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“Myalgic Encephalopathy/Chronic Fatigue Syndrome/Systemic Exertion Intolerance Disease” Mark A Rosenberg, M.D.
“Myalgic Encephalopathy/Chronic Fatigue Syndrome/Systemic Exertion
Intolerance Disease”
Mark A Rosenberg, M.D.
I have a special bonus gift for you at the end of this
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What is it?
• Severe fatigue (>6 months)
• Post-exertional malaise
• Often associated with• Cognitive disturbances
• Pain
• Sleep problems
• Sensory hypersensitivity
• Symptoms related to immune
• and autonomic dysfunction
Prevalence
• 836,000-2.5 million; prevalence not truly known because an estimated 84-91% of individuals with ME/CFS have not been diagnosed
• Affects females more than males; most are Caucasian but some studies suggest it is more common in minority groups; average onset is 33 yo, but has been seen in younger than 10 and older than 70
• Fewer than 1/3 of medical school curricula and less than half of medical school textbooks include information about ME/CFS.
Economic Burden
These individuals experience a loss of productivity and high medical costs that contribute to a total economic burden of 17-24 billion annually.
Old CDC Diagnostic Criteria
• Severe chronic fatigue of at least 6 months’ duration
• Other known medical conditions excluded by clinical diagnosis
• Concurrently have 4 or more of the following symptoms:
Old CDC Diagnostic Criteria
• Substantial impairment in short-term memory or concentration
• Sore throat
• Tender lymph nodes
• Muscle pain
• Multi-joint pain without swelling or redness
• Headaches of a new type, pattern or severity
• Unrefreshing sleep
• Post-exertional malaise lasting more than 24 hours
Re-evaluation
• The Dept. of Health and Human Services, the NIH, The Agency for Healthcare Research and Quality, the CDC, and the Social Security Administration asked the Institute of Medicine (IOM) to convene an expert committee to examine the evidence base for ME/CFS.
• Recently renamed “systemic exertion intolerance disease” (SEID) to better reflect the condition's hallmark defining symptom, post-exertional malaise. This new name captures a central characteristic of this disease, the fact that any sort of exertion, physical, cognitive, or emotional, can adversely affect patients in many organ systems
New Diagnostic Criteria from IOM
• A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
• Post-exertional malaise, and
• Unrefreshing sleep
New Diagnostic Criteria from IOM
• The CDC case definition also states that any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before further classification is attempted.
Sleep Alteration• Complaint of unrefreshing sleep is
universal among patients with ME/CFS (SEID)
• Absence of a specific objective alteration in sleep architecture
• While polysomnography is not required to diagnose ME/CFS (SEID), its use to screen for treatable sleep disorders when indicated is appropriate.
• Diagnosis of a primary sleep disorder does not rule out a diagnosis of ME/CFS (SEID).
Post-exertional Malaise
• Dr Chris Snell, Staci Stevens, Dr Todd Davenport, and Dr Mark VanNess’s study aimed to objectively demonstrate the problem of post-exertional malaise, by using a repeat Cardiopulmonary Exercise Test (CPET). As they formally hypothesized in their paper: “an exacerbation of symptoms following the first test would be reflected in physiological responses to the second.”
Post-exertional Malaise II
• The 51 CFS patients were all deconditioned women, met Fukuda criteria and also reported PEM.
• Controls, also female, were similar in age and BMI, and were fairly sedentary. In fact, the results of the first CPET revealed that the controls were in the bottom 10% of published population norms and would count as deconditioned.
CPET: Cardiopulmonary Exercise Testing Explained
• CPET is the Gold standard for measuring physical capacity, used by athletes wanting to measure the effectiveness of their training programs. It’s also used to diagnose cardiovascular, breathing and muscle disorders.
• The principle is to get someone to exercise to exhaustion, using a protocol that starts easy and gets increasingly difficult until the subject can do no more.
• The key measures for this study are the Volume of Oxygen consumed (VO2) and the amount of work done, measured in Watts on the exercise. bike.
Study Results• The big differences between the groups emerged on
the second maximal CPET test, 24 hours after the first.
• The biggest difference of all was for Watts output at anaerobic threshold (VT), down for the patient group by over half.
• The study found the repeat test could separate CFS patients from controls in this sample with 95% accuracy.
Utility of the CPET Test
• Where there is doubt about the reality of symptoms, as can happen with disability insurance claims, an objective test can demonstrate that a patient really is sick.
• It’s useful in legal or medical disputes; according to Dr. Snell, “the reduced performance on VT is impossible to fake; the post-exertional state in CFS is characterized by objectively measurable deficits in submaximal metabolism and workload that would be nearly impossible for patients to fabricate.”
Unique to ME/CFS?
• Dr Snell has reported that their clinic has tested patients with numerous illnesses including MS and CHF, but have only seen the problem in ME/CFS patients.
• Published studies show normal repeat CPET performance for sarcoidosis, angina, chronic airflow obstruction, pulmonary hypertension and heart disease.
• I’ve seen no studies showing failure to reproduce CPET results in other illnesses, but it’s probably too soon to say if this is unique to ME/CFS, or just very unusual.
At Least One Of The Two Following Manifestations is also Required
• Impairment in ability to engage
• Post-exertional malaise
• Unrefreshing sleep• Cognitive Impairment
• Orthostatic Intolerance
Cognitive Impairment• Problems with thinking or executive function
exacerbated by exertion, effort, or stress or time pressure.
• There is sufficient evidence that slowed information processing is common in patients with ME/CFS (SEID), and a growing body of evidence shows that it may play a central role in overall neurocognitive impairment associated with the disease (memory impairments, attention deficits, and impaired psychomotor function).
• Such a deficit may be responsible for disability that results in loss of employment and loss of functional capacity in social environments.
Orthostatic Intolerance
• Worsening of symptoms upon assuming and maintaining upright posture.
