-65 - PMID: 12944327 Objective - Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). Method - The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results - Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Conclusions - Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/12944327?dopt=Abstract
Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma Nemeroff CB, Heim CM, Thase ME, Klein DN, Rush AJ, Schatzberg AF, Ninan PT, McCullough JP Jr, Weiss PM, Dunner DL, Rothbaum BO, Kornstein S, Keitner G, Keller MB - Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322 : firstname.lastname@example.org - Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14293-6. Epub 2003 Nov 13 - PMID: 14615578 Major depressive disorder is associated with considerable morbidity, disability and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP) or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/14615578?dopt=Abstract
Reported sexual abuse predicts impaired functioning but a good response to psychological treatments in patients with severe irritable bowel syndrome Creed F, Guthrie E, Ratcliffe J, Fernandes L, Rigby C, Tomenson B, Read N, Thompson DG - School of Psychiatry and Behavioural Science, University of Manchester, Manchester, UK : email@example.com - Psychosom Med. 2005 May-Jun;67(3):490-9 - PMID: 15911915 Objective - We assessed the effect of reported sexual abuse on symptom severity and health-related quality of life in patients with severe irritable bowel syndrome (IBS) undergoing psychological treatments. Methods - IBS patients entering a treatment trial who reported prior sexual abuse were compared with the remainder in terms of symptom severity and health-related quality of life (SF-36) at trial entry and 15 months later. Analyses used ANCOVA with age, sex, marital status, and treatment group as covariates. We assessed possible mediators using multiple regression analysis. Results - Of 257 patients with severe IBS, 31 (12.1%) reported a history of rape and 28 (10.9%) reported forced, unwanted touching. People who reported abuse were more impaired than the remainder on the SF-36 scales for pain (adjusted p = .023) and physical function (p = .029); these relationships followed a "dose-response" relationship and were mediated by SCL-90 somatization score. At 15 months follow-up, the associations between reported abuse and SF-36 scores were lost because people with reported abuse, especially rape, improved more than the remainder when treated with psychotherapy or paroxetine (selective serotonin reuptake inhibitor antidepressant); this improvement was mediated by change in SCL-90 somatization score. Conclusions - In severe IBS, the association between self-reported sexual abuse and impaired functioning is mediated by a general tendency to report numerous bodily symptoms. A reported history of abuse is associated with a marked improvement following psychological treatment. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/15911915?dopt=Abstract
Sources : Heim, C. Archives of General Psychiatry, January 2009; vol 66: pp 72-80 William C. Reeves, MD, MSc, chief, chronic viral diseases branch, CDC Anthony L. Komaroff, FACP, professor of medicine, Harvard Medical School Archives of General Psychiatry, November 2006; vol 63: pp 1258-1266
Jan. 5, 2009 -- Experiencing serious trauma during childhood may increase a person's risk for developing chronic fatigue syndrome later in life, a new study suggests.
In the study from the CDC and Atlanta's Emory University, patients with chronic fatigue syndrome (CFS) reported much higher levels of childhood trauma than people without the disorder.
Severe childhood trauma -- including sexual abuse, emotional abuse and neglect -- was associated with a sixfold increase in CFS.
Chronic fatigue syndrome remains a poorly understood disorder and the suggestion that early-life stresses play an important role in the disease remains controversial.
Harvard Medical School professor and CFS expert Anthony L. Komaroff, FACP, did not take part in the new study. But he tells WebMD that the findings make a strong case for childhood trauma altering brain chemistry in a way that makes some people more vulnerable to CFS.
"These researchers are definitely not saying that early-life trauma is the cause of chronic fatigue syndrome," he says : "To say that something is a risk factor is very different from saying that it is the cause."
Childhood Trauma and CFS
The newly reported study builds on previous research from the CDC and Emory team, which first suggested the link between early-life trauma and an increased risk for CFS.
CDC estimates suggest that as many as 2.5% of American adults have CFS, even though many have not been diagnosed.
In that study, researchers examined and interviewed 43 CFS patients and 60 people without the disorder living in Wichita, Kan.
Self-reported childhood trauma was associated with a three- to eightfold increased risk for CFS, with the highest risk seen in patients who had suffered from more than one early-life trauma.
The new study involved 113 CFS patients and 124 people without the disorder living in urban, suburban, or rural Georgia.
In addition to interviews to determine whether study participants had experienced childhood trauma, all participants underwent screening for depression, anxiety and posttraumatic stress disorder.
The interviews revealed that :
62% of CFS patients reported being the victims of severe childhood traumas compared to 24% of study participants without CFS.
33% of CFS patients reported a childhood history of sexual abuse, compared to nearly 11% of study participants without CFS.
33% of CFS patients reported being the victims of emotional abuse, compared to 7% of study participants without CFS.
New perspective on chronic fatigue syndrome - Lessons from developmental neuroscience - Part II
New perspective on chronic fatigue syndrome - Lessons from developmental neuroscience -
The researchers also tested all participants for levels of the hormone cortisol, which is associated with stress and the so-called "fight or flight" response.
Low cortisol levels may indicate that the body does not respond to stress normally, CFS researcher William Reeves, MD, of the CDC tells WebMD.
Reeves and colleagues found reduced cortisol levels in the CFS patients who had experienced childhood traumas, but not in CFS patients who did not report early-life exposure to trauma.
This suggests that early trauma may "rewire" the brain in a way that makes people more vulnerable to developing chronic fatigue syndrome in adulthood, he says, adding that the finding could have implications for diagnosis and treatment.
"We know that cognitive behavioral therapy works for many people with CFS, and this is especially true for people who have a history of childhood trauma," Reeves says.
Viral triggers likely
While 60% of CFS patients had a history of childhood trauma, Komaroff points out that 40% did not and that a significant number of the participants who had experienced severe childhood trauma did not develop chronic fatigue syndrome.
"The danger is that people will jump to the conclusion that early-life trauma causes CFS even though this study showed that a large number of people with CFS had no history of trauma," he says.
Komaroff believes, as many CFS researchers do, that multiple viruses trigger the disorder in people who are vulnerable due to genetics or other reasons.
"I don't believe that any single virus is the cause of CFS in the way that HIV is absolutely critical to causing AIDS," he says.
Verbod natuurlijke geneesmiddelen - Teken de petitie !
De natuur als dokter Andrew Stanway , Hetty Einzig – Bruna – ISBN10 : 9051541856 – ISBN13 : 9789051541854 Deze uitgebreide, praktisch ingedeelde zelfhulpgids geeft advies over alles wat een natuurlijke, algemene gezondheid kan bestendigen en bevorderen. Het boek bevat een omvangrijke lijst van veilige natuurgeneeswijzen voor de meest voorkomende klachten en kwalen alsmede remedies die zelf zijn toe te passen. De behandelingsmethoden van de verschillende therapieën zijn zo opgesteld dat in een oogopslag diverse oplossingen van gezondheidsproblemen te vinden zijn. Besproken worden : gezond zijn en blijven, voeding, bewegen, ademen, ontspannen, verzorging, homeopathie, bloementherapie van Bach, aromatherapie, acupunctuur, osteopathie, shiatsu, yoga, massage, Oosterse bewegingstherapieën enz. Het bevat ook tips voor eerste hulp en noodgevallen. Cfr. : http://www.bol.com/nl/p/boeken/de-natuur-als-dokter/1001004005148062/index.html
Verbod natuurlijke geneesmiddelen
- Actie ELIANT - ('ELIANT' staat voor 'European Alliance of Initiatives for Applied Anthroposophy')
De overheid is steeds meer natuurlijke geneesmiddelen en biologische voeding aan het verbieden. Eind 2009 zou immers de zogenoemde 'Codex Alimentarius'-regel (1) ingaan.
