What is Myalgic Encephalomyelitis & Chronic Fatigue Syndrome?
The disease known as chronic fatigue syndrome (CFS) in the United States has historically been called myalgic encephalomyelitis (ME) abroad. The acronym ME/CFS is currently used by researchers to reflect the difference in nomenclature. Even though the case definitions of the two illnesses do not match, specialists in the US who treat chronic fatigue syndrome acknowledge that the diseases are fundamentally the same.
The primary characteristics of the illness are a profound, unrelenting loss of energy that is not relieved by rest; post-exertional malaise, which is a worsening of all symptoms following minimal mental or physical exertion; sleep disorder; cognitive impairment resulting in slowed processing of information, reduced focus and attention, and pain.
Chronic Fatigue Syndrome & ME is a "multi-system disease," that is, it affects several systems in your body simultaneously: the immune system, the nervous system, and the endocrine system. Because cells of all three systems share the same receptors, any illness that affects one of these systems will affect the other two.
There have been thousands of research papers on ME/CFS documenting multiple physiological abnormalities in patients with ME/CFS. The most consistent among these abnormalities is immune system dysfunction, notably reduced natural killer cell (NK) function.
Natural killer cells are part of the innate immune system, which means they don't need prior contact with pathogens in order to form antibodies. (That is why they are "natural" killer cells.) NK cells provide a rapid response to viral infections and tumor cells. Reduced NK function indicates, among other things, that the immune system is unable to clear viruses.
Reduced NK function has been one of the most consistent immunological findings among people with ME/CFS. In fact, it is so consistent that the Japanese originally called the disease LINKS, which stood for Low Natural Killer Cell Syndrome.
One of the earliest immune system studies was performed in 1994 by Barker et al. They found that NK cell dysfunction was a "common manifestation of CFS." Further studies led by Ogawa, and Ojo Amaize confirmed that NK cells were not properly activated, and, when they were, had low cytotoxicity. Ojo Amaize et al. concluded that low cytotoxicity of NK cells was consistent with flu-like symptoms, and, perhaps, the reactivation of viruses.
Not every study has found a reduction of NK function, which has led to a debate in the research community as to whether ME/CFS should be classified an immune disease.
The most recent of the NK studies, conducted by Brenu et al., cleared up some of the confusion. The immune system changes minute by minute. As a consequence, studies that take a "snapshot" of immune markers through a single blood draw will have variable results. Brenu's group looked at immune markers over a period of a year. The study demonstrated that NK (natural killer) cytotoxic activity remained consistently decreased in ME/CFS patients during the course of the disease.
Brenu's group also found consistent pro-inflammatory cytokines (immune system chemicals). The persistent upregulation of pro-inflammatory cytokines is a marker of chronic inflammation and persistent viral infection in many disease states. In 1990 Nancy Klimas was one of the first researchers to find a distinct pattern of cytokines in ME/CFS patients. More recently, Maes et al. found that inflammatory cytokines and immune markers were not only elevated, but were associated with specific symptoms, including fatigue, sadness, autonomic symptoms, and a flu-like malaise, concentration difficulties, failing memory, and a subjective experience of infection.
Other immune irregularities, such as antibodies to cardiolipin, seem to indicate that an autoimmune process is involved (Hokama). Anticardiolipin antibodies (ACA) are found in autoimmune diseases such as lupus, rheumatoid arthritis, autoimmune hepatitis, and scleroderma. Other indicators of an autoimmune process are the presence of antinuclear antibodies (ANA) in about one-third of ME/CFS patients, as well as antiphospholipid antibodies (Berg).
The most telling evidence that ME/CFS is fundamentally an immune disorder comes from the fact that it is chronic. Any chronic illness points to an immune system that is not operating efficiently.
There have been many studies documenting nervous system abnormalities in patients with ME/CFS. In the early 1990s, the late Dr. Jay Goldstein developed a theory in which he proposed that ME/CFS was the result of an injury to the limbic system, which is an area located deep in the brain just above the brainstem, and is involved with memory, emotion, and regulation of the autonomic nervous system. The autonomic nervous system regulates homeostasis in the body: appetite, body temperature, blood pressure, blood sugar, sleep, wakefulness, heart rate, digestion, and sex drive. Goldstein's theory was based on a careful observation of symptoms in his patients, but he also made SPECT scans that showed blood flow was reduced in the brains of people with ME/CFS.
