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Chronic fatigue syndrome

Description

An in-depth report on the causes, diagnosis, and treatment of chronic fatigue syndrome.


Causes

Theories abound about the causes of chronic fatigue syndrome. Indeed, no primary cause has been found that explains all cases of CFS, and no consistent biologic factors allow objective measures, such as blood tests or brain scans, to definitively diagnose the condition.

Overall, however, doctors are increasingly adopting the view that CFS probably denotes a disease category that includes a range of subtypes, in the same way that cancer is a broad term within which numerous specific forms occur. Mounting evidence suggests that different subtypes of CFS have different causes and manifestations, and that these various types require different treatment approaches.

Research on subgroups of CFS is underway, but is still in very early stages. To date, however, clinical experience and limited data suggest that subgroups of CFS may include the following:

Observations that disparate treatments work for select patients appear to support the idea that subtypes of CFS require distinct approaches. The existence of subgroups may also explain why CFS researchers are frequently unable to replicate their results in subsequent studies; patient selection in studies to date has not reflected such careful discrimination. Researchers are now, however, working to define the subgroups of CFS and identify which treatments are most effective for each.

It should be noted that while the subgroup theory is interesting, in some cases the differences among patient populations may also reflect stages of disease. For instance, in initial stages of the disease, many patients are extremely symptomatic and fit a particular psychological profile including alarm, denial, and anger. In contrast, patients in later phases of the disease typically have learned to cope better with their symptoms and have a degree of acceptance. Patients' mental and emotional status may have biological consequences that bear on their physical symptoms. Such a relationship is not yet documented in CFS patients, however, and remains subject to research.

Convergence of Factors. A number of experts believe that CFS develops from a convergence of conditions that may include the following:

For example, the majority of patients report some preceding moderate to serious physical illness (such as a chronic viral infection) or emotional event (like an episode of depression). Some experts theorize that such events, alone or in combination, may interact with certain neurologic and genetic abnormalities to trigger the event. Still, it is not clear what sequence of events actually leads to the fatigue and other prominent symptoms of this disorder. Nor is there any specific brain or nervous system abnormality that experts can point to with assurance. Research published in 2001 indicates that CFS is more common among identical twins (who share the same genes) than fraternal twins (who share only some genes). Inheritance, then, may play a role in roughly 30 - 50% of cases, similar to the influence thought to occur in depression or alcoholism, although specific genes have not yet been identified.

Sudden- and Gradual-Onset CFS. One interesting theory is that CFS can be categorized as either sudden- or gradual onset, with each subgroup having different causes. In over half of patients, the onset is sudden, while the remaining patients have a slow onset. Some experts believe that sudden-onset CFS may be triggered by a virus or neurologic abnormality, while gradual-onset CFS might have a psychological or other cause. Supporting this theory was a study that observed that MRI scans of the brains of CFS patients without an accompanying psychiatric problem showed small injuries suggesting either a viral infection or neurologic problem. Still other experts believe that in some cases, gradual-onset CFS may be traced to cognitive disorders that were present during childhood, but went unrecognized until symptoms advanced into adulthood.

Genetic Defects

New evidence suggests genes involved in the body's response to stress may play key roles in CFS. A series of 14 articles published in 2006 linked CFS with genes involved in the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Julie Gerberding, MD, MPH, director of the Centers for Disease Control, called the research, "the first credible evidence of a biological basis for chronic fatigue syndrome." The researchers were able to locate a common variation of DNA sequences that predicted CFS with 76% accuracy. The genes control response to trauma, injury, and other stressful events. Nevertheless, the researchers were unable to find genetic markers of CFS or to determine how the genetic variations influenced symptoms.

In 2005, English researchers found that people with CFS are more likely than people without CFS to have human leukocyte antigen (HLA) class II alleles, variations that produce antibodies to certain immune factors. Another British study of people with CFS found alternations in 16 specific genes involved with immune function, communication between cells, and transfer of energy to cells.

Central Nervous System and Hormone Abnormalities

Another subgroup of CFS involves abnormalities in the central nervous system, particularly abnormal levels of certain chemicals regulated in the brain system known as the hypothalamus-pituitary-adrenal (HPA) axis. This system controls important functions, including sleep, response to stress, and depression. Of particular interest to researchers are the following chemicals and other factors controlled by the HPA axis:

Infections

Because most of the features of CFS resemble those of a lingering viral illness, many researchers have focused on the possibility that a virus or some other infectious agent causes the syndrome in some cases. There are three basic theories for infection-related causes of CFS:

Still, not all CFS patients show signs of infection. While experts have long been divided on whether infections play any role in this disorder, subtypes of viral-related and non-viral CFS may both exist.

