U.S. Centers for Disease Control publishes pilot study on gentically-based metabolic differences on exercise challenge between CFIDS patients and controls.
- Last Updated: 02 December 2015 02 December 2015
The following excerpted article was published by researchers at the U.S. Centers for Disease Control & Prevention (CDC). We have, ourselves, italicized some of the more interesting findings.
The findings contained in the article demonstrate distinct metabolic changes on exercise challenge as a result of altered gene expression in Chronic Fatigue Syndrome (CFS) patients versus healthy controls.
Please note: The pilot study report excerpted below is based on an extremely small sample: 5 women with CFS and 5 female healthy controls. Therefore, a new study with a larger sample-size would have to be done to confirm these findings.
Moreover, the CFS subjects were selected according to the 1994 CDC CFS case definition. As we know, this definition is a very broad one that can lead to a confounding of research findings due to inclusion of subjects who may not have ME/CFS.
We do, however, find the results interesting and hope they will be replicated in a larger study.
Toni Whistler, James F. Jones, Elizabeth R. Unger and Suzanne D. Vernon, "Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects," BMC Physiology (2005) 5:5 doi:10.1186/1472-6793-5-5
Chronic fatigue syndrome (CFS) is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge.
Women with CFS and healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum workload. Blood was obtained before and after the challenge, total RNA was extracted from mononuclear cells…We identified differences in gene expression among and between subject groups before and after exercise challenge and evaluated differences in terms of Gene Ontology categories.
Exercise-responsive genes differed between CFS patients and controls... Differences in ion transport and ion channel activity were evident at baseline and were exaggerated after exercise, as evidenced by greater numbers of differentially expressed genes in these molecular functions.
These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.
In a state of health, physical exercise has a quantifiable effect on neuroendocrine, autonomic, and immune systems influencing metabolic and immune responses. However, in the initial phase of acute illness, there is an avoidance of physical stressors so energy can be dedicated to healing and a return to homeostasis. While physiologic disturbance in acute illness is transient, chronic illnesses, such as chronic fatigue syndrome (CFS), have prolonged disturbances that have a debilitating effect both physiologically and psychologically. Consequently, activities that are physiologic stressors, such as physical exercise, exacerbate the symptoms that define CFS.
CFS is a complex, multifactorial illness whose etiology and pathophysiology remain unclear . CFS is defined by a characteristic symptom complex in the absence of other medical or psychiatric conditions with similar clinical characteristics [2,3]. Subtle differences in hypothalamic-pituitary-adrenal axis function , immune system function , and psychological profiles  between CFS patients and controls have been reported; however, no consistent distinguishing difference or frank abnormality has been confirmed [7,8], and it remains unclear whether CFS represents a unique disease or a common illness response to a variety of insults.
Perhaps the greatest methodological problem with studying CFS is that many individuals identified in population studies have been sick for at least 5 years . During this time, the illness waxes and wanes, making it difficult to identify biomarkers or define pathogenesis. Physical, mental, and emotional stress exacerbate CFS and result in case-defining post-exertional fatigue  with measurable physiologic differences . Therefore, exercise challenge of people with CFS is an effective method for calibrating CFS subjects and thus increasing the likelihood of uniformly identifying biomarkers and/or physiologic abnormalities.
We used gene expression profiling of peripheral blood to evaluate differences between CFS subjects and sedentary healthy controls both before and following an exercise challenge. Overall, we found the gene expression profiles to be quite similar, and of importance, most differences were present prior to exercise challenge. These differences were in G protein-coupled receptor and ion transport and ion channel activity ontologies. The latter was exaggerated after exercise as evidenced by differential expression of a greater number of genes involved in these molecular functions. Differences were also evident in exercise response, including chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport and G-protein coupled receptor ontologies. These differences may help explain the symptoms of CFS.
Exercise response genes were evaluated using a random variance test in a paired, class comparison analysis of control subjects before and after exercise, and 21 genes were identified as being differentially expressed…
Since these 21 genes reflect a healthy subject's peripheral blood gene expression response to exercise challenge, we reasoned that the expression of these would be altered in CFS subjects… The response of 10 of the 21 genes was quite similar in terms of magnitude and direction for both CFS and control subjects… For the other 11 genes, the magnitude of the exercise change was considerably smaller in CFS subjects… than in control subjects… However, 5 genes classified in vesicle-mediated and protein-transport ontologies differed between CFS and control subjects…
…Exercise-related changes that were seen only in CFS subjects were related to G-protein-coupled receptor signaling (purple, Figure 2b).