Een paar voorbeelden van de nieuwe regels :
geen natuurlijke vitaminen meer in baby- en kindervoeding (zogenaamde voedselveiligheid)
een groot deel van alle antroposofische geneesmiddelen (en ook van andere natuurlijke middelen, zoals ayurvedische) valt buiten de toegestane samenstelling en wordt dus verboden (de enige reden is dat de registratie-criteria zo zijn opgesteld dat deze middelen erbuiten vallen).
Weinig mensen weten hiervan omdat het niet in het reguliere nieuws te vinden is. We moeten dus opletten dat deze regels niet sluipsgewijs van kracht worden en we nog alleen kunnen kiezen uit giftig bespoten voedsel en chemisch/syntetische medicijnen. En dan is het te laat !
Als we één miljoen handtekeningen verzamelen kunnen we inspraak krijgen !
Met één miljoen handtekeningen kunnen we de EU verplichten te luisteren.
Het gaat niet alleen om alternatieve geneeskunst en babyvoeding maar om de vraag in hoeverre wij toestaan dat de overheid (in dit geval de EU) onze vrije keuze beperkt.
en stuur dit berichtje aan je gehele adressenbestand !
(1) – Wat zegt men op de site van de Codex Alimentarius ?
Uit berichten in de media zou blijken dat de Codex Alimentarius per 31 december 2009 vitaminen en mineralen zou verbieden en dat geen enkel land hierop invloed zou kunnen uitoefenen. Deze berichten zijn niet waar. De regelgeving voor voedingssupplementen zoals die nu al geldig is in Nederland verandert niet per 31 december 2009.
Situatie in Nederland
In Nederland is de regelgeving voor voedingssupplementen gebaseerd op de Europese richtlijn 2002/46/EG. Hierin staan kwaliteits- en veiligheidseisen voor vitaminen en mineralen in voedingssupplementen. Deze richtlijn is door alle lidstaten omgezet in nationale wetgeving. In Nederland zijn de eisen aan voedingssupplementen opgenomen in het Warenwetbesluit voedingssupplementen en de Warenwetregeling voedingssupplementen.
Maximale en minimale hoeveelheden
Wél moeten nog de maximale en minimale doseringen van de vitaminen en mineralen worden vastgesteld door de Europese Commissie in samenwerking met alle lidstaten. Dat is eerder afgesproken in artikel 5 van de Europese richtlijn (2002/46/EG). Bij het vaststellen van de maximale bovengrens van vitaminen en mineralen speelt de veiligheid de belangrijkste rol. Er zijn vitaminen die bij een te hoge dosering giftig zijn of bijwerkingen hebben. Er wordt daarbij ook gekeken naar specifieke doelgroepen die extra risico lopen op een overdosering en naar wat in een gemiddelde voeding al wordt ingenomen. Daarnaast speelt ook een rol hoeveel gemiddeld nodig is om tekorten te voorkomen. Minimale hoeveelheden kunnen ook worden vastgesteld om te voorkomen dat consumenten een oneerlijk product kopen. Voor elke vitamine of mineraal wordt die afweging apart gemaakt. Het Nederlandse standpunt is dat maximum en minimum hoeveelheden alleen hoeven worden vastgesteld wanneer het echt nodig is en wordt gebaseerd op wetenschappelijk onderzoek.
De handelsnormen die in de Codex Alimentarius zijn opgenomen voor voedingssupplementen komen voor het grootste deel overeen met de Europese en Nederlandse regelgeving. Zo is bijvoorbeeld vastgelegd in de Codex dat voedingssupplementen ten minste 15% van de aanbevolen dagelijkse hoeveelheid vitaminen en mineralen moeten bevatten. Ook is in de Codex vastgelegd dat overmatige consumptie van bepaalde vitaminen en mineralen schadelijk kan zijn. En dat om die reden, waar nodig, maximumgehalten voor een veilig gebruik in voedingssupplementen moet worden vastgesteld en moeten zijn gebaseerd op wetenschappelijk onderzoek.
In Nederland is het ministerie van Volksgezondheid, Welzijn en Sport verantwoordelijk voor het beleid ten aanzien van voedingssupplementen. Voor verdere vragen verwijzen wij u door naar dat ministerie : www.minvws.nl -.
Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function - Part I
Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function -
Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function
Chronic Fatigue Syndrom - Comments on deconditioning, blood volume and resulting cardiac function
Circulating Blood Volume in Chronic Fatigue Syndrome
Circulating blood volume
Blood volume - Importance and adaptations to exercise training, environmental stresses and trauma/sickness
Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion
Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue
A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome
Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome
Illness and disability in Danish Chronic Fatigue Syndrome patients at diagnosis and 5-year follow-up
A sedentary childhood could lead to chronic fatigue latter in life
Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome - A population-based study
I. - Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function -
Hurwitz BE, Coryell VT, Parker M, Martin P, Laperriere A, Klimas NG, Sfakianakis GN, Bilsker MS - Clin Sci (Lond). 2009 May 26 - PMID: 19469714
This study examined whether deficits in cardiac output and blood volume in a Chronic Fatigue Syndrome (CFS) cohort were present and linked to illness severity and sedentary lifestyle. Follow-up analyses assessed whether differences between CFS and control groups in cardiac output levels were corrected by controlling for cardiac contractility and total blood volume (TBV). The 146 participants were subdivided into two CFS groups based on symptom severity data, severe (n=30) vs. non-severe (n=26) and two healthy non-CFS control groups based on physical activity, sedentary (n=58) vs. non-sedentary (n=32). Controls were matched to CFS participants using age, sex, ethnicity and body mass. Echocardiographic measures indicated that the severe CFS participants displayed 10.2% lower cardiac volume (i.e., stroke index and end diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups. Dual tag blood volume assessments indicated that CFS groups had lower TBV, plasma volume (PV) and red blood cell volume (RBCV) than control groups. Of the CFS subjects with a TBV deficit (i.e., >/=8% below ideal levels), the mean +/-SD percent deficit in TBV, PV and RBCV were 15.4+/-4.0, 13.2+/-5.0 and 19.1+/-6.3, respectively. Lower CFS cardiac volume levels were substantially corrected by controlling for prevailing TBV deficits, but were not affected by controlling for cardiac contractility. Analyses indicated that the TBV deficit explained 91-94% of the group differences in cardiac volume indices. Group differences in cardiac structure were offsetting and hence no differences emerged for LV mass index. Therefore, the findings indicate that lower cardiac volume levels, displayed primarily by persons with severe-CFS, were not linked to diminished cardiac contractility levels, but were likely a consequence of a comorbid hypovolemic condition. Further study is needed to address the extent to which the CFS cardiac and blood volume alterations have physiological and clinical significance.