• Symptoms are improved, although not necessarily abolished, by lying back down or elevating the feet.
• Sufficient evidence indicates a high prevalence of orthostatic intolerance conditions in ME/CFS (SEID.
• These findings indicate that orthostatic intolerance is a common and clinically imortant finding in ME/CFS (SEID).
Frequency and Severity of Symptoms
• Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS (SEID) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
• In Individuals with ME/CFS, symptoms can persist for years and most individuals never regain their pre-illness level of functioning.
Other Common Manifestations
• Failure to recover from a prior infection and abnormal immune function• Sufficient evidence supports the finding of immune
dysfunction in ME/CFS (SEID).
• Specifically, the committee’s literature search yielded data demonstrating poor NK cell cytotoxicity (NK cell function, not number) that correlates with illness severity in ME/CFS (SEID) patients and could serve as a biomarker for the severity of the disease, although it is not specific to ME/CFS (SEID).
Less Common Manifestations
• Gastrointestinal impairments
• Genitourinary impairments
• Sore throat
• Painful or tender axillary/cervical lymph nodes
• Sensitivity to external stimuli (e.g., foods, drugs, chemicals)
Patient Communications to IOM Committee
• “When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain. It hurts to lay in bed, it hurts to think, I can’t hardly talk—I can’t find the words. I feel my insides are at war.”
• “My personal experience of having ME/CFS feels like permanently having the flu, a hangover, and jet lag while being continually electrocuted (which means that pain plays at least as much of a role in my condition as fatigue).”
Etiology
• Unknown
• Genetic predisposition has been demonstrated.
• Probably an infectious disease with immunologic manifestations.
• CFS is not synonymous with chronic EBV infection or chronic infectious mononucleosis.
• There is sufficient evidence to suggest that ME/CFS (SEID) can follow infection with EBV and possibly other specific infections, but there is insufficient evidence to conclude that all cases of ME/CFS are caused by EBV or that ME/CFS (SEID) is sustained by ongoing EBV infection.
• There is also insufficient evidence for an association between ME/CFS (SEID) and bacterial, fungal, parasitic, and other viral infections.
Etiology
• Comorbidities such as fibromyalgia and irritable bowel syndrome are common in ME/CFS (SEID) patients.
• These comorbidities should be diagnosed and treated when caring for patients.
• The presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses
Etiology
History
All questions should explore frequency and severity regarding impairment in function with profound fatigue
Physical Exam• No abnormalities (most common)
• Axillary node involvement or crimson crescents (not specific for CFS) are the most consistent abnormal findings on physical examination.• red-to-purplish erythema, arching across the soft palate on either side of
the uvula
• Many patients have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, or inguinal region.• Lymph nodes that are very large, tender, or immobile suggests a
diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.
Laboratory Evaluation
• Laboratory tests have 2 functions in CFS/ME.• First, they may be used to assess the possibility that another
condition is causing the fatigue
• Second, they may be used to help diagnose CFS.• CFS laboratory abnormalities are not specific, but, taken together, they can
make up a pattern consistent with CFS in patients who have a cognitive dysfunction in whom other diseases have been excluded as a cause for their fatigue.
Laboratory Evaluation II
• The CDC has recommended a “basic battery” that includes the following:• Complete blood count (CBC)
• Liver function tests
• Thyroid function tests
• Erythrocyte sedimentation rate (ESR)
• Serum electrolyte level measurement
• Some clinicians also include antinuclear antibody and morning cortisol measurements. Adrenal function tests are useful for the purposes of exclusion.
Laboratory Evaluation III
• The most consistent laboratory abnormality in patients with CFS is an extremely low ESR, typically in the range of 0-3 mm/h.
• A normal ESR or one that is in the upper reference range suggests another diagnosis.
Laboratory Evaluation IV
• Most patients with CFS usually have 2 or 3 of the following nonspecific abnormalities:• Elevated IgM/IgG coxsackie virus B titer
• Elevated IgM/IgG human herpesvirus 6 (HHV-6) titer
• Elevated IgM/IgG C pneumoniae titer
• Decrease in natural killer (NK) cells (either percentage or activity)
Laboratory Evaluation V
• The WBC count in patients with CFS is Normal.• Leukopenia, leukocytosis, or an abnormal cell differential count
indicates a diagnosis other than CFS, and another cause should be pursued to explain these findings.
• LFTs – Normal
• SPEP – Normal
• Urinalysis - Normal
Brain Imaging and ME/CFS
• An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.
• The Stanford investigators compared brain images of 15 CFS to those of 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing symptoms similar to those of CFS.
Brain Imaging and ME/CFS II
• The analysis yielded three noteworthy results:• First, an MRI showed that overall white-matter content of CFS patients’
brains, compared with that of healthy subjects’ brains, was reduced (This finding wasn’t totally unexpected since inflammation is known to take a particular toll on white matter).
• But a second finding was entirely unexpected. Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients’ brains. This tract, which connects the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.
Brain Imaging and ME/CFS III
• Furthermore, there was a fairly strong correlation between the degree of abnormality in a CFS patient’s right arcuate fasciculus and the severity of the patient’s condition, as assessed by performance on a standard psychometric test used to evaluate fatigue.
• Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. Its correspondence with the observed abnormality in the white matter joining them makes it unlikely that the two were chance findings, Zeineh said. The Stanford scientists are in the planning stages of a substantially larger study.
Differential Diagnosis
• CFS is, in large measure, a diagnosis of exclusion.
• The key diagnostic task is to differentiate it from other disorders that also have a fatigue component.