Gene ontology comparison was also used to evaluate differences between control and CFS subjects before…and after…exercise. Baseline differences between CFS subjects and controls that continued after exercise involved GO terms relating to ion transport… After exercise, these differences appear to be amplified, as evidenced by increased numbers of genes present in these GO categories and also by inclusion of more GO terms pertaining to ATPase transmembrane movement of ions… G-protein-coupled receptor binding… part of the broad functional category of signal transduction, differed between CFS subjects and controls prior to exercise. This baseline difference between controls and CFS subjects was not significant after exercise. Interestingly, complement activation…was one of the exercise-induced differences between subjects and controls that was present only after challenge. Genes in most of the ontologies identified as different between CFS and control subjects had lower expression levels in CFS subjects.
Gene expression profiling affords a unique opportunity to characterize CFS at a systems biology level. Changes in gene expression underlie many biologic processes and may provide insight into disease-specific gene expression and the response of genes to environmental stimuli. In a proof-of-concept study, we found that CFS patients had different blood mononuclear cell gene expression patterns than non-fatigued controls… and that CFS is a heterogeneous illness as evidenced by different gene expression profiles for patients reporting gradual onset of their illness compared with those reporting sudden onset of illness… In addition, differential display polymerase chain reaction on a small number of CFS and control subjects identified candidate biomarkers in the peripheral blood…
CFS is defined by a post-exertional fatigue that does not subside 24 hours following physical stress. In contrast, exercise in healthy, untrained people induces changes in cellular homeostasis in 1 to 4 hours and a return to basal levels within 24 hours, as measured in muscle… In contrast, 11 of the genes were unchanged in CFS subjects before and after exercise; with 5 being classified in a transport-related ontology. Because this difference in gene expression is so dramatic, it implicates a fundamental perturbation in the biochemical activity of lymphocyte and monocyte peripheral blood fractions from CFS subjects compared with control subjects that does not affect classical immunologic markers (i.e, CD45) that have been shown to be unaffected in CFS patients… Rather, low expression of these genes may have subtle effects on immune function. Immune dysfunction has been inconsistently implicated in CFS pathogenesis…
Class comparison was used to identify these 21 differentially expressed genes, which indicated the possible disturbance of biologic pathways… To explore this possibility, we used the GO comparison that is based on the knowledge that gene expression levels are dependent variables in biological processes, cellular components, and molecular functions. In this way, multiple genes in the same category reinforce each other and enhance the power for identifying the significance of the category. The GO categories considered significantly different (p < 0.005) when comparing CFS subjects with controls after exercise challenge were those pertaining to ion transporter activity (a total of 87 genes applied to this category in the comparison of CFS and controls after exercise) and ATPase activity coupled to transmembrane movement (42 genes). When the CFS and control classes are compared prior to exercise, ion transport activity and voltage-gated, ion channel activity are identified (38 and 44 genes within the GO categories, respectively).
It is evident that ion transport and ion channel activity segregate cases from controls and that exercise seems to intensify these differences. Several other conditions have been reported in which fluctuating fatigue occurs that are known to be caused by abnormal ion channels. These conditions include genetically determined channelopathies and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis, and polyneuropathies… There are other transmembrane functions associated with differences between controls and CFS patients, including signal transducer activity through receptor binding/activity… Signal transduction of transmembrane receptors occurs by a number of mechanisms, including structural changes, ion channels, and changes of transmembrane potentials. The G-protein-coupled receptors play an important role in the membrane trafficking machinery… The most obvious exercise-induced changes in CFS cases pertain to gene regulation at the point of chromatin structure; whether these changes reflect the differences seen in the mRNA transcripts relating to membrane trafficking differences between cases and controls has not yet been determined. One interesting correlate of this study was the finding that the complement pathway showed significant differences between CFS and control subjects after exercise. This has been reported previously in the analysis of these same exercise challenge-derived specimens. Sorensen et al.… measured levels of complement split products in the sera of these subjects and found differences between CFS and control subjects in C4a after exercise challenge. Complement activation was identified as an ontology that was significantly different between CFS and control subjects after exercise. The correlates on the data are interesting as their study measured protein levels (i.e., gene product levels) and this study measured the transcript levels…
The lack of statistical significance in the 3 other class comparison analyses performed (CFS cases compared before and after exercise, comparison of cases to controls at baseline, and the comparison of cases to controls 24 hours after exercise) reflects low experimental sensitivity, most likely due to a small number of subjects, rather than an absence of biological effect…
The next line of research will detail larger numbers of subjects in the expression arrays. The emphasis in such studies will be on developing a gene expression-based multivariate function, or predictor, that accurately predicts the class membership of a new sample on the basis of the expression levels of key genes. Class discovery tools will also be applied to CFS subjects' expression profiles in an attempt to further describe discrete subsets of this disease on the basis of gene expression as we have done for gradual and sudden onset of illness… However, the methods used in this study will be applied to these data sets too, as these analytical tools will prove to be very helpful in defining the pathophysiology of CFS. It is hoped that this broader, more fully encompassing approach to CFS research will open many doors to the understanding of this syndrome and perhaps of fatigue and un-wellness in general.