Cardiovascular and autonomic dysfunction have been suggested to underly the symptoms accompanying CFS (chronic fatigue syndrome). In the present issue of Clinical Science, Hurwitz and colleagues have investigated whether deficits were present in cardiac output and blood volume in a cohort of patients with CFS and whether these were linked to illness severity and sedentary lifestyle. The results clearly demonstrated reduced cardiac stroke volume and cardiac output in more severely afflicted patients with CFS, which is primarily attributable to a measurable reduction in blood volume. Similar findings are observed in microgravity and bedrest deconditioning, in forms of orthostatic intolerance and to a lesser extent in sedentary people. The circulatory consequences of reduced cardiac output may help to account for many of the findings of the syndrome.
The interesting paper by Hurwitz et al entitled “Chronic Fatigue Syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function”  is important because it aligns current thinking regarding chronic fatigue syndrome with ongoing work concerning circulatory regulation particularly as it relates to decreased overall blood volume and issues of orthostatic intolerance. Also, despite significant cardiac findings, the paper effectively puts to rest arguments in favor of a causative role for heart disease in CFS.
This requires explanation. There is no controverting these data, which demonstrate decreased blood volume in a subset of CFS patients effectively reducing venous return to the heart, diastolic cardiac volume and cardiac output. The data do not imply heart disease but rather point to circulatory impairment. Classically, cardiac stroke volume is determined by preload and afterload, by contractility and by geometry; where preload corresponds to stretch or ventricular wall stress imposed by venous return before active contraction occurs, afterload corresponds to active intramural wall stress of contraction, contractility is the intrinsic cardiac muscle ability to contract and geometry includes chamber sizes, wall thicknesses and their shapes . Reduced venous return and diastolic heart volume (preload) thus results in a decrease in stroke volume and cardiac output. Using a corrected velocity of circumferential shortening (Vcfc) the authors also conclude that cardiac contractility is modestly reduced in the most severely ill CFS patients. Vcf combined with measures of end-systolic force (the force-velocity relationship) [3, 4] is one of two classic load independent means to assess cardiac contractility. However, Vcfc alone, even when corrected for HR, is preload dependent increasing when cardiac preload is increased (increased cardiac filling) and decreasing when cardiac preload is decreased (decreased cardiac filling) as occurs in CFS patients and some sedentary control subjects. Vcfc is therefore a load-sensitive measure and may overestimate or underestimate global systolic contractility under different loading conditions.
Thus, significant cardiac output findings derive from the effects of reduced venous return and cardiac unloading. Interestingly, while diastolic cardiac size is reduced in CFS, cardiac mass is not decreased. This defines the designation of “the under filled heart”  which may be observed in hypovolemia of whatever cause.
A major attribution is made to deconditioning. Use of the term deconditioning needs cautious interpretation because deconditioning may not be a single entity : there is cardiac deconditioning taking its most extreme form during heart failure and gravitational deconditioning exemplified by prolonged microgravity exposure and easily duplicated by chronic bedrest or prolonged head down tilt [6,7]. On the one hand cardiac deconditioning is best demonstrated during exercise stress while gravitational deconditioning is best demonstrated during orthostatic stress as experienced by every astronaut, every long-bed rested subject and many CFS patients especially those with the severest symptoms. All forms of gravitational deconditioning produce a reduction of blood volume and may result in loss of bone and muscle mass as in chronic bedrest and microgravity. Decreased blood volume has not been entirely explained, although redistribution of extracellular fluids has a role. Changes in patterns of peripheral vasoconstriction occur . Hypovolemia leads to larger decreases in both venous return and SV particularly during orthostatic stress, thus compromising blood pressure control. There are also changes in autonomic regulation during all forms of microgravity deconditioning which when combined with hypovolemia place the patients at risk for orthostatic intolerance . The chronic reduction in blood volume under conditions of microgravity may account for the actual reduction in cardiac mass as well as decrease in end-diastolic chamber volume  and this has further been demonstrated to occur preferentially in women (Cardiac atrophy in women following bed rest . Blood volume can also be affected by inactivity and it is clear that athletes develop both an increase in blood volume as well as a form of benign cardiac hypertrophy known as “athletes’ heart”  which regresses along with expanded blood volume with progressive detraining.
Blood volume reduction is part of the underlying the pathophysiology of chronic orthostatic intolerance also known as postural tachycardia syndrome (POTS) in which symptoms of orthostatic intolerance such as impaired consciousness, dizziness, headache, fatigue and cognitive loss, are associated with an excessive increase in heart rate when upright and may be related to abnormalities in the renin angiotensin aldosterone system [12, 13]. Symptoms of POTS and other forms of orthostatic intolerance overlap with CFS and may represent an underlying pathophysiology for CFS in younger patients and are associated with CFS in older patients [14, 15]. Although orthostatic testing was not performed, a relatively large fraction (55%) of those with posturally related symptoms relieved by recumbence were documented in the present study, suggesting a large overlap between the CFS patients and patients with chronic forms of orthostatic intolerance.
The reduction in cardiac output reported in the paper can be entirely explained in terms of reduced venous return to the heart, reduced cardiac preload and therefore reduced stroke volume. In this context a reduction in diastolic dimension makes perfect sense. The authors noted unchanged cardiac mass and, to an approximation, cardiac mass ~ wall thickness x chamber surface area where chamber area ~ chamber length x chamber diameter. Given constant mass but reduced stroke volume, the patient with severe CFS and a reduction in diastolic size should have an increase in diastolic wall thickness : ventricles are “less thinned” in diastole due to reduced ventricular filling. Thus, changes in wall thickness and chamber dimensions go hand in glove and all differences among the analyzed groups can be attributed to reduced venous return presumably due to reduced blood volume. Correlative analysis would be welcome.
In summary the authors have importantly and clearly demonstrated a reduction in blood volume, both in plasma and in red cell mass that produces a reduction in cardiac filling via reduced venous return even when measured in the supine position. This reduction of cardiac input accounts entirely for reductions in cardiac output in severely afflicted patients and should not be regarded as evidence for heart disease per se. I applaud the authors for their meticulous data collection and analysis.
Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA (1994) - Anesthesiology. 81:376-87 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/8053588
Nine months in space - Effects on human autonomic cardiovascular regulation Cooke WH, Ames JE IV, Crossman AA, Cox JF, Kuusela TA, Tahvanainen KU, Moon LB, Drescher J, Baisch FJ, Mano T, Levine BD, Blomqvist CG, Eckberg DL (2000) – J Appl Physiol. 89:1039-45 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/10956348
Cardiac atrophy after bed rest and spaceflight Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist CG, Zerwekh JE, Peshock RM, Weatherall PT, Levine BD (2001) – J Appl Physiol. 9:645-53 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/11457776
Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome Raj SR, Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne DW, Robertson D (2005) - Circulation. 111:1574-82. Epub 2005 Mar 21 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/15781744
Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume Stewart JM, Glover JL, Medow MS (2006) - Clin Sci (Lond). 110:255-63 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/16262605
Chronic fatigue syndrome (CFS) is an illness associated with severe activity limitation and a characteristic pattern of symptoms despite a relatively normal physical examination and routine laboratory evaluation. The recent description of delayed orthostatic hypotension in patients with CFS and previous findings of reduced red blood cell (RBC) mass in other patients with orthostatic hypotension not known to have CFS, led us to measure RBC mass and plasma volume in 19 individuals (15 female, four male) with well characterized, severe CFS. RBC mass was found to be significantly reduced (p < 0.001) below the published normal range in the 16 women, being subnormal in 15 (93.8%) of them as well as in two of the four men. Plasma volume was subnormal in 10 (52.6%) patients and total blood volume was below normal in 12 (63.2%). The high prevalence and frequent severity of the low RBC mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients.