• CFS may be distinguished from other causes of fatigue on the basis of the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Once a specific cause of fatigue has been diagnosed, CFS is excluded by definition
Differential Diagnosis II
• Chronic heart disease
• Psychiatric illnesses
• Thyroid disease
• Connective tissue diseases
• Chronic anemia
• Neoplastic disease
Differential Diagnosis III
• Chronic infections (eg, AIDS)
• Endocrine diseases (eg, Addison disease)
• Inflammatory bowel disease
• Drug abuse
• Liver disease
• Renal disease
Immune Dysfunction in ME/CFS
• Alteration in cytokine profile (increased pro-inflammatory cytokines)
• Decreased function of natural killer (NK) cells
• Presence of autoantibodies
• Reduced responses of T cells to mitogens and other specific antigens
• Increased number of CD8+ cytotoxic T lymphocytes have been reported
Immune Dysfunction in ME/CFS VI
• There are limited data on the role of B-lymphocytes in CFS. One study of gene expression in peripheral blood mononuclear cells indicated that B cells might be altered in CFS.
• The B-cells have multiple immune functions, the main ones being antibody production, antigen presentation and regulation of the function and activity of other immune cells, i.e. T-regulatory cells, NK cells and macrophages.
• B cell depletion?
ME/CFS and Viruses
• A diverse range of viruses including herpes virus reactivation is frequently observed in CFS and a dysfunctional immune response may play a key role. • Does virus reactivation trigger CFS in a subset of patients or is viral
infection reactivation is yet another outcome of a CFS episode triggered by other agents.
• On the basis of the observation that the immune alteration pattern of CFS has a striking resemblance to the one caused by developmental immune toxicology, it has been suggested that this disease could be the consequence of environmental insults (xenobiotic, infectious agents, stress) to the developing immune system.
Conclusions Regarding Immune Dysfunction and ME/CFS
• CFS has a propensity to over-produce pro-inflammatory cytokines, coupled with a mis-regulation of anti-inflammatory cytokines.
• CFS patients seem to have a specific immune dysfunction profile with enhanced baseline activation of lymphoid subsets but suppression of certain immune responses, particularly Th1-driven ones (anti-viral, anti-tumor responses). On the basis of these findings, some therapeutic approaches have been proposed with a view to controlling immune activation.
Conclusions Regarding Immune Dysfunction II
• Alteration of the immune response profile may be the consequence of environmental insults in early life development.
• Monitoring for toxicants adversely affecting the immune system in early life could possibly help prevent the disease.
• The variability observed when measuring immunological parameters suggests a genetic basis for the pathology.
• New findings arising from gene expression studies have confirmed the activation of certain genes related to immune function and are candidate markers of the disease.
Gut Inflammation in Chronic Fatigue Syndrome
Shaheen E Lakhan; Annette Kirchgessner; NutrMetab. 2010;7(1)
Gut Inflammation
• Patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome or experience IBS-related symptoms.
• Evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis.
• There is now evidence that CFS is associated with marked alterations in the gut microbiota, with lower levels of Bifidobacteria and higher levels of aerobic bacteria.
Gut Inflammation II
• Gut pathogens can communicate with the CNS and influence emotional behaviors such as anxiety and depression, even at extremely low levels and in the absence of an immune response.
• Probiotics or live microorganisms have the potential to decrease mood-regulating systemic pro-inflammatory cytokines, decrease oxidative stress and improve nutritional status when orally consumed.
Gut Inflammation III
• Probiotic lactic acid producing-bacteria have been shown to prevent and alleviate GI disturbances and to normalize the cytokine profile which might be of an advantage for patients suffering from CFS.
• Evidence for a synergism between aberrant gut microbiota, mucosal barrier dysfunction, and altered mucosal immunity contributing to the disorder's pathogenesis has begun to evolve.
Gut Inflammation IV
• The enteric nervous system controls virtually all GI functions (e.g., motility, secretion, blood flow, mucosal growth and aspects of the local immune system).
• Whether the persistent alterations in gut function observed in the majority of CFS patients are due to inflammation-related changes in the properties of enteric nerves is unknown.
Gut Inflammation V
• Emerging studies have demonstrated that pathogenic and non-pathogenic gut microbiota may influence mood-related symptoms and even behavior in animals and humans. These findings lend further support to the presence of a gut-brain interface, one that may be modulated by gut microbiota.
Endotoxemia and ME/CFS
Could gut pathogens be related to CFS onset?
Endotoxemia
• Elevated serum concentrations of IgA and IgM to lipopolysaccharide (LPS) of gram-negative enterobacteria, such as Pseudomonas aeruginosa, Morganella morganii, Proteus mirabilis, Pseduomonas putida, Citrobacter koseri, and Klebsiella pneumoniae have been reported in CFS patients.
• The prevalence and median values for serum IgA against the LPS of enterobacteria were significantly greater in patients with CFS than in normal volunteers and patients with partial CFS.
Endotoxemia II
• Serum IgA levels were significantly correlated to the severity of illness, as measured by the FibroFatigue scale.
• The increased serum IgA and IgM levels against LPS in CFS indicate the presence of increased gut permeability and an immune response mounted against LPS of the enterobacteria.
Gut Microbiota
• The human GI tract contains a delicately balanced ecosystem of more than 17 bacterial families encompassing 400 to 500 different microbial species; the large intestine is populated with an excess of 10 11
bacteria per gram of fecal material .
• The main genera of these commensal bacteria are: Lactobacillus, Bifidobacteria, Bacteroides, Clostridia, Fusobacteria, Eubacteria, Peptococcus, Streptococcus, Escherichia and Veillonella.
Gut Microbiota II
• Alteration of the balance of gut microbiota can contribute to functional disorders.• The number of different commensal bacteria is altered in
IBD.
• IBD patients have increased bacteroides, adherent or invasive Escherichia coli, and enterococci, and reduced Bifidobacteria and Lactobacillus species.
Gut Microbiota III; Stress and Gut Flora
• The composition of gut microbiota can be altered by various factors including stress. Psychological stress alters the gut microbiota towards decreased numbers of Bifidobacteriaand Lactobacilli.• Bifidobacteria have been shown to reduce intestinal LPS levels
and LPS-induced activation of nuclear factor-kappa B (NF-κB) in mice.