- Last Updated: 02 December 2015 02 December 2015
A research team from Glasgow University in Scotland announced in 2005 an altered pattern of gene activity in 50 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Dr. John Gow, the senior researcher, said, "We have identified genes which were up-regulated compared with genes in normal healthy individuals... This means the genes are switched on or off an at inappropriate time... It looks like the immune system is working overtime when it shouldn't be..."
Dr. Gow and his team mapped the entire genome of 33,000 genes in the ME/CFS sufferers and then compared them with the genes of healthy people. Despite the initial results, Dr. Gow stressed that more testing of ME/CFS patients is needed to make sure that the unusual gene activity is specific for Chronic Fatigue Syndrome. He thinks this further testing would take about a year.
Diagnostic Test and Treatments
The research team is hopeful that the potential "CFS gene signature" could lead to a specific diagnostic test, and has already patented the genes which would be involved in diagnostic testing. A prototype diagnostic testing kit has been developed which would give a yes or no answer as to whether CFS is present.
Even more exciting is the promise of medication to treat the abnormal gene/immune dysfunction. Dr. Gow stated, "Our work has given us clues as to which pathways are up- or down-regulated and we know which drugs activate different pathways, so we think we can find drug treatments that will be beneficial to patients."
These specific drugs are already on the market and therefore could be available to ME/CFS patients in the immediate future. Dr. Gow said, " ...it really needs to go through proper trials before these drugs become widely available."
This is important research since it includes a possible mechanism of action, a diagnostic test, and potential medication. Of course, we must wait and see.
Sources: BBC News, UK Edition, 28 May 2005; The Scotsman, 20 May 2005; Co-Cure; ME Association.
Updated Information on Dr. Gow's Research
Since this article was written, two groups in Britain: MERGE (ME Research Group for Education and Support) and the ME Association have provided substantial funding to enable Dr. Gow and his associates to begin the second phase of their research. MERGE has provided an interim award of 8,000 pounds and the ME Association has granted 28,675 pounds (in addition to the nearly 9,000 pounds that the MEA has already provided).
The following update on the research is taken with permission from a Co-Cure post dated June 27, 2005:
"So the second phase of the study should now be able to commence in August.
Why is this type of genetic research so important in ME/CFS?
In very simple terms, the Glasgow University research group will be using a technique called DNA chip microassay analysis to map out what is happening to a vast amount of individual genetic information—over 33,000 gene sequences in each individual. The scientists will be carrying out this genetic analysis on a large group of people with ME/CFS, another large group of healthy matched controls, and a further large group of people with a range of other illnesses—such a multiple sclerosis and depression—in which fatigue is a major clinical symptom. In particular, the scientists will be trying to identify whether there is a unique profile of genetic abnormalities in people with ME/CFS by looking for data which indicates that certain specific genes are either up-regulated or down-regulated—roughly meaning that they are being over-active, under-active or 'switched-off'.
The activity of these genes—gene expression in medical jargon—can have very important consequences on the types of cellular activity, including crucial biochemical pathways, that they control in the nervous system, immune system, and all other parts of the body. So the ultimate aim of the study is to identify specific gene abnormalities which may then lead to new avenues of research and the presence of a diagnostic biomarker or diagnostic biomakers which is/are only present in ME/CFS.
Preliminary results from phase one of this study already indicate that significant abnormalities in gene expression are present in the ME/CFS group, but this data now needs to be confirmed in a much larger trial.
This type of information on gene expression will also be highly relevant to new forms of treatment which are worth assessing. And as the data becomes clearer, a further phase of the research will hopefully then involve a clinical trial of drug treatment aimed at the underlying cause of ME/CFS."