Chronic fatigue syndrome (CFS) is an illness of unknown etiology, characterized by profound exhaustion, orthostatic intolerance and numerous somatic complaints. The illness is characterized by a severe activity restriction despite normal or relatively minor abnormalities on physical examination and routine laboratory studies. CFS occurs in both children and adults (1-5), may be sudden or gradual in onset (6,7) and follows a variety of initiating insults (2,8,9).
Recent observations have linked CFS with neurally mediated hypotension (10,11) and delayed orthostatic intolerance (12). Previous studies of the pathogenesis of both hyperadrenergic and hypoadrenergic orthostatic hypotension have shown that, in addition to the almost invariable finding of excessive orthostatic blood pooling in the lower limbs (13,14) attributable to subnormal venous constriction of the legs (15), reduction of red blood cell (RBC) mass is frequently present (13,16). For this reason we have explored the prevalence of abnormalities in the total circulating volumes of RBC's, plasma and whole blood in a series of nineteen patients with well documented CFS.
The 19 patients included in this paper are drawn from the clinical practice of one of the investigators (DSB) and most had been followed clinically for many years. Nine patients underwent autonomic nervous system testing in Syracuse, the results of which will be reported separately. Subjects were selected sequentially if they met the 1994 Center for Disease Control (CDC) diagnostic criteria for CFS (17), met the severity criteria of less than five hours of upright activity daily and wished to participate in the study.
Severity instruments used at the time of the blood volume studies included : - sum of the visual analog scores for 12 prominent symptoms seen in CFS (7); - a modified Karnofsky score (7); - estimation of total activity (7) and - the Fisk Fatigue Impact Scale score (18). These four rating scales had been taken on numerous occasions on the majority of the patients reported in the present paper and have been remarkably consistent over a period of years despite a variety of therapeutic trials in which the patients participated (data not shown). While many of the patients in this study have experienced episodes of depression in the past, none was considered to have emotional factors as the cause of his or her illness. None of the patients in this study were taking mineralocorticoids, diuretics or other medications known to influence circulating blood volume at the time of the study. One patient had type II diabetes mellitus with blood sugar in the normal range with oral hypoglycemic medication. The demographics and severity ratings of the patient population are presented in Table 1 (cfr. : http://www.ncf-net.org/library/Bell-StreetenJCFS1998.htm -).
RBC mass and plasma volume were determined with standard methods, using 51Cr-labeled autologous red blood cells (19) and 125I-labeled human serum albumin (19), respectively, in five university affiliated radiology departments. Normative data was taken from published studies (20) and no healthy controls were evaluated at the time of this study.
Blood pressure measurements (Table 2 - cfr. : http://www.ncf-net.org/library/Bell-StreetenJCFS1998.htm -) were the average of pressures taken during office visits, in the course of routine follow up of their illness. The peripheral hematocrit (Table 2) was the average of peripheral hematocrits recorded in the patients' chart during their illness. There was no unusual variation between the average hematocrit and the hematocrit taken nearest to the blood volume studies (data not shown). Whole body hematocrit was calculated from the circulating blood volume data (RBC mass/total blood volume)
Table 1 shows that the patients included 15 women and 4 men, aged 14-50 years, whose ability to perform normal upright activity had been reduced to between one and four hours per day, estimated at 20% to 30% of their previous capacity. The sum of visual analog scores and Fisk Fatigue Impact Scale scores indicate the degree of their incapacitation.
RBC mass, plasmu volume and whole blood volume measurements
The data in Table 2 show that RBC mass was below the normal range (25-30 mL/Kg) in 14 of 15 female patients and 2 of 4 males. In the 15 female patients, the RBC mass (Mean 18.8, SD 3.1 mL/Kg) was significantly lower than the 20 normal female subjects reported by Huff and Feller (20), viz. 24.4 + 2.6 mL/Kg (p < 0.001), as displayed in Table 3 (cfr. : http://www.ncf-net.org/library/Bell-StreetenJCFS1998.htm -). The small number (4) of male patients precluded determination of statistical significance of the differences between their data and those of normal subjects reported by Huff and Feller.
Plasma volume was quite variable in our patients, being below the normal range in 10, normal in 4 and elevated in 2 of the 15 female subjects (Table 2). The mean plasma volume in these 15 individuals (38.77 +/-19.5 mL/Kg) was not significantly different from the mean of normal female subjects, 34.8 + 3.2 mL/Kg (18). Similarly, the total blood volume in our 15 female subjects (Mean 57.49, SD 20.47) was not significantly different from the values found in the same 20 normal females (58.9+/-4.9 mL/Kg).
It is evident from Table 2 that the peripheral hematocrit was below 37% in only 4 of our patients. In fact, mean peripheral hematocrit was significantly higher (p > 0.01) than whole body hematocrit (i.e., RBC mass/total blood volume) in our patient group. Blood pressures, measured in the sitting position, were normal) (95-140/60-90) in all but one subject whose blood pressure was 150/87.
The characteristic elements which comprise the chronic fatigue syndrome (CFS) are asthenia, fatigue, orthostatic intolerance and numerous somatic complaints. The lack of detectable tissue damage in routine laboratory testing has led to assumptions that CFS may be either a trivial illness, a psychosomatic disorder or a variant of depression. Blood volume measurements have traditionally been used in the management of polycythemia but not in the evaluation of CFS until recently (12).
Of the 19 patients reported here, abnormalities in blood volume were very common. The most common, found in 16 of 19 patients, was a reduction in red blood cell mass. Eleven subjects had low plasma volumes and total circulating blood volume was subnormal in 12 of 19 subjects. In some individuals this abnormality was strikingly severe. Patient #15, for example, had an RBC mass of 12.9 mL/Kg, which is 46% of the expected normal and a total blood volume of 35.8 mL/Kg, which represents 49.7% of the expected normal value (21). Her peripheral hematocrit was not impressively low at 33.8%, presumably because of the symmetrical reduction in both RBC mass and plasma volume. In other patients the plasma volume was normal or even elevated in the face of a low RBC mass and in nqne of these patients was the RBC mass abnormality detected by conventional interpretation of the peripheral hematocrit.
All of the subjects in this study had symptoms of orthostatic intolerance which probably contributed to their activity restriction, but tilt table and autonomic nervous system testing was not carried out systematically in these individuals. Normal sitting blood pressures were recorded in all patients under office visit circumstances, except for relatively low values in three and a mildly elevated blood pressure in one. Some of these patients have been tested subsequently and found to have delayed orthostatic hypotension (12), which may be characteristic for CFS (11,12). In general, blood pressure measurements were not predictive of the results of circulating blood volume measurements.