• Inhibition of LPS-induced NF-κB activation was accompanied by a dose-dependent decrease of pro-inflammatory cytokines and cyclooxygenase 2.
Stress and Gut Flora II
• Stress in neonatal Rhesus monkeys was reported to suppress the numbers of Lactobacilli in the fecal flora in association with increased susceptibility for opportunistic infections.
• Restraint conditions, acoustic stress and food deprivation have all been shown to negatively alter gut microbiota in various animal studies.
• Interestingly, stress (e.g., psychological, physical exhaustion) is a well-established trigger factor for CFS.
Stress and Gut Flora III
• In 1998, Dr. Henry Butt from the University of Newcastle, presented the first evidence of altered fecal microbiota in CFS patients compared to normal, healthy controls.
• The mean distribution of the Gram negative Escherichia colias a percentage of the total aerobic flora of control subjects was 92.3% compared to 49% in CFS patients. Among aerobes, the D-lactic acid producing Enterococcus and Streptococcus species were strongly over-represented in CFS patients.
D-Lactic Acidosis
• D-lactic acid, if found elevated in serum, has been reported to be associated with cognitive dysfunction and neurological impairment in patients with intestinal bacterial overgrowth;these symptoms are attributed to the increased colonization of lactic acid producing Gram positive bacteria in the gastrointestinal tract .
• Patients with CFS present remarkably similar symptoms to patients with D-lactic acidosis including headaches, weakness, cognitive impairment, fatigue, pain and severe lethargy.
D-Lactic Acidosis II
• High count of lactic acid bacteria in the gastrointestinal tract may lower intestinal pH levels resulting intestinal permeability, and may perpetuate an increased absorption of microbial metabolites such as D-lactic acid.
• D-lactic acid, unlike L-lactic acid, is poorly metabolized in mammalian hosts as mammals lack the metabolic enzyme D-lactate-dehydrogenase.
• Increased intestinal colonization of D-lactic acid producing bacteria, as demonstrated in this study, may result in pathophysiological cognitive and neurological responses in CFS patients as reported in patients with D-lactic acidosis.
D-Lactic Acidosis III
• In addition to the above findings, the higher the aerobic enterococcal count, the more severe the neurological and cognitive deficits including nervousness, memory loss, forgetfulness and confusion.
• Consequently, high plasma LPS levels in CFS could result from an increased production of endotoxin upon changes in the gut microbiota.
D-Lactic Acidosis and Hydrogen Sulfide
• Professor Kenny De Meirleir of the Brussels Free University and his team say high levels of H2S caused by an intestinal overgrowth of Gram positive D/L lactate-producing bacteria play a major role in CFS and lead to a series of reactions in your body that leave cells devoid of oxygen and energy.
• Excess H2S causes the intestinal epithelial barrier to break down.
• Increased levels of bacterial H2S stimulate the production of ROS, which inhibit mitochondrial function directly.
Bacteroidetes/Firmicutes ratio
• Firmicutes and Bacteroidetes account for approximately 90% of all microbiota in the human intestine.
• There is an emerging hypothesis that gut microbiota is a modulator for the obese genotype by way of an increase in the Firmicutes/Bacteroidetes (F:B) ratio.
B/F Ratio
• One study compared the dietary intake, fecal SCFA concentrations and gut microbial profiles in 52 lean and 42 overweight or obese participants, finding a positive relationship between the combination F:B ratio and SCFAs with one’s BMI.
• These results were reproduced in a separate study that recorded fecal SCFA and F:B ratios in 11 lean and 11 overweight or obese individuals. It was similarly found that overweight or obese individuals had a higher relative Firmicutes abundance, a higher F:B ratio, and increased fecal SCFA.
Conclusion I
• It is suggested that Firmicutes, whose numbers have been found to be increased in obese individuals, express genes that encode enzymes that break down otherwise indigestible dietary polysaccharides, thus increasing the host’s ability to harvest more energy.
• SCFAs are suggested to be the mediator in this obesity epidemic as a high F:B ratio leads to excess SCFA production, leading to increased colonic energy availability, contributing to overall weight gain.
Conclusion II
• These results are consistent with the hypothesis that overweight or obese individuals produce more colonic SCFA than lean individuals due to the differences in colonic microbiota.
Mucosal Barrier
Mucosal Barrier
• To protect itself from uncontrolled inflammatory responses, the intestinal epithelium has developed mechanisms to: • restrain bacterial growth
• limit direct contact with the bacteria
• prevent bacterial dissemination into underlying tissue
Mucosal Barrier II
• Maintained by several interrelated systems• mucous secretion
• chloride and water secretion
• binding together of epithelial cells at their apical junctions by tight junction proteins
• Together, they act as the "gatekeeper" of the mucosal barrier
Mucosal Barrier III
• Disruption of mucosal barrier function occurs in CFS as demonstrated by the increased serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria.
• Psychological stress disrupts the mucosal barrier allowing increased entry of antigens and microorganisms, which in turn is expected to stimulate hyperactive responses in the mucosal immune system.
Mucosal Barrier IV
• Chronic water avoidance stress in rats induces increases in the adherence of bacteria to intestinal epithelial cells, bacterial internalization into enterocytes and the appearance of bacteria in the lamina propria.
• Consequently, mucosal barrier dysfunction causes alterations in gut motility, abnormal secretion, and changes in visceral sensation that could contribute to symptom generation. This may at least partially explain the link between stress and CFS.
Therapeutic Restoration of Mucosal Barrier Function
• Since altered intestinal microbiota and gut barrier dysfunction barrier are found in CFS, they offer potential targets for intervention that would include modulation of the gut microbiota to correct an imbalance, as well as tightening of inter-epithelial junctions.