- Last Updated: 07 November 2015 07 November 2015
Compiled by R. Sanderson
Reviewed and edited by K. Casanova
Editor's Note, 2015: Dr. Klimas is now the Director of the Institute for Neuro Immune Medicine at Nova Southeastern University, professor of medicine, and chair of the Department of Clinical Immunology at NSU’s College of Osteopathic Medicine. She is no longer President of IACFS/ME. She won the Annual Provost’s Research and Scholarship Award at Nova in 2015 and the 2014 Perpich Award from the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) for distinguished community service. She also was featured as a “Woman to Watch” on WFOR CBS 4.
On Sunday, April 30, 2006, Dr. Klimas presented a lecture titled, “Research Advances in Chronic Fatigue Syndrome: Impact on Treatment,” at the Connecticut CFIDS & FM Association’s Spring Conference.
Dr. Nancy Klimas is Professor of Medicine at the University of Miami and the Director of Research for the Clinical AIDS/HIV Research at the Miami Veterans Affairs Medical Center. She has been a leader in the field of ME/CFS research, is a founding editor of the Journal of Chronic Fatigue Syndrome [no longer published as of 2009] and is the current President of the International Association for CFS/ME (IACFS/ME).
As much as everyone looks forward to hearing Dr. Klimas speak, such an event is never long enough. She always has a great deal of information to share with her audience, and it can be very hard to keep up with her. Therefore, please note that a lot of data was incorporated directly from a copy of her PowerPoint presentation (which includes complete information on the articles cited), along with elaborations made by Dr. Klimas on specific topics. In this way, we hope to provide you with as much information as is possible on recent research advances.
Since CFS was the term used in the lecture, this name is used throughout this summary.
Dr. Klimas began her presentation with a brief review of issues that continue to affect our patient population: including the clinical case definition for CFS (Canadian Consensus Panel Clinical Case Definition for CFS/ME vs. the CDC 1994 criteria); CFS epidemiology and the high percentage of undiagnosed CFS cases; and the economic impact of CFS on productivity.
She emphasized how these issues, along with the trivializing name, have negatively impacted treatment. Klimas acknowledged that many physician attitudes show a negative bias towards CFS due to its name. A survey of 811 GPs revealed that 44% did not feel confident making the diagnosis [of CFS], and 41% did not feel confident in treating it. Physicians had reported they would likely have more confidence in the diagnosis if they had a friend or family member with CFS. The doctors also reported that education that emphasizes acceptance of CFS as a real entity would improve their confidence in treatment. (Source: Bowen J et al, Family Pract April 1 (2005)).
She provided an update regarding recent research advances and publications (2003 through early 2006) using her well-known model as a basis.
Model for CFS pathogenesis
Triggering event/ infection
Mediators (Immune, endocrine, neuroendocrine, psychosocial)
Health Outcome/ Persistence
Dr. Klimas went over some of HLA DR haplotypes identified in an earlier study of CFS patients that revealed these patients were at a 4 to 6-fold increased relative risk for haplotypes DR4, DR3, and DQ3 (Keller et al, 1992). Klimas explained that gene array data can separate patients into subgroups by their patterns of gene dysregulation in both immune and HPA gene clusters.
Technological progress has made it possible to analyze genes to a greater depth than we are presently able to medically understand what the data mean. Klimas further noted individuals with CFS cannot be lumped together, as they are part of subgroups and therefore should be treated differentially.
A brief review was done of prior studies that demonstrated an association between onset of CFS and an acute viral-like illness in 60-80% of patients (Komaroff and Buchwald). Furthermore, a percentage of patients remained sick after acute viral infections, such as EBV, Q fever or Ross River Virus (according to Australian and UK research). One of the newer theories of great interest to Dr. Klimas is the possibility that only fragments of viruses (like EBV) could “trash” [i.e., dysregulate] a patient’s system.
Ronald Glaser et al.1 have found evidence that regulatory peptides encoded by EBV are expressed in CFS despite the absence of replicating virus. These peptides are known to modulate immune function by inducing pro-inflammatory and Type-2 cytokines.
A. Martin Lerner2 and his group have found evidence of a two subgroups of CFS patients with incomplete viral multiplication (CMV viral “fragments” and EBV antigen.)
[The remainder of this discussion of Lerner’s recent paper (see citation below) departs from what Dr. Klimas presented in her lecture. We reviewed Lerner’s paper and we present some of his more interesting findings in the next three paragraphs. Then we return to Dr. Klimas' lecture.]
