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 CFS.
Overall, however, physicians 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:
- Post-ADD CFS: young adults who had attention-deficit disorder as children, who have flipped from hyperactivity to fatigue. Such patients have severe hypersomnolence (sleeping too much, sleeping any time or anywhere). Such patients respond well to psychostimulants.
- Neurological CFS: patients have more severe cognitive symptoms than patients in the other groups, including trouble thinking, remembering, and paying attention. While cognitive difficulties affect the vast majority of patients with CFS, this group experiences significantly more severe symptoms. Visual-spatial problems are common as are sensitivities to light and noise. Other symptoms in this group include seizure-like episodes and other abnormalities suggestive of temporal lobe seizures. Patients in this group tend to have severe sleep problems in which they never achieve stages 3 or 4 of the sleep cycle, awaken unrefreshed, and respond well to sleep-improving drugs.
- Post-viral CFS versus gradual-onset CFS: According to some experts, an estimated 70% of patients are healthy until a particular illness strikes at a definite time. In gradual-onset patients, however, symptoms develop gradually, and patients are unable to recall any specific viral or infectious illness that initiated the process.
- Patients with immune abnormalities versus those without such abnormalities: immune dysfunction (such as CD4, CD8, RNase, and TH1-TH2 imbalances) can leave some CFS patients both unable to fight viruses effectively and launching wrongful attacks against healthy tissues. Other CFS patients, however, do not have these immune abnormalities, or have only borderline shifts in immune factors.
- CFS with Orthostatic Intolerance or NMH versus patients without orthostatic irregularities.
- Patients with neuroendocrine abnormalities such as dysregulation of cortisol or ACTH levels.
- Low-active versus high-active patients.
- Patients with CFS alone, versus patients with other conditions such as fibromyalgia and /or multiple chemical sensitivity.
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:
- Genetic factors.
- Brain abnormalities.
- A hyper-reactive immune system.
- Viral or other infectious agents.
- Psychiatric or emotional conditions.
For example, the majority of patients report some preceding moderate to serious physical illness (e.g., a chronic viral infection) or emotional event (e.g., 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% to 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.
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:
Changes in Important Neurotransmitters. Other research has reported that some patients with CFS have abnormally high levels of serotonin, a neurotransmitter (chemical messenger in the brain). Such elevated levels in the brain are associated with fatigue. Studies also suggest that deficiencies in dopamine, an important neurotransmitter associated with feelings of reward, may play a role in CFS. Imbalances between neuroepinephrine and dopamine have been identified in certain CFS patients in several studies. Unfortunately, routine clinical testing for such chemical imbalances is cost-prohibitive.Drugs that improve the chemical balance in the brain are very effective for certain patients, however.
Stress Hormone Deficiencies. A number of studies on CFS patients have observed deficiencies in cortisol levels, a stress hormone produced in the adrenal glands. Cortisol is a precursor of dehydroepiandrosterone (DHEA), a weak male hormone that may also be important in CFS. Deficiencies may be the reason why CFS patients have an impaired and weaker response to psychological or physical stresses, such as infection or exercise. (Administering replacement cortisol, however, does not appear to improve symptoms, indicating other factors are involved.)
Disturbed Circadian Rhythms. Evidence suggests that in certain patients, CFS is a disorder of the sleep-wake cycle, which is regulated by the so-called circadian clock, a nerve cluster in the hypothalamus-pituitary-adrenal (HPA) axis. In a 2003 study of identical twins, those with CFS complained of disturbed sleep although they didn't differ from their non-CFS twins in their ability to fall or stay asleep or other objective measures of insomnia. The CFS twins did, however, exhibit more REM sleep, which is the active, dreaming phase of sleep, suggesting this may play some role. Some experts suggest that some mentally or physically stressful event, such as a viral infection, may disrupt natural circadian rhythms, and that an inability to reset these rhythms results in a perpetual cycle of sleep disturbances. Medications that improve sleep can be very helpful for certain patients.
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:
- One theory referred to as "hit and run" suggests that chronic fatigue syndrome might be the result of a virus or bacteria that infects the body, causes immune abnormalities, and is then eliminated. It leaves behind a damaged immune system, however, that continues to cause flu-like symptoms even in the absence of the virus.