• Enhancement of barrier function by probiotic bacteria has been observed in both in vitro models and in vivo animal models.
• Inhibit mucosal adhesion of pathogens
• Improve the barrier function of the epithelium
• Alter the immune activity of the host
• May regulate intraluminal fermentation and stabilize the gut microbiota
• Promising adjunctive therapy in treating IBS, with B. infantis becoming the frontrunner for treatment
Probiotics II
• Lactobacilli spp.
• Certain types of Streptococcus (S. thermophiles; S. salvarius)
• Bifidobacteria spp.
• E. coli-Nissle 1917
• Yeasts such as Saccharamyces boulardii
Probiotics III• Secrete short chain fatty acids (SCFA)
• Causes decreased luminal pH and production of bactericidal proteins.
• Butyric acid, a SCFA byproduct of bacterial fermentation of fiber, has been shown to nourish colonic enterocytes, enhancing mucosal integrity.
• Probiotics may improve bowel dysmotility.
• Have been shown to regulate mood in CFS patients.
Altering Mood in CFS Patients with Probiotics
• Administration of Lactobacillus casei strain Shirota (LcS; 24 billion cfu/day) to adult patients meeting the formal diagnostic criteria for CFS, was found at eight weeks to cause a significant rise in both Lactobacillus and Bifidobacteria in those taking the LcS and there was also a significant decrease in anxiety symptoms.
• The elevation of Bifidobacteria levels should be considered a positive finding, particularly when considering that Bifidobacterialevels may be low in CFS.
Bifidobacteria and Gut Barrier
• Play an important role in maintaining the gut barrier.
• An increase in Bifidobacteria in ob/ob mice was associated with a significant improvement of gut permeability measured in vivo; this improvement was linked to an increase in tight junction mRNA expression and protein distribution.
• The rise in Bifidobacteria was correlated with a decrease in plasma LPS concentrations; therefore, a significant reduction in markers of oxidative and inflammatory stress.
Bifidobacterium and Mood
• Bifidobacterium infantis can boost serotonin levels in areas of the brain associated with anxiety and depression, by increasing tryptophan serum levels.
• Improvements in anxiety scores among those CFS patients consuming LcS bacteria are especially noteworthy.
Gut-Brain Connection,HPA Axis, and ME/CFS
• Physical and psychological stressors have been found to activate the HPA axis, an important link between the brain and the immune system.
• Corticotrophin-releasing hormone produced in the hypothalamus, is the primary hypothalamic regulatory peptide of the HPA axis and its release has been shown to be controlled by circulating pro-inflammatory cytokines, especially IL-6.
• Thus, the increase in pro-inflammatory cytokines seen in CFS patients may be involved in an dysregulation of the HPA axis.
Gut-Brain Connection and HPA Axis
• Research suggests that the gut–brain axis, a bi-directional neurohumoral communication system in the human body, functions as a pathway for the gut microbiota to modulate brain function of its host.
• The postnatal microbial colonization of the GI tract results in a long-lasting impact on the neural processing of sensory information regarding the hypothalamic-pituitary-adrenal axis stress response.
Gut-Brain Connection and HPA Axis II
• In humans and rodents, a probiotic formulation (Lactobacillus helveticus RO52 and Bifidobacterium longumR175) displays anxiolytic activity.
• In a mouse study, treatment with the probiotic above attenuated the HPA axis response to stress, as reflected by a decrease in serum corticosterone and prevented the stress-induced reduction of cell proliferation in the hippocampus.
HPA Axis and CFS/ME
• Basal hypocortisolism was first reported in CFS patients in 1981.
• Cortisol concentrations have since been measured in blood, saliva, and urine in a number of studies with rather varying results, but the notion of a hypocortisolemic picture in CFS is supported by a meta-analysis.
• Reduced cortisol levels are more apparent in female patients and also tend to occur during the later stages of the illness.
HPA Axis and ME/CFS
• Basal studies have also shown an attenuated diurnal variation particularly with a loss of the morning peak of ACTH or cortisol while challenge studies often, but not invariably, show a diminished HPA axis responsivity.
Cause of HPA Axis Dysregulation in CFS/ME
• Specific genes (acting on the HPA axis or otherwise) which confer an increased risk of CFS have not been identified. There is, however, evidence of a heritable component to the disorder.
• In addition, the role of early adversity also warrants consideration, particularly given the evidence of an increased rate of childhood trauma in patients with CFS. Around 50% of patients report at least one type of childhood trauma.
Cause of HPA Axis Dysregulation in CFS/ME II
• It has been estimated that childhood trauma increases the risk of CFS between 6- and 8-fold with a graded relationship between the severity of the trauma and the risk of developing CFS.
• An increased severity of symptoms has been noted in those who report childhood trauma.
• Animal models of early-life stress reveal HPA axis changes persist into, or became evident in, adulthood.
Cause of HPA Axis Dysregulation in CFS/ME II
• Early life stress also influences brain development.
• Teicher and colleagues have demonstrated the sensitivity of the hippocampus, particularly the subiculum, to adversity. This is noteworthy because the subiculum has an important role in regulating the HPA axis; hence, neuroarchitectural change secondary to early adversity would be expected to alter the dynamics of the HPA axis in adulthood.
Relationship between HPA Axis Dysfunction and Symptoms
• The magnitude of HPA axis dysfunction correlates with symptom severity.
• HPA axis dysregulation is a poor prognostic factor for CFS patients undergoing psychological treatment.
• Experimentally induced, or pathological, hypocortisolemia (such as that seen in Addison’s disease) is associated with symptoms typical of CFS, including fatigue, weakness, and abdominal pain, but it is also associated with a range of other features which are not typical of CFS.
ME/CFS and Oxidative Stress
• Multiple studies reveal that CFS is accompanied by increased oxidative stress, as measured by many markers of oxidative stress.