At the same time, Lerner has found abnormal oscillating cardiac T-waves (by 24 Holter monitor) in a significant percentage of CFS patients (as opposed to controls). A smaller percentage of patients had Abnormal Cardiac Wall Motion.
Lerner suggests that the findings of incomplete viral multiplication and cardiac anomalies may be causally linked in subsets of CFS patients. The link may be direct in terms of viral damage or mediated by immune system activity. He stresses that further research must be done in this area. He also notes that “one preliminary trial of antiviral therapy (valacyclovir) in a cohort of CFS patients with single virus Epstein-Barr Virus (EBV) persistent infection is promising.”
However, Lerner also notes that the other subset of patients with CMV incomplete viral multiplication did not respond to the antiviral. He says this makes sense because the antiviral is known to have anti-EBV effects, “but does not have significant anti-HCMV activity…”
Lerner, interestingly for CFS patients, also discusses Gunther Stent’s theory regarding: “Premature scientific discovery. Premature scientific discoveries are met by the scientific community with resistance and ridicule.” [Here Lerner is saying that much of the pioneering CFS research remains in the “premature scientific discovery” category.]
Dr. Klimas indicated HHV-6 is another prevalent virus in individuals with CFS. It has been detected in 22% - 54% of patients in cross-sectional studies (Ablashi, Krueger, and Knox) and in 79% of CFS patients in longitudinal studies (HHV-6 PCR assay, Knox). Dr. Klimas emphasized that the only reliable lab for patient HHV-6 testing is the Wisconsin Viral Research Group in Milwaukee, WI. This is the laboratory in which Dr. Konstance Knox has done extensive research on the virus. However, Klimas cautioned HHV-6 does not respond to traditional antivirals, but requires aggressive treatment with very potent agents administered through IVs.
1. Glaser R et al, “Stress-associated Changes in the Steady-State Expression of Latent Epstein–Barr virus: Implications for Chronic Fatigue Syndrome and Cancer,” Brain, Behavior and Immunity 19 (2) (2005): 91-103.
2. Lerner AM et al, "Prevalence of Abnormal Cardiac Wall Motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with Chronic Fatigue Syndrome," In Vivo Jul-Aug; 18(4) (2004): 417-24.
Mediators (immune, endocrine, neuroendocrine, psychosocial)
An Immune Cascade chart was used to illustrate how various immune response processes are activated in response to an infection. Basically, the helper T-cell function in individuals with CFS no longer remains balanced; instead, it shifts to a TH-2 pattern, which in turn, triggers pro-inflammatory cytokines.
More recent endocrinology studies show evidence of reduced cortisol output (by the adrenals) via several mechanisms, such as heightened negative feedback, heightened receptor function and impaired ACTH and cortisol responses to challenge. Research data also supports DHEA functional abnormality, abnormal serotonin function, and IL-6 increase associated with low cortisol. (The low cortisol is mediated by a hypothalamic dysregulation of Cortisol Releasing Hormone.) In spite of these findings, Dr. Klimas stated that cortisol treatment, especially long-term, is not being recommended. The following two studies address this issue:
Cleare AJ, “The Neuroendocrinology of Chronic Fatigue Syndrome,” Endocrine Reviews 24 (2) (2003): 236-252.
Papanicolaou DA et al (representing a large US panel), “Neuroendocrine Aspects of Chronic Fatigue Syndrome," Neuroimmunomodulation 11(2) (2004): 65-74.
Some of the latest research on Autonomic Nervous System abnormalities in CFS (as shown on the chart for ANS) and other sources, are as follows:
- Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. 1
- Heart rate variability as a predictor of CFS. 2
- Gastric emptying delayed in 23 out of 32 CFS subjects. 3
1. Naschitz J, “The Head-up Tilt Test with Haemodynamic Instability Score in Diagnosing Chronic Fatigue Syndrome,” QJM 96(2) (2003): 133-42.
2. Yamamoto et al, “A Measure of Heart Rate Variability Is Sensitive to Orthostatic Challenge in Women with Chronic Fatigue Syndrome,” Experimental Biology and Medicine 228 (2003):167-174.