A subnormal RBC mass and/or decreased circulating blood volume may well result in diminished cerebral blood flow with subnormal oxygen-carrying capacity (22). These abnormalities, by reducing cerebral oxygenation, might well be important factors in the pathogenesis of chronic fatigue and deserve further evaluation. It is important to note, however, that 3 of the 19 patients in this study had normal RBC mass and plasma volume and thus a deficiency of circulating blood volume could not account for their symptomatology. Clinically, there was no obvious difference in the degree of fatigue, orthostatic intolerance or somatic symptoms in these patients as compared with those who'se RBC mass was reduced (Table 1).
The high prevalence of reduced RBC mass in our patients with severe CFS suggests that this abnormality may well be important to the pathogenesis of their persisting symptoms, though not necessarily in that of the initiating event. While most frequently seen after a viral infection and with no obvious precipitating cause (1), CFS has also developed after ciguatera poisoning (23), head injury (personal observation) and lead poisoning (personal observation). Post-polio fatigue bears striking resemblance to CFS (24,25). Hereditary factors may also play a role, perhaps through effects on autonomic nervous system function. Thus, whatever its initiating cause, CFS may be perpetuated, at least in part, by low RBC mass in many patients.
In this study, matched control subjects were not assessed for circulating blood volume and thus the data presented here should be considered a preliminary report. Since significant reduction of RBC and whole blood volume may be among the few objectively demonstrable laboratory abnormalities in the majority of patients during the chronic stages of CFS, we believe that further studies of these changes would be worthwhile.
Symptoms and signs of chronic fatigue syndrome Komaroff AL, Buchwald D - Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S8-11 - PMID: 2020806
The chronic fatigue syndrome Shafran S - Amer J Med 1991; 90:730-739
Chronic fatigue syndrome Klimas N, Fletcher MA - Current Opinion in Infectious Diseases. l995; 54: l45-148
An overview of chronic fatigue syndrome Krupp LB, Mendelson WB, Friedman R - J Clin Psychiatry l 99 l; 52: 403- l0
Chronic fatigue syndrome in children Bell DS - Journal of Chronic Fatigue Syndrome 1995; I: 9-33
Chronic fatigue syndromes - Relationship to chronic viral infections Komaroff AL - J Virol Methods 1988; 21: 3-10
Illness onset characteristics in children with chronic fatigue syndrome and idiopathic chronic fatigue Bell DS - Journal of Chroic Fatigue Syndrome I 997; 3: 43-52
Muscle vs. Brain - Chronic fatigue syndrome Lloyd A - Med J Aust 1990; 153: 530-534
Chronic fatigue syndrome - What triggers it off ? Valesini G, Priori R, Conti F - Clinical anil Experimental Rheumatology 1994; t 2(5): 473-476
Is neurally mediated hypotension an unrecognized cause of chronic fatigue ? Rowe PC, Bou-Holaigah I, Kan JS, Calkins H - Lancet l995; 345: 623-624
The relationship between neurally mediated hypotension and the chronic fatigue syndrome Bou-Holaigah I, Rowe PC, Kan 3, Calkins H - JAMA 1995; 274: 961-967
Delayed orthostatic intolerance Streeten DNP, Anderson GH - Arc lntern Med l 992; I 52: 1066- I 072
Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function - Evidence for excessive venous pooling Streeten DHP, Anderson GH, Richardson R, Thomas FD - J Lab Clin Med 1988; I)1: 326-335
Excessive gravitational blood pooling caused by impaired venous tone is the predominant non-cardiac mechanism of orthostatic intolerance Streeten DHP, Anderson GH, Scullard TF - Clin Sci 1996; 90: 277-285
Pathogenesis of hyperadrenergic orthostatic hypotension - Evidence of disordered venous innervation exclusively in the lower Streeten DHP - J Clin Invest l 990; 86: 1582-1588
Treatment of orthostatic hypotension with erythropoictin Hoeldtke RD, Streeten DHP - N Eng J Med l 993; 329: 6l l-615
The chronic fatigue syndrome - A comprehensive approach to its definition and study Fukuda K, Straus SE, Hickie I et al - Ann Intern Med 1994; 121: 953-959
Measuring the functional impact of fatigue - Initial validation of the fatigue impact scale Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie-TJ, Schlech WF - Clin Infect Dis 1994; I 8 (S l): S79-S83
Standard techniques for the measurements of red cell and plasma volume Internationa1 Committee for Standardization in Haematology (lCSH), panel on diagnostic applications of radioisotopes in haematology - Br J Haematol 1973; 25: 801-814
Relation of circulating red cell volume to body density and obesity Huffspace, Feller DO - J Clin Invest l 956; 35: l
Polycythemia : erythrocytoses Athens JW, Lee GR – Chapter 45 in 'Winthrobes Clinical Hematology, 9th Edition, Vol I' - Lee R, Bithwell TC, Foerster J et al. Eds. - Philadelphia: Lea & Febiger, l993:1249
Polycythemia : erythrocytoses Athens JW, Lee GR – Chapter 45 in 'Winthrobes Clinical Hematology, 9th Edition, Vol I' - Lee R, Bithwell TC, Foerster J et al. Eds. - Philadelphia: Lea & Febiger, l993:1247
Chronic ciguatera - One organic cause of the chronic fatigue syndrome Pcarn J - Journal of Chronic Fatigue Syndrome 1996; 2: 29-34
Fatigue secondary to chronic illness - Post-polio syndrome, chronic fatigue syndrome and multiple sclerosis Packer TL, Sauriol A, Brouwer B - Arc Phys Med Rehabil 1994; 75: 1122- I 126
The neuroanatomy of post-polio fatigue Bruno RL, Cohen JM, Galski T, Frick NM - Arch Plus Med Rehabil 1994; 75: 498-1065.
David S. Bell, MD, FAAP - Lyndonville News, July 1999
Several questions have come up regarding the issue of circulating blood volume. I would like to outline my current feelings on this subject.
The first mention of this issue from the CFS perspective was in a paper by Dr. Streeten several years ago showing decreased circulating blood volume in orthostatic intolerance (1). We subsequently published a paper together about this in the JCFS (2). Other publications will be forthcoming, I hope.
Blood is made up of two components : fluid and red blood cells. There are other things there of course, but the volume of circulating blood in the body is mainly these two things. Two separate issues : total blood volume and anemia - they are quite different. The total volume is just that. It is the amount of blood in the whole body, both cells and fluid. It can be measured by draining all the blood out of the body into a bucket (not a good idea) or by the Cromium 51 study. Anemia is where the proportion of cells to fluid is abnormal, but the total volume of blood is normal. Anemia is routinely checked for in a CBC, but total circulating blood volume is not checked for, unless a Cromium 51 study is done.
In CFS, about 80% of patients will have decreased circulating blood volume. We have measured it in about fifty patients and sometimes it is quite dramatic. A normal circulating blood volume is 71 ml/kg or roughly five quarts in a 180 pound person. Most of the persons we measure have about 50 ml/kg, with a symmetrical decrease in both the cells and the fluid (this is the reason that anemia is not found).