• Individuals with chronic conditions, such as CFS have lower levels of reduced L-glutathione.
• Research has shown that L-glutathione levels in cells can be dramatically depleted by excessive oxidative stress. In turn, L-glutathione deficiency has been shown to contribute to oxidative stress and disease, resulting in a vicious cycle.
8-OH-2 deoxy guanosine (8-OHdG)
• 8-OHdG is a commonly used and highly sensitive marker of total oxidative stress in the body. Upon DNA repair, 8-OHdG is excreted in the urine.
• 8-OHdG is a risk factor for many diseases including CFS. Elevated urinary 8-OHdG DNA was detected in patients with CFS.
• The level of urinary 8-OHdG in CFS correlated with the severity of depression and malaise.
• Measuring urinary 8-OHdG may be a convenient method for evaluating oxidative DNA damage in patients with CFS and could be a sensitive biomarker helpful for the early diagnosis of patients with CFS.
Mitochondrial Failure and CFS
• Dr. Sarah Myhill and colleagues have proposed that CFS is linked to mitochondria failure.• ATP recycles approximately every 10 seconds in a healthy individual.
However, when mitochondria are impaired the energy supply will be impaired and so the individually has poor stamina, as in CFS.
• If the body is short of ATP, it can make a very small amount directly from glucose by converting it into lactic acid. This is exactly what many individuals with CFS do. They readily switch into anaerobic metabolism. However, this results in serious problems.
Mitochondrial Failure and CFS II
• Lactic acidosis is associated with muscle pain, heaviness, aching and soreness ("lactic acid burn"), and might actually damage muscle and nerve tissue.
• People suffering from CFS have difficulty increasing their fitness.[ Their response to incremental exercise is increased oxidative stress with marked alterations of muscle membrane excitability.
• Thus, mitochondrial dysfunction results in fatigue and could produce symptoms of CFS.
Mitochondrial Failure and CFS III
• There is considerable evidence that mitochondrial dysfunction is present in some CFS patients.• Muscle biopsies have shown abnormal mitochondrial
degeneration in CFS patients.
• Mitochondrial dysfunction occurs in neutrophils in CFS patients.
• The degree of mitochondrial dysfunction in neutrophils was strongly correlated with the severity of their illness suggesting that the severity of a person's CFS relates to the severity of the mitochondrial dysfunction.
Association of mitochondrial dysfunction and fatigue: A review of the literature
• Purpose: examine markers of mitochondrial function that have evidence of an association with fatigue in order to identify areas needed for further research.
• Included studies focusing on the markers of mitochondrial function in relation to fatigue.
• Dysfunctions in the mitochondrial structure, mitochondrial function (mitochondrial enzymes and oxidative/nitrosative stress), mitochondrial energy metabolism (ATP production and fatty acid metabolism), immune response, and genetics were investigated as potential contributors to fatigue.
Association of mitochondrial dysfunction and Carnitine Levels
• Carnitine was the most investigated mitochondrial function marker reported in this review. Dysfunctional carnitine levels were reported in all six studies (five studies included CFS patients and one study included MS patients) that investigated the biomarker.
• Acylcarnitine serum levels were significantly lower in CFS patients compared to healthy controls; however, free l-carnitine serum levels were not significantly different between the two groups.
• Another study observed significantly lower serum levels of total and free carnitine in CFS patients of both genders when compared to healthy controls, as well as lower serum levels of acylcarnitine in CFS patients compared to controls, using historical data.
Association of mitochondrial dysfunction and CoQ10 Levels
• It was the only mitochondrial biomarker found to have a consistent association with fatigue identified in this review.
• Four articles examined the levels of CoQ10 in fatigued patients with CFS compared to healthy controls.
• CFS patients had significantly lower plasma levels of CoQ10 compared to healthy controls.
• Significant, inverse relationships were observed with plasma CoQ10 levels and severity of illness scores of ME/CFS patients, specifically, greater fatigue and autonomic symptoms were associated with lower levels of CoQ10.
• The presence of CFS independently predicted low plasma CoQ10 levels.
Association of mitochondrial dysfunction and CoQ10 Levels II
• CoQ10 is endogenously produced and therefore, dietary intake has minimal influence on the CoQ10 concentration in the body. However, if CoQ10 is found to be depleted, especially with primary deficiency, supplementation is the remaining recommended therapeutic option
• In clinical practice, vitamins such as riboflavin B2 (50-400 mg/d, niacin B3 (nicotinamide riboside), vitamin E, Co Q10, vitamin C and other mitochondrial cofactors including levo-carnitine, lipoic acid, acetyl-l-carnitine, creatine, selenium, beta carotene 10,000 IU, biotin 5 mg are used as supplemental treatment for mitochondrial disorders, in order to enhance ETC enzyme activity as an antioxidant defense.
ATP Production
• Four cross-sectional studies investigated mitochondrial energy metabolism as a potential marker in fatiguing conditions. Mitochondrial energy metabolism was assessed from muscle biopsies in two of the studies and from peripheral blood in the remaining studies.
• In the vastus lateralis muscle biopsy samples, there was no difference seen between CFS patients and healthy controls for either parameter.
ATP Profile Test
• The ATP profile tests measures three parameters of mitochondrial function in neutrophils extracted from peripheral blood• ATP concentration (how much ATP is present) and ATP ratio (what fraction of
ATP is available for energy supply)
• The efficiency of oxidative phosphorylation (ADP to ATP recycling efficiency)
• TL OUT (ADP out of cytosol into mitochondria) and TL IN (ATP from mitochondria into the cytosol). A Mitochondrial Energy Score (MES) was calculated by multiplying all five factors (ATP, ATP ratio, Ox Phos, TL OUT, TL IN, TL OUT × TL IN).
ATP Profile Test II
• One of the two studies that used this ATP Profile test observed that the percentage of participants with normal values of mitochondrial function increased as fatigue symptoms decreased.