3. Burnet R, “Gastric Emptying is Slow in Chronic Fatigue Syndrome,” BMC Gastroenterology 4 (2004): 32.
H. Modolfsky’s early studies have documented a variety of circadian sleep disturbances in CFS patients, such as altered diurnal patterns in cortisol, prolactin, and NK cell function, as well as alpha wave intrusion on sleep EEG, and a reduced state of stage III and IV sleep. A more recent study by Nathanial Watson has shown a higher percentage of REM sleep in CFS twins (Twin Study of 22 discordant twins 1). This finding suggests an element of sleep-state dysregulation.
Dr. Klimas mentioned there are several new Stage IV sleep inducer medications being used. The strongest of these is Xyrem (a form of gamma hydroxybutyrate (GHB))—a beneficial drug in treatment of narcolepsy; but it is also known for its illegal use as a date-rape drug. Currently, it is only available through enrollment in a special program (not through retail pharmacies) and is so potent, it must be taken when already in bed.
Remeron is a medication—actually, this is an antidepressant that promotes stage III and IV sleep—that Klimas has prescribed, often in ¼ doses. She recommended that individuals with sleep problems consult with sleep doctors and pointed out these physicians are in two specialties: pulmonology and neurology. It is also important to choose a doctor who will provide continuing care after the initial evaluation.
1. Watson et al, “Comparison of Subjective and Objective Measures of Insomnia in Monozygotic Twins Discordant for Chronic Fatigue Syndrome,” Sleep May 1; 26(3) (2003): 324-8.
Though research findings pertaining to muscle function/ disturbances, including those of the heart, were not discussed in any great detail. A summary of these findings is included for your information:
- An oxidative stress study measuring protein carbonyls suggested higher levels of protein oxidation in CFS subjects as opposed to controls 1.
- Exercise testing in 189 CFS subjects resulted in clinically significant subgroups with 50% of subjects showing moderate to severe functional impairment. An unexpected blunting of Heart Rate and Blood Pressure responses was noted. 2
- Sarcoplasmic reticulum defect: conduction and calcium transport abnormalities. 3
- Cardiac muscle—cardiac output found related to illness severity and the predicted exercise-induced relapse 4.
- Subset of CFS patients with IgM-EBV or CMV-Antibody found to be at risk for cardiac motility abnormalities and occasionally true cardiomyopathy 5.
- Raises the issue of incomplete viral replication activating immune responses as suggested by Glaser et al 6.
[Again, for a moment we depart from Klimas’ lecture. Our review of Glaser’s paper sheds somewhat more light on Klimas’ note on his research. Glaser’s team for a number of years has studied the workings of EBV and its effects in a variety of illnesses. In CFS, Glaser found strong indications that constituent components or expressions of the latent virus may by themselves account for immune dysregulation and symptoms in subgroups of CFS patients. The same process may occur for other viruses, including CMV and HHV-6.]
1. Smirnova IV, “Elevated Levels of Protein Carbonyls in Sera of Chronic Fatigue Syndrome patients,” Mol Cell Biochem Jun 248(1-2) (2003): 93-5.
2. Vanness JM et al, "Subclassifying Chronic Fatigue Syndrome through Exercise Testing." Med Sci Sports Exerc. Jun 35(6) (2003): 908-913.
3. Fulle S et al, “Modification of the Functional Capacity of Sarcoplasmic Reticulum Membranes in Patients Suffering from Chronic Fatigue Syndrome,” Neuromuscular Disorders 13 (2003): 479–484.
4. Peckerman A et al, "Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome," Am J Med Sci. Aug 326(2) (2003): 55-60.
5. Lerner AM et al, "Prevalence of Abnormal Cardiac Wall motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with Chronic Fatigue Syndrome," In Vivo 18( 4) (2004): 417-424.
6. Glaser R et al, “Stress-associated Changes in the Steady-state Expression of Latent Epstein–Barr virus: Implications for Chronic Fatigue Syndrome and Cancer,” Brain Behavior and Immunity 19 (2) (2005): 91-103.
New studies on the brain—important research findings published over the last 12 months
- After a fatigue-inducing mental task, imaging studies showed decreased brain responsiveness to auditory stimulation (study of 6 male CFS patients and 7 male healthy controls carried out by researchers in Japan). 1
- Decreased absolute cortical blood flow in the brain (25 CFS patients, 7 controls). When stratified for psychiatric disorders, CFS subjects with psychiatric disorders had decreased blood flow in one region only (left cerebral artery) in contrast to CFS subjects without any psychiatric disorders who had reduced flow in both the right and left middle cerebral arteries. Therefore, those patients having CFS only (devoid of psychopathology) had the largest reduction in flow. 2
- Using more brain physiology to process tasks—A study using BOLD fMRI done in NJ (see the brief summary below). 3
- Reduced grey matter in the brain was linked to reduced activity (study done in the Netherlands of 2 groups of 15 females each, one group was younger than the other). 4
Briefly digressing from Dr. Klimas’ lecture, information has been included about the specific findings of the New Jersey study (the 3rd one listed just above) by the researcher herself, Grudin Lange, PhD at one of the afternoon workshops. Lange’s study group, that also included Drs. DeLuca and Natelson (Univ. of Medicine & Dentistry of NJ), looked at mental concentration in CFS patients.