Functional MRIs (fMRI) measuring brain responsiveness during the performance of mental tasks show that people with ME/CFS have slower processing speed, loss of focus, and poor short-term memory (Caseras, Tanaka). Using a similar technique, a group of Dutch researchers in Holland led by de Lange, mapped structural brain structure and volume in CFS patients and healthy controls with high-resolution structural magnetic resonance images using voxel-based morphometry, a form of statistical analysis that measures the shape, size and position of brain structures. The de Lange study found "substantial and consistent" reductions in gray matter volume in two groups of ME/CFS patients as compared with controls.
Reductions in both white and gray matter have been found by subsequent researchers (Barnden, Puri et al.). In 2011, Puri et al. concluded that their data supported the hypothesis that "significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness." Their data also indicated that "subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS/ME."
One of the most significant brain studies was recently published by a group of Japanese researchers. Using PET scans, Yasuhito Nakatomi et al. found that neuroinflammation is higher in ME/CFS patients than in healthy controls. They also found that inflammation in certain areas of the brain - the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons - correlated with the symptoms. Patients who reported impaired cognition, for example, showed neuroinflammation in the amygdala, which is known to be involved in memory. This research not only demonstrates the connection between neuroinflammation and cognitive symptoms, it takes us full circle back to Jay Goldstein's limbic hypothesis, as most of the areas of the brain showing inflammation were located in the limbic system.
The third major system affected by ME/CFS is the endocrine system. The endocrine system is a collection of glands that secrete hormones directly into the circulatory system. These hormones are then carried to a target organ. The major endocrine glands are the pineal gland, hypothalamus, and pituitary gland in the brain; the pancreas; the sex glands (ovaries, testes); the thyroid and parathyroid glands; the gastrointestinal tract; and the adrenal glands. When glands signal each other in sequence this is referred to as an axis, e.g. the hypothalamic-pituitary-adrenal (HPA) axis.
The HPA axis figures prominently in ME/CFS literature. In 1991 a research team led by Dr. Mark Demitrack published a study demonstrating abnormalities in the HPA axis in patients with ME/CFS. The study showed decreased levels of cortisol, blunted response of the pituitary gland to corticotropin releasing hormone (CRH), and enhanced sensitivity to adrenocorticotropic hormone (ACTH). While the test results ruled out primary adrenal insufficiency (Addison's disease), they did indicate a dysregulation in the HPA axis, which would lead to excessive fatigue, as well as many other symptoms typical of low adrenal function. The authors concluded that their test results indicated "a mild central adrenal insufficiency" in ME/CFS patients, most likely originating in the hypothalamus.
Subsequent studies by Dinan et al., Maes et al., Cleare et al., and Scott et al. found significant disruptions of the HPA axis, as well as reductions in DHEA (a precursor to sex hormones), and blunted responses to chemical signals sent by the brain (De Becker). Low growth hormone (GH) levels have also been found in ME/CFS patients (Berwaerts at al.) Growth hormone is released during sleep by the pituitary gland. Given that insomnia is one of the primary symptoms of ME/CFS it is not surprising that GH levels would drop. Low GH is associated with a loss of vitality in adults, or, in common parlance, fatigue.
The mitochondria are small structures within cells that produce adenosine triphosphate (ATP), the molecule that generates cellular energy. ATP is essential for every function in the body, which means that when the powerhouses of energy production, the mitochondria, are damaged and levels of ATP decline, the body literally runs out of energy. If low levels of ATP are sustained, there can be lasting damage to the heart, which is highly dependent on ATP. Mitochondrial dysfunction has also been linked to diabetes, Alzheimer's disease, Huntington's disease, cancer, and liver disease, all of which produce profound fatigue.
The first doctor to suggest mitochondrial damage in people with ME/CFS was Dr. Melvin Ramsay, the physician who documented the Royal Free Hospital outbreak in the 1950s. In an article written in 1978, Dr. Melvin Ramsay proposed that "abnormal muscular fatigability is the dominant clinical feature and it is suggested that mitochondrial damage may provide an explanation for this phenomenon."
Not long after Dr. Ramsay's observation, the Drs. Behan found concrete evidence of damaged mitochondria in muscle biopsies of patients with post-viral syndrome. Out of 50 samples, mitochondrial degeneration was obvious in 40 of the biopsies. Significantly, they also noted the presence of "ragged red mitochondria," a sign of mitochondrial disease. The authors concluded that their findings provided the first evidence that post-viral syndrome "may be due to a mitochondrial disorder precipitated by a virus infection."