• In addition, the MES was positively correlated with scores on the CFS Ability scale indicating that greater mitochondrial efficiency was associated with higher levels of activity and function in those with CFS/ME.
ATP Profile Test III
• A second study by the same group confirmed the presence of mitochondrial dysfunction in patients with ME/CFS by observing partial blockage of the ADP–ATP translocator protein (TL).
• Cells can compensate for some of the dysfunction in ATP production through two alternative pathways: by increased glycolysis and the use of adenlyate kinase pathway of ATP formation. Therefore, partial blockage of the TL protein can lead to impaired energy production.
Oxidative/Nitrosative stress
• Three cross-sectional studies investigated oxidative and nitrosative stress in CFS/ME patients compared to healthy controls. All three used peripheral blood specimens for biologic analyses.
• Antioxidants (Glutathione, superoxide dismutase, catalase, GSH peroxidase, and GSH reductase) were significantly decreased, while ROS and reactive nitrogen species (RNS) (malondialdehyde[MDA], conjugated dienes, hydroperoxides, and nitric oxide) were significantly increased in the plasma/serum samples of CFS patients compared to healthy controls
Genetics
• Five articles explored the association between gene expression profiles in fatiguing conditions versus controls.
• Common mitochondria-specific functional pathways were reported from the results of the gene expression studies included in review, to include pathways related to metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection.
Immune Modulators
Treatment with Rituximab
• Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.
Treatment with Rituximab II
• In this double-blind, placebo-controlled phase II study, 30 CFS patients were randomized to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months.
• Responses generally affected all CFS symptoms.
• Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group.
Treatment with Rituximab III
• Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44).
• Responses were delayed, starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion.
• Four Rituximab patients had clinical response durations past the study period.
• The differences in fatigue were most evident between 6 and 10 months after intervention
Rituximab and ME/CFS trial #2
• The RituxME study has just started recruiting patients.
• Hypothesis: The hypothesis is that a subgroup of patients with CFS/ME have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment.
Rituximab and ME/CFS trial #2
• Double-blind and placebo-controlled to include 152 patients, in five centers in Norway.
• 1:1 randomization between rituximab and placebo.
• First two infusions two weeks apart (500 mg/m2, max 1000 mg, or placebo) followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months.
• Follow-up will be for 24 months.
Primary Outcome Measures
• Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient.
• Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up.
B Lymphocytes and CFS/ME
• The pilot case series suggested that B-cell depletion was associated with clinical improvement in CFS patients.
• B-cell targeting therapy has been increasingly used for diverse autoimmune diseases.
• The monoclonal anti-CD20 antibody Rituximab has been the major B-cell depleting agent so far.
B Lymphocytes and CFS/ME II
• An alternative explanation for the observed clinical improvement from B-cell depletion could be elimination or reduction of B-lymphotrophic viruses such as CMV or EBV.
• A recent study showed clinical benefit from long-term valacyclovir or valgancicliovir treatment in a subset of CFS patients with evidence of active on-going herpes virus infections, also shown in a previous small study of 12 patients with elevated antibodies to EBV or human herpes virus 6.
Symptomatic Therapy
• Antidepressants (especially MAOI)
• Sleep aids
• Methylphenidate• A double-blind randomized placebo-controlled crossover study was
conducted in 60 patients who fulfilled criteria for chronic fatigue syndrome and had concentration difficulties. Random assignment to 4 weeks treatment with methylphenidate 2 x 10 mg/day, followed by 4 weeks of placebo treatment, or 4 weeks of placebo treatment, followed by methylphenidate treatment.
Results of Methylphenidate Study
• Fatigue scores fell significantly during methylphenidate intake in comparison with baseline and in comparison with placebo.
• Concentration disturbances improved significantly under methylphenidate treatment compared with baseline and compared with placebo.
• A clinically significant on fatigue was achieved in 17% of patients, who were considered responders; on concentration in 22% of patients.
Low Dose Hydrocortisone (HPA Axis Therapy)
• Low-dose hydrocortisone and DHEA have both been used as treatment agents (individually) in pilot studies in CFS, and have benefitted some patients.
Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial.
• A total of 56 women and 14 men aged 18 to 55 years who met the 1988 CDC criteria for CFS and who withheld concomitant treatment with other medications.
• A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996.
• Intervention - oral hydrocortisone, 13 mg/m2 every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks.
Results• Number of patients showing improvement on the Wellness scale was
19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients.
• Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo.
• Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group.
A pilot study employing Dehydroepiandrosterone (DHEA) in the treatment of chronic fatigue syndrome.
• The purpose of this uncontrolled, prospective, 6 month study of 23 women, ages 35-55 was to identify CFS patients with suboptimal levels of DHEA-S, defined as DHEA-S <2.0 microg/mL, and to treat those patients with oral DHEA.
• DHEA-S levels were re-measured after 4-6 weeks of oral DHEA therapy (25 mg). If DHEA-S remained <2.0 microg/ mL, or if no clinical response was achieved after 4-6 weeks of therapy, then an increased dose of DHEA was given. Physical and psychological impairment and disability status were measured by the MHAQ before DHEA intervention and at 3-month intervals.
Results
• Of initially screened patients with CFS, 76% (116 of 153) were ages 35-55, and 89% (103 of 116) had suboptimal (<2.0 microg/mL) production of DHEA-S.
• Supplementation with DHEA to CFS patients lead to a significant reduction in the symptoms of CFS: pain (improved by 18%, p = 0.035), fatigue (decreased by 21%), activities of daily living (improved by 8.5%), helplessness (decreased by 11%), anxiety (decreased by 35%), thinking (improved by 26%), memory (improved by 17%), and sexual problems (improved by 22%) over the period of the trial.