Using a particular type of imaging technique—Blood Oxygen Level Dependent (BOLD) functional MRI, they measured differences in blood flow in the brains of CFS patients compared to controls, especially when challenged with complex auditory processing while doing a simple task. This study shows that people with CFS have to exert more effort to process the same data as healthy controls and provides “evidence of increased neural resource allocation when processing more complex auditory information.”
This conclusion was taken from the study.
Dr. Klimas remarked Japan has become very active in CFS research and that more money is being spent on CFS research there than in the US].
1. Tanaka M et al, “Reduced Responsiveness is an Essential Feature of Chronic Fatigue Syndrome: a fMRI Study,” BMC Neurol Feb 22; 6 (2006): 9.
2. Yoshiuchi K, “Patients with Chronic Fatigue Syndrome have Reduced Absolute Cortical Blood Flow.” Clin Physiol Funct Imaging Mar 26(2) (2006): 83-6.
3. Lange G et al, "Objective Evidence of Cognitive Complaints in Chronic Fatigue Syndrome: a BOLD fMRI Study of Verbal Working Memory," Neuroimage Jun 26(2) (2005):5 13-24.
4. De Lange FP et al, "Gray Matter Volume Reduction in the Chronic Fatigue Syndrome," Neuroimage Jul 1; 26(3)(2005): 777-81.
Microarray technology and genes
In microarray testing, samples are arranged in a grid-like order, within a defined area, on glass microscope slides. This technology allows a huge number of genes to be surveyed at one time.
Samples appear as series of spots (that represent genes) which undergo a binding process and produce signals relating to the gene still present from the samples. It is the intensity of these spots (like an on/off type of mechanism) that provide the data—so for example, the intensity of one spot (CFS) can be compared to the intensity of the corresponding spot (control).
Agents are used to display the data in certain colors like red and green to help facilitate analysis. In one sample chart, Dr. Klimas pointed out how the red pattern was showing downregulated mitochondrial function, while the green one was showing upregulated cytokines.
In that particular study, gene expression helped to demonstrate a difference between sudden and gradual onset of illness. The importance of this technology is that it will help to identify specific gene markers associated with CFS and ultimately lead to better treatments.
Gene research has provided meaningful information about CFS (again, as taken from Dr. Klimas’ presentation chart):
A CDC study of 20,000 genes studied the activity of 26 genes—activity that could accurately predict which of 6 categories of chronic fatigue a patient had on the basis of symptoms and other clinical tests.
- Most of these genes are involved in immune system regulation, the adrenal gland, and the brain’s hypothalamus and pituitary glands.
- Studies of hormones and immune factors confirm these findings.
- Kerr’s study revealed differential expression of 35 genes in 25 patients as compared with 25 controls. The differential expression in patients suggested T-cell activation and disturbances of neuronal and mitochrondrial function.
Other studies have pinpointed 5 specific genes that correlate with an apparent susceptibility to chronic fatigue—more specifically with levels of serotonin and glutamate affected.
Speaking of the recent CDC study, Dr. Klimas felt newspapers had misreported the study findings and the role of stress. She stated there is a “huge difference” between stress as implied in these articles (assuming she meant how one might psychologically cope under pressure) and one’s stress response.
In the latter, there are biological defense mechanisms called into action, which involve everything from the autonomic nervous system, the cardiovascular system, the neuroendocrine axis, and the immune system. These systems react automatically to stressors.
Such stressors would include environmental triggers, infections, or disruptions caused by illness. Klimas also announced that on or around June 1st, the CDC is supposed to release another press release. She is optimistic this may have something to do with upcoming treatments.
Management of CFS
Time had run out by the time we got to this part of the presentation. Nearly a dozen charts summarized a variety of interventions, which were broken down into 4 major categories (pathogenisis directed): immune modulatory approaches, HPA-axis interventions, neurally mediated hypotension (NMH) treatment, and sleep. Since many of these were not discussed in detail, most have been left off because their use, benefit or status is uncertain. (A number of therapies are in various phases of study.)