Since that time, ME/CFS specialists have accepted the fact that ME/CFS produces mitochondrial damage. Dr. Cheney has long held that ME/CFS is a mitochondrial disease, a position strongly supported by research showing mitochondrial dysfunction in the muscles of ME/CFS patients - as indicated by the production of excess lactate.
Because the heart is composed of muscle tissue, cardiac function will be affected by reduced mitochondrial output. A 2003 study by Peckerman et al. documented cardiac impairment in ME/CFS patients. Test results showed that patients with severe ME/CFS had "significantly lower stroke volume and cardiac output than the controls and less ill patients." The authors proposed that in patients with ME/CFS, "blood pressure is maintained at the cost of restricted flow, possibly resulting in a low flow circulatory state. Thus, there might be periods in daily activities when demands for blood flow are not adequately met, compromising metabolic processes in at least some vascular compartments."
Dr. Cheney has proposed that this impairment in diastolic function is what lies at the heart of the majority of ME/CFS symptoms. If cardiac output is low to begin with, standing up would reduce it to levels so low that a person would experience dizziness, black-outs, and even fainting. Once cardiac output is sufficiently reduced, all other systems would decline as well. The body, in an effort to supply blood to the heart, would restrict blood flow to other organ systems, such as the gut. As a consequence, digestion would be impaired, with resultant dysbiosis, malabsorption, and a host of GI problems.
Blood flow to the brain would also decline, leading to cognitive problems, depression and anxiety, and impairment of hypothalamic function. With reduced blood flow, the immune system, which depends on the vascular system for transport, could not function efficiently; latent viruses and secondary infections would proliferate. The liver, an organ which relies heavily on blood flow, could not detox the body sufficiently, leading to a buildup of toxins. Under these conditions, exercise would not only strain the system, it could be dangerous.
According to Dr. Sarah Myhill, mitochondrial dysfunction is the central mechanism of ME/CFS. Her explanation of mitochondrial damage is that when the body is stressed, the demands placed on ATP production can exceed the supply. In people with ME/CFS, the body is continually stressed by an overworked immune system and secondary infections, resulting in a depletion of overall ATP, which damaged mitochondria cannot regenerate. Once stores are low, the cells begin to convert glucose into lactic acid, which is the reason why ME/CFS patients so quickly switch to anaerobic metabolism during exercise. The net result is exhaustion at the metabolic level.
In a study conducted in 2009 by Dr. Myhill and two colleagues, Dr. Myhill measured the levels of five biomarkers indicative of mitochondrial function in the sera of ME/CFS patients. The results of the study indicated that when analyzed together, these markers were predictive of illness severity in ME/CFS patients. The researchers concluded that their findings strongly implicated mitochondrial dysfunction as the immediate cause of ME/CFS symptoms. However, they could not determine whether the damage to mitochondrial function was a primary effect, or an effect secondary to cellular hypoxia or oxidative stress.
Oxidative stress is both the product and the cause of mitochondrial dysfunction. That being said, there is also ample evidence that viruses can directly cause extensive damage to mitochondria. The herpes simplex virus causes massive damage to mitochondrial DNA, contributing to cell death and tissue damage. Viruses can also use mitochondrial proteins for replication, induce cell apoptosis (cell death), and increase the production of free radicals.
Mitochondrial disease shares many common features with ME/CFS. Both illnesses share similar markers - evidence of oxidative stress, high lactate levels, low acyl-carnitine, and low glutathione levels (which has been proposed as a marker for mitochondrial diseases) are common lab findings in both mitochondrial disease and ME/CFS. Both illnesses are heterogeneous, manifesting in different organs and at different rates of severity. Both are difficult to diagnose. And finally, exercise intolerance is a hallmark characteristic of both illnesses, a feature which no doubt led Dr. Ramsay to conclude that ME was a mitochondrial disease. Given the overlap in lab results, symptoms, and treatment, there is no reason not to consider ME/CFS as an acquired mitochondrial disease.
Dr. Kenny De Meirleir has proposed that the translocation of intestinal flora into the bloodstream is what causes the chronic immune activation of ME/CFS. The mechanism through which intestinal bacteria enter the bloodstream is known as "leaky gut" (intestinal permeability), a condition that compromises the protective barrier of the intestinal wall, allowing large molecules and bacteria that would otherwise be trapped in the intestines to pass through.
In 2012 Dr. Maes et al. measured responses to intestinal flora in blood samples from 128 patients with ME/CFS. The researchers found higher levels of IL-1, TNF alpha, neopterin and elastase (an enzyme that destroys bacterial proteins) than in controls, indicating an immune response to bacteria in the bloodstream. Furthermore, IL-1, TNF alpha and neopterin were significantly related to fatigue, flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability. The authors concluded that "increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients."