Cognitive Behavioral Therapy
• Objectives• To examine the effectiveness and acceptability of CBT for CFS,
alone and in combination with other interventions, compared with usual care and other interventions.
• Search Methods• CCDANCTR-Studies/References (Cochrane Collaboration
Depression, Anxiety & Neurosis Group) were searched on 28/3/2008. We conducted supplementary searches of other bibliographic databases. We searched reference lists of retrieved articles and contacted trial authors and experts in the field for information on ongoing/completed trials.
Results
• Fifteen studies (1043 CFS participants) were included in the review.
• When comparing CBT with usual care (six studies, 373 participants), the difference in fatigue mean scores at post-treatment was highly significant in favor of, with 40% of CBT participants (four studies, 371 participants) showing clinical response in contrast with 26% in usual care.
Author’s Conclusions
• CBT is effective in reducing the symptoms of fatigue at post-treatment compared with usual care, and may be more effective in reducing fatigue symptoms compared with other psychological therapies.
• The evidence base at follow-up is limited to a small group of studies with inconsistent findings. There is a lack of evidence on the comparative effectiveness of CBT alone or in combination with other treatments, and further studies are required.
Results II
• Findings at follow-up were inconsistent. For CBT versus other psychological therapies, comprising relaxation, counselling and education/support (four studies, 313 participants), the difference in fatigue mean scores at post-treatment favored CBT.
Graded Exercise Therapy
• GET aims to increase the patient’s ability to undertake physical activity by preventing/reversing the physical deconditioning and exercise intolerance related to prolonged (relative) inactivity.
• GET includes the establishment of a baseline of achievable patient-specific exercise or physical activity, followed by increments in the duration of physical activity.
• The overall aim is to help the patient gradually increase physical activity, and become more independent in their everyday life.
Graded Exercise Therapy II
• In patients with CFS, GET has been shown to reduce fatigue, prevent physical deconditioning and improve physical functioning, as well as improve sleep, cognition and mood.
• GET has also been shown to improve muscle strength, cardiovascular endurance and symptoms in a wide variety of conditions that have chronic fatigue as a symptom, such as heart disease, cancer and COPD.
Graded Exercise Therapy III
• Despite currently held views by government health departments on the usefulness of GET, there are still many doubts as to the effectiveness of using such treatment for those suffering from ME/CFS, as raised by studies made by those working more closely with this disease.
Acupuncture
• Multiple randomized controlled trials using acupuncture for a minimum of 4 weeks have shown improvement in fatigue symptoms in individuals with CFS/ME.
Vitamins and Supplements
L-Carnitine
• Carnitine is the carrier molecule that takes fuel in the form of acetate groups from the cell across mitochondrial membranes where it is needed to fuel energy production by the TCA cycle and oxidative phosphorylation.
• Acetate groups in the cell bind to carnitine to form acetyl L-carnitine, which can then pass through the mitchondrialmembrane. The acetate group is then given up and L-carnitine passes back through the mitochondrial membrane into the cell in order to pick up another molecule of acetate.
L-Carnitine II
• Carnitine can be made in both the liver and the kidney from cysteine and methionine and requires iron and vitamin C for its synthesis.
• In muscle meats L-carnitine makes up 0.1% of dry matter.
• There is very little carnitine in plant derived foods, which may partly explain why vegetarianism seems to be a risk factor for chronic fatigue.
L-Carnitine III
• Multiple studies have shown L-carnitine and acetyl-l-carnitine, at a dose of at least 2 grams per day, improves fatigue in CFS/ME , as well as fatigue from other causes.
Lipid Replacement and Antioxidant Nutritional Therapy
• Oxidative damage to membrane lipids (mitochondrial membranes as well as other cell membranes) diminishes mitochondrial function through loss of efficiency in the ETC.
• Lipid Replacement Therapy (LRT) administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage, and LRT can be used to restore mitochondrial and other cellular membrane functions via delivery of undamaged replacement lipids to cellular organelles.
Lipid Replacement and Antioxidant Nutritional Therapy
• Clinical trials have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue.
• Multiple clinical trials, using a proprietary blend of phosphoglycolipids combined with antioxidants, have shown significant reduction in fatigue with CFS/ME patients, as well as patients receiving chemotherapy.
Panax Ginseng
Anti-fatigue Effects of Panax ginseng C.A. Meyer: A Randomized, Double-Blind, Placebo-
Controlled Trial
Panax Ginseng
• The present study investigated the antifatigue effects of Panaxginseng C.A. Meyer in 90 subjects (21 men and 69 women) with idiopathic chronic fatigue (ICF) in a randomized, double-blind, placebo-controlled and parallel designed trial.
• 20% ethanol extract of P. ginseng (1 g or 2 g/day) or a placebo was administered to each group for 4 weeks, and then fatigue severity was monitored using a self-rating numeric scale (NRS) and a visual analogue scale (VAS) as a primary endpoint. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), total glutathione (GSH) contents and glutathione reductase (GSH-Rd) activity were determined.
Panax Ginseng II
• After 4-week, P. ginseng administration decreased the total NRS score, but they were not statistically significant compared with placebo (P>0.05).
• Mental NRS score was significantly improved by P. ginsengadministrations as 20.4±5.0 to 15.1±6.5 for 1 g and 20.7±6.3 to 13.8±6.2 for 2 g compared with placebo 20.9±4.5 to 18.8±2.9.
Panax Ginseng III
• Only 2 g P. ginseng significantly reduced the VAS score from 7.3±1.3 to 4.4±1.8 compared with the placebo 7.1±1.0 to 5.8±1.3.
• ROS and MDA levels were lowered by P. ginseng compared to placebo.
• P. ginseng 1 g increased GSH concentration and GSH-Rd activity.
• Our results provide the first evidence of the anti-fatigue effects of P. ginseng in patients with ICF, and we submit that these changes in antioxidant properties contribute in part to its mechanism.
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