The current record in our office is 34 ml/kg. This means that the total blood volume is less than half of what it should be. A person with 45 ml/Kg would have a blood volume of 63.3% of normal (45 divided by 71). This degreased amount of blood circulating in the body is certainly able top cause problems.
If there is not enough blood in the system, circulation to certain organs, particularly the brain, could be impaired. If a normal person looses 40% of their blood volume in a car accident it is usually fatal. In CFS the loss is obviously not all at once, so it is not fatal. But it can cause problems in getting adequate oxygen to the brain, particularly if one is standing up.
It was my hope two years ago that this was the problem in CFS. Therefore, get the volume up to normal and the symptoms would disappear. Unfortunately...well, you know the rest. It didn't work. In a number of patients we were able to correct the circulating volume using different agents. But they did not resolve their symptoms. Maybe some improvements, but it was not the answer. Also 20% of patients have a normal volume determination to start with.
Therefore the volume decreases in 80% of CFS patients must be secondary to something else, perhaps the autonomic nervous system. Correction of the primary problem would thus lead to automatic correction of the volume deficiency. In this regard I now see the volume problem is a possible help in diagnosis and important to understanding the illness, but certainly not the answer. It is like the immunological abnormalities - very real, and possibly helpful, but not the central issue.
It remains to be seen what the value of the circulating blood volume studies will be in the future. They may be important as a proof of organic abnormality in disability cases. It may be a diagnostic marker and it may have treatment implications. I feel sure that it is related to the abnormality of vasopressin secretion, but that story will have to wait a month or so.
Delayed orthostatic intolerance Streeten DHP, Anderson GH - From the Department of Medicine, State University of New York Health Science Center, Syracuse - Arch Intern Med. 1992; 152: 1066-72 In seven patients who presented with lightheadedness, fatigue, "weakness" and sometimes syncope, blood pressure was found not to fall after standing for 3 to 4 minutes but to fall severely, frequently with syncope or presyncopal symptoms, after 13 to 30 minutes when measured every minute with an automatic device. This delayed orthostatic hypotension could be corrected with inflation of a pressure suit to 45 mm Hg. Its mechanism was further investigated with measurements of plasma catecholamines, plasma cortisol and aldosterone responses to corticotropin and the effects of norepinephrine infusions on blood pressure and venous contractility. There was normal or excessive orthostatic norepinephrine release in all patients, evidence of impaired venous innervation in the legs in some and various disorders in the other patients. Since therapeutic improvement in the orthostatic hypotension greatly reduced the symptoms, we concluded that orthostatic hypotension occurring after more than 10 minutes of standing is a potentially debilitating and often correctable disorder. Cfr. : http://archinte.ama-assn.org/cgi/content/abstract/152/5/1066
Circulating blood volume in chronic fatigue syndrome Streeten DHP, Bell DS - David H. P. Streeten is Professor of Medicine at the State University of New York Health Science Center, Syracuse, NY. And has his private practice in Lyndonville, NY - Address correspondence to : David S. Bell, 77 South Main Street, Lyndonville, NY 14098 - JCFS. 1998. 4:3-12 Chronic fatigue syndrome (CFS) is an illness associated with severe activity limitation and a characteristic pattern of symptoms despite a relatively normal physical examination and routine laboratory evaluation. The recent description of delayed orthostatic hypotension in patients with CFS, and previous findings of reduced red blood cell (RBC) mass in other patients with orthostatic hypotension not known to have CFS, led us to measure RBC mass and plasma volume in 19 individuals (15 female, four male) with well characterized, severe CFS. RBC mass was found to be significantly reduced (p < 0.001) below the published normal range in the 16 women, being subnormal in 15 (93.8%) of them as well as in two of the four men. Plasma volume was subnormal in 10 (52.6%) patients and total blood volume was below normal in 12 (63.2%). The high prevalence and frequent severity of the low RBC mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients. Cfr. : http://www.ncf-net.org/library/Bell-StreetenJCFS1998.htm -.
To see the original research on “Circulating Blood Volume in Chronic Fatigue Syndrome” David H. P. Streeten, MB, DPhil, FRCP, FACP David S. Bell, MD, FAAP go to : www.cfidsfoundation.org/Library/Bell.htm -.
V. - Blood volume - Importance and adaptations to exercise training, environmental stresses and trauma/sickness
Sawka MN, Convertino VA, Eichner ER, Schnieder SM, Young AJ – Collaborators : Convertino VA, Schneider SM.- U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760-5007, USA - Med Sci Sports Exerc. 2000 Feb;32(2):332-48 - PMID: 10694114
This paper reviews the influence of several perturbations (physical exercise, heat stress, terrestrial altitude, microgravity and trauma/sickness) on adaptations of blood volume (BV), erythrocyte volume (EV) and plasma volume (PV). Exercise training can induce BV expansion : PV expansion usually occurs immediately, but EV expansion takes weeks. EV and PV expansion contribute to aerobic power improvements associated with exercise training. Repeated heat exposure induces PV expansion but does not alter EV. PV expansion does not improve thermoregulation, but EV expansion improves thermoregulation during exercise in the heat. Dehydration decreases PV (and increases plasma tonicity) which elevates heat strain and reduces exercise performance. High altitude exposure causes rapid (hours) plasma loss. During initial weeks at altitude, EV is unaffected, but a gradual expansion occurs with extended acclimatization. BV adjustments contribute, but are not key, to altitude acclimatization. Microgravity decreases PV and EV which contribute to orthostatic intolerance and decreased exercise capacity in astronauts. PV decreases may result from lower set points for total body water and central venous pressure, while EV decreases may result from increased erythrocyte destruction. Trauma, renal disease and chronic diseases cause anemia from hemorrhage and immune activation which suppresses erythropoiesis. The re-establishment of EV is associated with healing, improved life quality and exercise capabilities for these injured/sick persons. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/10694114?dopt=Abstract
VI. - Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion
Stewart JM - Department of Pediatrics, The Center for Pediatric Hypotension, New York Medical College, Valhalla 10595, USA - Pediatr Res. 2000 Aug;48(2):218-26 - PMID: 10926298
The objective was to determine the nature of autonomic and vasomotor changes in adolescent patients with orthostatic tachycardia associated with the chronic fatigue syndrome (CFS) and the postural orthostatic tachycardia syndrome (POTS). Continuous electrocardiography and arterial tonometry was used to investigate the heart rate and blood pressure responses before and 3-5 min after head-up tilt in 22 adolescents with POTS and 14 adolescents with CFS, compared with control subjects comprising 10 healthy adolescents and 20 patients with simple faint. Heart rate and blood pressure variability, determined baroreceptor function using transfer function analysis and measured cardiac vagal and adrenergic autonomic responses were calculated using timed breathing and the quantitative Valsalva maneuver. Two of 10 healthy controls and 14 of 20 simple faint patients experienced vasovagal syncope during head-up tilt. By design, all CFS and POTS patients experienced orthostatic tachycardia, often associated with hypotension. R-R interval and heart rate variability were decreased in CFS and POTS patients compared with control subjects and remained decreased with head-up tilt. Low-frequency (0.05-0.15 Hz) blood pressure variability reflecting vasomotion was increased in CFS and POTS patients compared with control subjects and increased further with head-up tilt. This was associated with depressed baroreflex transfer indicating baroreceptor attenuation through defective vagal efferent response. Only the sympathetic response remained. Heart rate variability declined progressively from normal healthy control subjects through syncope to POTS to CFS patients. Timed breathing and Valsalva maneuver were most often normal in CFS and POTS patients, although abnormalities in select individuals were found. Heart rate and blood pressure regulation in POTS and CFS patients are similar and indicate attenuated efferent vagal baroreflex associated with increased vasomotor tone. Loss of beat-to-beat heart rate control may contribute to a destabilized blood pressure resulting in orthostatic intolerance. The dysautonomia of orthostatic intolerance in POTS and in chronic fatigue are similar. Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/10926298?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Discovery Panel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed
VII. - Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue
Farquhar WB, Hunt BE, Taylor JA, Darling SE, Freeman R - Center for Autonomic and Peripheral Nerve Disorders, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA - Am J Physiol Heart Circ Physiol. 2002 Jan;282(1):H66-71 - PMID: 11748048
Individuals with chronic fatigue syndrome (CFS) experience a number of somatic complaints including severe, disabling fatigue and exercise intolerance. We hypothesized that hypovolemia, through its interaction with central hemodynamics, would contribute to the exercise intolerance associated with this disorder. We examined blood volume, peak aerobic power, habitual physical activity, fatigue level and their interrelations to understand the physiological basis of this disorder. Seventeen patients who met the Centers for Disease Control criteria for CFS and 17 age-matched controls participated in the study. Blood volume was assessed using a single bolus injection of Evans blue dye. Peak oxygen consumption was measured during exercise on an upright cycle ergometer. Supine cardiac output and stroke volumes were measured using CO(2) rebreathing. Questionnaires were used to assess habitual physical activity and fatigue. Patients displayed a trend for a 9% lower blood volume (58.3 +/- 2.1 vs. 64.2 +/- 2.5 ml/kg, P = 0.084) and had a 35% lower peak oxygen consumption (22.0 +/- 1.2 vs. 33.6 +/- 1.9 ml/kg, P < 0.001). These two variables were highly related within the patients (r = 0.835, P < 0.001) and the controls (r = 0.850, P < 0.001). Peak ventilation and habitual physical activity were significantly lower in the patients. Fatigue level was not related to any of the measured physiological parameters within the CFS group. In conclusion, individuals with CFS have a significantly lower peak oxygen consumption and an insignificant trend toward lower blood volume compared with controls. These variables were highly related in both subject groups, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS.
The use of symptoms generated by head up tilt (HUT) is not a useful tool in identifying chronic fatigue syndrome (CFS). We investigated whether heart rate variability (HRV) assessed early during HUT might be useful. A sample of 46 female subjects (24 with CFS and 22 sedentary, age-matched healthy controls; CON) who had exhibited no difference in time to syncope during tilt was examined for HRV responses to 10 min of 70° HUT after 5 min of baseline in the supine position. HRV data were analyzed by the method of coarse graining spectral analysis. Variables compared between groups included mean and standard deviation (SDRRI) of RR intervals (RRI), amplitudes of low- (ALF; 0.04–0.15 Hz) and high-frequency (AHF; >0.15 Hz) harmonic as well as aperiodic, fractal (AFR; 1/fß) spectral components, the spectral exponent ß and the difference in these values between baseline and HUT for each subject. In the supine baseline, only mean RRI was significantly (P < 0.01) lower in CFS than in CON. During HUT, however, mean RRI (P < 0.01), SDRRI (P < 0.01), AHF (P < 0.05) and AFR (P < 0.01) were significantly lower in CFS than in CON. When the difference in values between baseline and HUT for each subject was examined, only the difference for AFR (AFR) was significantly (P < 0.01) lower in CFS than in CON, suggesting that AFRis a disease-specific response of HRV to HUT. When a cut-off level was set to AFR = -2.7 msec, the sensitivity and the specificity in differentiating CFS from controls were 90% and 72%, respectively. The data suggest that a decrease in aperiodic fractal component of HRV in response to HUT can be used to differentiate patients with CFS from CON.
Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function - Part II
Chronic fatigue syndrome - Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function -
IX - Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome
Arnold Peckerman, Phd., John J. Lamanca, Phd, Kristina A. Dahl, Md., Rahul Chemitiganti, Md., Bushra Qureishi, Md. An Benjamin H. Natelson, Md. - Am J Med Sci 2003;326(2):55–60
Background - Findings indicative of a problem with circulation have been reported in patients with chronic fatigue syndrome (CFS). We examined this possibility by measuring the patient’s cardiac output and assessing its relation to presenting symptoms.
Methods - Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n 18) and less severe (n 20) illness and compared with those from 27 matched, sedentary control subjects.
Results - The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Postexertional fatigue and flu-like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R 2 0.46, P 0.0002) of lower cardiac output. In contrast, neuropsychiatric symptoms showed no specific association with cardiac output.
Conclusions - These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.
X. - Illness and disability in Danish Chronic Fatigue Syndrome patients at diagnosis and 5-year follow-up
M.M Andersen (a), H Permin (a) & F Albrecht (b) - (a) Department of Infectious Diseases M5132, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark – (b) Regional Mid-Shore Mental Health Services, 17 S. Washington Street, Easton, MD, 21601, USA - Corresponding author : tel. : +45-35451492; fax : +45-35456648 – J. Of Psychomatic Research, Volume 56, Issue 2, Pages 217-229 (February 2004)
Objective - Evaluation of the life impact of Chronic Fatigue Syndrome (CFS) over 5 years.
Methods - Thirty-three adult patients meeting 1988 and 1994 CDC case criteria answered identical questionnaires at diagnosis and 5 years later, when a retrospective questionnaire was also completed.
Results - Work disability was very high and increased further, social isolation remained high, emotional adjustment improved. There were increased problems with reading and with allergies. Two measures of improvement were used : The relation between these measures was weak. Length of illness, extent of disability and emotional adjustment were poorly related to measures of improvement. Average illness scores were unchanged, but most individuals improved in some ways while worsening or remaining the same in others. Only one participant (3%) neared recovery, one other was substantially better but still severely disabled.
Conclusion - CFS patients exhibit severe, long-term functional impairment. Substantial improvement is uncommon, less than 6%. Allergies and aspects of cognition may worsen, emotional adjustment often improves.
XI. - A sedentary childhood could lead to chronic fatigue latter in life
Bio-Medicine, 14 October 2004
Chronic fatigue syndrome is an often disabling condition that affects primarily women. The condition is characterized by deep-seated fatigue that cannot be overcome with rest and often worsens with physical activity. The cause of the condition is unknown and there are no diagnostic tests or cures. A recent study explains that children who have sedentary behaviors are at increased risk for developing chronic fatigue later in life.
Researchers monitored more than 16,500 children over 30 years for the study. Participants were followed up at ages 5, 10, 16 and 29 or 30. Parents and teachers filled out questionnaires about the child’s activity level.
After examining the data, the researchers determined that being female, being in a high social class during childhood and having a long-standing medical condition in childhood were all factors that increased a person’s risk of developing chronic fatigue. However unlike previous studies, this study found no association between the development of chronic fatigue later in life and maternal behaviors, parental illness or childhood distress.