Viruses. The theory that CFS has a viral cause is not based on hard evidence but on various observations that suggest an association, such as the following:

Evidence suggesting that some CFS cases may not be due to a virus:

Immune System Abnormalities

CFS has sometimes been referred to as the "chronic fatigue immune dysfunction syndrome." A number of studies have found many irregularities of the immune system. Some components appear to be overreactive, whereas others appear to be underreactive, but no consistent picture has emerged to explain CFS as a disease of the immune system. Again, the theory of subgroups may explain the significant heterogeneity among patients.

Allergies. Some, although not all, studies have reported that a majority of CFS patients have allergies to foods, pollen, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a cascade of immune abnormalities leading to CFS. (Most allergic people, in any case, do not have CFS.) Some research indicates that people with both allergies and emotional disorders, such as anxiety or depression, may be more vulnerable to the effects of the inflammatory response. This is a harmful overreaction of the immune system that can cause fatigue, joint aches, and fever as well as hormone and brain chemical disturbances.

One theory that may help tie in some of the various factors common to CFS suggests that allergies, stress, and infections may deplete a chemical in the body called adenosine triphosphate (ATP). This chemical stores energy in cells, and studies have reported a deficiency in many CFS patients. Supporting this theory was a study in which patients reported reduced CFS symptoms after they took a vitamin-like supplement called NADH, which increases ATP levels.

Autoimmune Abnormalities. The risk profile for chronic fatigue syndrome is similar to the risk profiles for a number of autoimmune diseases, such as lupus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. These disorders also have early symptoms resembling CFS. Common to such diseases are the presence of high levels of autoantibodies, immune factors that mistakenly attack the patient's own cells. Studies are inconsistent, however, in reporting the presence of autoantibodies in CFS, and the disease is unlikely to be due to autoimmunity.

Overactive Immune System. Various studies have reported imbalances in various immune factors, importantly white blood cells called T cells, which serve as infection fighters in the immune system.

The result of some T-cell abnormalities is to produce an excess of inflammatory substances called cytokines , which has been observed in some CFS patients. Excess amounts of cytokines cause inflammation and damage in the cells of the body and play an important role in many chronic diseases. This activity also produces fatigue, muscle aches, and other symptoms of CFS. Nevertheless, not all studies have reported elevated cytokine levels in CFS patients.

Low Blood Pressure

Some studies have observed that a subgroup of patients who fit the strict criteria for chronic fatigue syndrome also has a condition known as neurally mediated hypotension (NMH). NMH causes a dramatic drop in blood pressure when standing up, even for as short a time as 10 minutes. Its immediate effect can be lightheadedness, nausea, and fainting. A less severe hypotension condition known as postural orthostatic tachycardia syndrome (POTS) is also associated with CFS. An estimated 30% of CFS patients may have POTS, and some experts believe that the key to understanding CFS will eventually be found in understanding orthostatic intolerance. To further confound the issue, different CFS patients display different types of orthostatic intolerances.

Some experts suggest that such events may be due to impaired blood flow in CFS patients, which might affect the leg and arm muscles. (This in turn might account for muscle fatigue in these patients.) Evidence suggests, however, that blood flow is not abnormal in CFS patients, with or without NMH.

In any case, not all CFS patients experience NMH or POTs. In fact, some studies have reported no higher incidence of NMH in chronic fatigue patients. More research is needed to determine how or if these conditions are associated.

Psychologic Factors

Psychological, personality, and social factors are strongly associated with chronic fatigue in most, but not all, patients. The complex relationship between physical and emotional factors has yet to be fully understood, however. Studies have not found any consistent association between emotional or personality disorders and CFS to explain a causal role. Psychological factors, then, are unlikely to be a primary cause of CFS. They may play a role in increasing susceptibility to onset or perpetuation of the disorder. Certainly, in many cases, CFS promotes psychological and social dysfunction.

Chemicals and Environmental Toxins

In another subgroup of patients, chronic fatigue and pain has been associated with exposure to various chemicals and environmental toxins, such as solvents, pesticides, or heavy metals (cadmium, mercury, or lead). Of note, some reports in Sweden have suggested that mercury found in dental preparations may trigger processes that might cause CFS in susceptible patients. However, most experts believe that dental amalgam is entirely safe. The most publicized example is Gulf War syndrome. Still, most people have been exposed to toxic chemicals at some point during their lives, and it is very difficult to determine specific chemicals that might be particularly dangerous. It is not clear, then, to what extent chemicals may cause CFS. A recently described condition called multiple chemical sensitivity may produce the same symptoms or even occur with CFS.


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