Not only do translocated intestinal flora activate the immune system, their by-products, particularly hydrogen sulfide (the gas that produces the "rotten egg" smell), can exert profound effects on the endocrine system, including a decrease in core body temperature, sleep apnea, reduced heart and respiration rates, and a severe metabolic drop. Excess hydrogen sulfide can also inhibit mitochondrial oxygen utilization.
In related work, Marian Dix Lemle has proposed that the production of excess hydrogen sulfide is responsible for the mitochondrial dysfunction that lies at the base of ME/CFS symptomatology. These three researchers have, between them, established a mechanism that would account for all ME/CFS symptoms. Marian Lemle has identified the chemical component. Dr. De Meirleir has explained the cause for its increase in the gut, and Dr. Maes has identified the mechanism through which it causes symptoms- translocation. All of these components directly reflect the influence of the microbiome.
Increasingly, scientists are looking at the microbiome's role in disease. The microbiome is the community of bacteria, and other micro-organisms that inhabit our bodies. Often, when researchers refer to the microbiome, they are talking about the trillions of bacteria that inhabit our intestines, and that enable us to digest our food, absorb nutrients, and protect us from pathogens.
Alterations in the microbiome have been found in a number of diseases and conditions, such as autism, diabetes, inflammatory bowel disease, major depression, and ME/CFS. Most promising for patients is the potential therapeutic value of altering the microbiome to treat these illnesses.
When Butt et al. analyzed the microbiota of patients with ME/CFS, they found that changes in the gastrointestinal microbial ecology were "significantly associated with fatigue symptoms" as well as neurological and cognitive function. Borody et al. addressed this problem by treating 60 patients with bacteriotherapy (fecal transplant). The results of the treatment were promising. Of the 60 patients, 42 responded well to the treatment. Most impressive was the fact that after 15 years, 12 of those patients were still symptom free. The authors concluded that "bacteriotherapy achieves initial success rate of 70% in CFS and a 58% sustained response."
Results like these have prompted Dr. Ian Lipkin to initiate a million-dollar project to study the microbiome of ME/CFS patients (McGrath). Lipkin believes that "populations of fungi, bacteria and viruses in the colon can have an impact on the immune system and give rise to cytokine activation which could cause the symptom complexes we see in ME/CFS."
How Many People Have ME/CFS?
It is difficult to estimate how many people suffer from ME/CFS when there are so many case definitions. Using a very broad case definition, such as the Oxford Case Definition, which only requires six months of fatigue, would result in enormously inflated numbers, as it could capture people with depression, deconditioning, and rare diseases, such as Behçet's, Ehlers-Danlos, Primary Immune Deficiency, early MS, rare forms of leukemia, and so on.
A narrow case definition, such as the Canadian Consensus Criteria or International Consensus Criteria, would produce more accurate statistics, but these definitions are used almost exclusively by ME/CFS experts, not by government agencies charged with establishing prevalence and incidence. The fact that so few doctors have the expertise to diagnose ME/CFS confounds the problem.
In 2003, Reyes et al. published a 4-year study conducted in Wichita, Kansas. The overall prevalence of CFS was 235 per 100,000 persons, which meant 800,000 people in the U.S. had the disease. CFS was more than four times more common among women (373 per 100,000) than among men (83 per 100,000). Only 16 percent had received a diagnosis and medical treatment for their illness.
According to the CDC, there are currently one million people in the U.S. with ME/CFS.
In Great Britain, there are roughly 250,000 people with ME/CFS. One study estimated the minimum prevalence rate of ME/CFS at 0.2%. (Nacul et al.) ME/CFS Australia estimated that there were 180,000 Australians with ME in 2002. That number has since grown.
The 2005 Community Health Survey conducted by Statistics Canada indicated that there were 333,816 Canadians diagnosed with ME/CFS.
In the Netherlands, prevalence may be as high as 3.6% in the working population, which is considerably higher than the US rate. (Huibers et al.) Sweden has also reported a high prevalence rate of 2.6%. (Evengård et al.)
There have been very few systematic epidemiological studies conducted in Africa, but one study suggested that the rates might be higher in Nigeria than in the US. (Njoku et al.) The prevalence of CFS in a community population in Japan was 1.0% in 2011, or roughly 300,000 nationwide.
List of brain scan research studies
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List of epidemiological studies up to the year 2000.
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