Thus researchers say compared to previous suggestions that showed high levels of exercise to increase the risk, they say that they found that the most sedentary children were at greatest risk.
XII. - Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome - A population-based study
Boneva RS, Decker MJ, Maloney EM, Lin JM, Jones JF, Helgason HG, Heim CM, Rye DB, Reeves WC, Chronic Viral Diseases Branch, National Center for Zoonotic, Vector-borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA : firstname.lastname@example.org - Auton Neurosci. 2007 Dec 30;137(1-2):94-101. Epub 2007 Sep 12 - PMID: 17851136
Autonomic nervous system (ANS) dysfunction has been suggested in patients with chronic fatigue syndrome (CFS). In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders. Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] (p<0.0004, each) and reduced low frequency (LF), very low frequency (VLF) and total power (TP) of HRV (p<0.02, all). CFS cases had significantly lower plasma aldosterone (p<0.05) and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine (r=0.23, p=0.05) and moderately with vitality and fatigue scores (r=-0.49 and 0.46, respectively, p<0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p=0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders case-control differences in HR and TP remained significant (p<0.05). Conclusion - The presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed.
Autonomic testing in patients with chronic fatigue syndrome De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne K, Hagers Y - Am J Med 105:22S–26S, 1998 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/9790478
Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome Stewart J, Weldon A, Arlievsky N, Li K, Munoz J - Clin Auton Res 8:221–230, 1998 Cfr. : http://www.ncbi.nlm.nih.gov/pubmed/9791743?dopt=Abstract
Finding the energy to fight - Chronic Fatigue patients struggle for normal lives
Terry Hedrick of Cobb Island was suddenly hit with chronic fatigue syndrome in 1994. She now has learned to pace herself and finds ways to deal with the disease, but is unable to work or have a normal social life.
Finding the energy to fight
Chronic Fatigue patients struggle for normal lives
Terry Hedrick knows not only the day, but the hour that her life changed forever.
It was 4 p.m. May 9, 1994. She was recovering from a minor operation on her sinuses that was supposed to solve a few issues she had had for years, when she suddenly became ill.
Her symptoms were sudden and severe. Doctors at first thought she had been hit with a viral infection as a result of the surgery. They gave her pain medication to get her through it.
‘‘They assumed it would go away in a few days,” the Cobb Island resident said.
It did not.
‘‘The days passed and I didn’t need the pain medication, but it just kept going,” Hedrick said : ‘‘I was sleeping 12 to 14 hours a day, I couldn’t stay upright.”
Eventually, Hedrick was diagnosed with chronic fatigue and immune dysfunction syndrome.
Before that day, Hedrick was an active person, taking her dog on long walks and spending time in her garden. She was dedicated to her career as a member of the Senior Executive Service at the congressional agency General Accountability Office. There, she said, she headed a division of researchers who did studies for congressional committees.
Once the illness hit, everything changed.
‘‘I was housebound for a couple years, but now can manage to get out to buy groceries and take care of myself,” Hedrick wrote in an e-mail. But once those chores are done, Hedrick has no energy left for work or having a normal social life.
‘‘Gardening got reduced to clipping a flower or two,” she said : ‘‘If I wash my hair in the morning, it takes about three hours to recover. ... You learn to pace yourself very carefully. If I need to buy groceries, I plan it the day before. I get my clothes out and take a shower the night before. I get my groceries, put them away, and that’s the day.”
Living with the illness for more than a decade now, Hedrick has managed to work her life around it to an extent. She has formed a book club that meets about every six weeks and provides her with a social life and the other people in the club are sympathetic, which can actually be rare for people with CFS.
‘‘The name sounds so trivial that people don’t understand,” Hedrick said.
Dr. Coryse Brathwaite, a physician at A Woman’s Place in Waldorf, said people often think CFS is an imaginary disorder.
‘‘People say it’s in your head,” Brathwaite said : ‘‘Very few people are even treated for the disease, because it may not be correctly diagnosed.”
Despite the major changes the illness has brought about for Hedrick, she said she still feels somewhat lucky, mostly because of where she was in her career.
‘‘I was a federal employee at a fairly high level,” she said, which was especially lucky because being in her mid-40s when the disease hit her, Hedrick had not even considered long-term insurance coverage. But the ability to take long-term disability was already a privilege for her because of her federal job. Before the diagnosis, Hedrick had rarely used her sick leave during the 13 years she was working for the government.
Now on disability retirement, her pay is barely comparable to what she made when she was working, but she still has insurance coverage and feels fortunate to at least have that.
‘‘I am one of the lucky ones,” she said.
A diagnosis of exclusion
Brathwaite said she has given several of her patients the diagnosis of chronic fatigue syndrome, but overall, she thinks the disease is underestimated.
‘‘It’s a growing problem,” Brathwaite said : ‘‘I think it’s one of the underdiagnosed but more prevalent problems.”
She said it is difficult for doctors to pin down because there is not a specific set of symptoms that define it.
‘‘It’s become a diagnosis of exclusion, but I think that’s changing,” she said.
There are now research centers all over the world that are dedicated to finding the source of CFS, as well as making it easier to diagnose and treat. Brathwaite said a patient who faces the diagnosis should consider major lifestyle changes, especially in their stress levels and environment. Some patients are still able to work, but have to constantly be mindful of pacing themselves. For some, the disease lasts the rest of the their lives, while others recover after a few years.
Brathwaite said patients and doctors have to take a multidisciplinary approach to the illness and be flexible throughout treatment.
‘‘Things change,” she said : ‘‘One week, exercise is working great. Next week, they can barely get out of bed.”
Anne C. Crowley is an acupuncturist in La Plata who said she sometimes sees patients who suffer from CFS and other fatigue-related illnesses. Crowley said she works on the energy patterns of people who suffer from the illness, in hopes of increasing their overall energy levels.
‘‘I’m looking at the total person,” Crowley said. She said she looks at the pulses of energy in each person and if they are too low or too high, she tries to reduce the symptoms : ‘‘I’m going to treat all of it.”
Theories and more theories
The Chronic Fatigue and Immune Dysfunction Syndrome Association is dedicated to finding the cause and perhaps someday a cure, to the disease. But the road has been a long one and there doesn’t seem to be an end in sight. In the CFIDS Chronicle, a publication created by the association, there are details of many theories about the disease.
The top theory is that the immune system is the focus, if not the cause, of the problem. It seems that the immune system is in a low-grade battle with an unseen virus or infection, activating cells that are used to fight disease.
Some patients have abnormalities in brain metabolism or in the hypothalamus. Also, some patients cannot maintain their blood pressure once they stand up. Others may have low levels of blood volume. There are studies that indicate genetic problems in energy metabolism and enzymes that come from diet. The symptoms vary considerably and range widely in severity.
For Hedrick, being diagnosed with the illness has changed her life, but she hopes to channel what energy she has into helping others who have it. She now dedicates her time to helping the CFIDS Association with grant-making efforts that support research into the disease.
The association ‘‘was the only place I could find good information on how to live with this,” Hedrick said : ‘‘I admire them. They’re very careful about not endorsing things. They’re more of a catalyst. Their goal is just really to find a cure.”