Overall, Dr. Klimas indicated that sleep should be one of the first problems to be treated. Earlier, she talked about the Stage III and IV sleep inducers. She also mentioned Doxepin as another helpful medication for sleep.
On her chart, it is noted that short acting hypnotics should be avoided (as they can “trap” a person in light alpha wave sleep).
Melatonin and Ritalin were also noted as still being studied for effectiveness in CFS, but the response/results to these appear to be rather poor. (In one study of 60 CFS patients, placebo-controlled, using 10 mg. BID of Ritalin, only 17% of subjects reported decreased fatigue with 22% showing improvement in concentration.)
The following information on immune modulatory treatments comes not from her lecture, but directly from Klimas’ PowerPoint notes. The text of the notes is as follows: “Ampligen, a immune modulator and antiviral (Phase 3 recently completed); Allergic immunotherapy to dow-regulate allergic drive; Future immunomodulators (trials underway): Isoprinosine, thalidomide, anti-TNF-alpha monoclonal Ab.”
Dr. Klimas’s PowerPoint notes (not mentioned in lecture) also state, under HPA-axis interventions—“Growth hormone study – was in Phase 1 (Antwerp study).”
Dr. Klimas mentioned a drug that is being used in Japan called Neurotropin is used to treat reflex sympathetic dystrophy and other painful conditions. Neurotropin is a “non-protein extract of cutaneous tissue from rabbits inoculated with vaccinia virus.” There is some indication it may be helpful with CFS. However, the drug has not undergone clinical therapeutic testing in the United States.” (Source: Clinical Trials – NIH site).
A survey was been done at the University of Iowa to determine things that patients have tried and found to be helpful. (Bentler SE, J Clin Psychiatry May 66(5) (2005): 625-32). A few supplements: Co-Q10, DHEA and ginseng were found to be helpful.
[Ed. Note: Treatment with DHEA can have very serious side effects and must be managed and monitored by a competent physician. Dr. Klimas has stated she is against such treatment. Also, there is some literature that of 3 types of ginseng, only one is helpful to CFS patients, while the other two types may worsen symptoms.]
Vitamins predicted improvement. Yoga seemed to be the most helpful form of exercise and treatment. However, the subjects in this study were described as having “unexplained chronic fatigue of unknown etiology for at least 6 months”—hence participants may or may not have had CFS.
Another study at the Univ. of Georgia (Black CD and McCully KK, Dynamic Medicine Oct 28; 4 (2008): 10) examined how people with CFS were initially able to meet target goals in a prescribed daily walking program (for 4 to 10 days), but then these individuals developed exercise intolerance and worsening of symptoms.
Dr. Klimas feels exercise is beneficial, but it is usually is best tolerated in short intervals (even 5 minutes at a time) with many rest breaks in between.
Dr. Klimas’ PowerPoint presentation (not presented in lecture) also noted certain dangers of nutritional interventions including: “Licorice root—potassium deficiencies [that can affect the heart]; ‘supplements’ that are actually hormones [including DHEA]; ‘supplements’ that have iffy contents—eg., St. John’s Wort, melatonin; products that make unsubstantiated claims; Under and overhydration.”
[Ed. note: either of these states can be very serious. Having enough water is important, but drinking too much water can harm essential physiological systems and processes.]
Everyone should really exercise caution about taking supplements without a full appreciation of their side effects or interactions with current medications.
So, what we can take away from this latest presentation is that there have been ongoing studies to help better understand ME/CFS. The breadth and depth of biologically-based ME/CFS research is expanding. There is some promise of more effective therapies—targeted to specific physiological systems—becoming available. Researchers conducting gene expression studies also hold out hope that their research may yield effective therapies.
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Notice about names
The Massachusetts ME/CFS & FM Association would like to clarify the use of the various acronyms for Chronic Fatigue Syndrome (CFS), Chronic Fatigue & Immune Dysfunction Syndrome (CFIDS) and Myalgic Encephalomyelitis (ME) on this site. When we generate our own articles on the illness, we will refer to it as ME/CFS, the term now generally used in the United States. When we are reporting on someone else’s report, we will use the term they use. The National Institutes of Health (NIH) and other federal agencies, including the CDC, are currently using ME/CFS.
Massachusetts ME/CFS & FM Association changed its name in July, 2018, to reflect this consensus.