- Another theory posits that an abnormal immune response reactivates a virus that had persisted in a latent (inactive) stage after an initial infection.
- A psychological response to viral infections occurs in susceptible individuals.
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.
Evidence that Supports a Viral Subtype. 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:
- CFS patients typically have elevated levels of antibodies to many organisms that cause fatigue and other CFS symptoms. Such organisms include those that cause Lyme disease, candida ("yeast infection"), herpesvirus type 6 (HHV-6), human T cell lymphotropic virus (HTLV), Epstein-Barr, measles, coxsackie B, cytomegalovirus, or parvovirus. Many of these infectious agents are very common, however, and none has emerged as a significant cause of CFS.
- In up to 80% of cases, chronic fatigue syndrome starts suddenly with a flu-like condition.
- In the US, there have been reports of cluster outbreaks of CFS occurring within the same household, workplace, and community (but most have not been confirmed by the Centers for Disease Control).
- Some researchers are suggesting that changes in normally harmless bacteria found in the intestine may play a role in the development of CFS symptoms.
Evidence suggesting that not all CFS has a viral cause:
- Most cases of CFS occur sporadically, cropping up individually without appearing to be contagious.
- There is no evidence that CFS is spread through casual contact, such as shaking hands or coughing, or by intimate sexual contact.
- No single virus has been implicated in chronic fatigue syndrome. Well-designed studies of patients who met strict criteria for chronic fatigue syndrome and of patients with idiopathic chronic fatigue have not found an increased incidence of any specific infections.
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, Sjogren'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.
Neurally Mediated Hypotension and Abnormal Blood Flow
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 ten 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.
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.
Exposure to 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, for example). 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.
Gulf War Syndrome and Chronic Fatigue
An estimated 7% of Gulf War veterans have reported symptoms resembling chronic fatigue syndrome. Women veterans had three times the risk as men. Interestingly, 15% of the noncombat personnel representing the general population reported the same problems, although these cases in general were less severe than in the veterans.
Symptoms of Gulf War Syndrome. Persian Gulf War veterans have been intensively studied because of a high percentage reporting symptoms that are similar to those in CFS. They include:
- Impaired thinking.
- Confusion and lack of coordination.
- Joint and muscle pain.
- Fear of doing simple tasks.
- Weakness and incontinence.
Whether the syndrome in Gulf War soldiers can be applied to civilian cases of CFS is not known. Symptoms do appear to differ. For example, in one study, CFS patients are more likely to have headaches, diarrhea, skin rashes, and night sweats than those with Gulf War Syndrome. In another, researchers measured ratings of perceived exertion (RPE), were higher in Gulf War veterans during exercise tests than civilian CFS patients. RPE describes the effort a person attributes to exercise (with scores ranging from 0 (falling asleep) to 20 (maximum all-out exertion). For example, oxygen demand or emotional effects (anxiety, negative feelings) may increase RPE.
Possible Causes of Gulf War Syndrome. Researchers in 2000 reported evidence of injury to nerve clusters in the left side of the brain in Gulf War Veterans with CFS symptoms. Another 2000 study found that these veterans had an abnormally low rise in blood pressure in response to mental challenges, suggesting some sort of circulatory problem. Among the theories for the cause of such injuries or why certain veterans were susceptible to it are the following:
- During this period, many veterans were exposed to a number of environmental toxins, including oil-well fires, pesticides, insect repellents, pyridostigmine bromide (a drug used to prevent injury from nerve gas), depleted uranium used in tank armor and ammunition, and other harmful chemical agents. A survey of 20,000 troops who were within 50 miles of stockpiles of the nerve gas sarin, however, reported no higher incidence of serious nerve injury than troops located further away.
- Some studies have heavily implicated multiple vaccinations given to military personnel during the Gulf War (but not those given before). In addition some specific vaccines, such as anthrax or botulinum, may have adverse long-term effects. Some researchers suspect that the symptoms were caused by a substance called squalene that was added to some vaccines to boost effectiveness. High levels of antibodies to this compound have been found in the blood of veterans with CFS symptoms.
- More than a dozen different illnesses have been detected in over 70,000 soldiers examined for this problem. Some researchers identified an unusual bacteria-like organism known as Mycoplasma fermentans in nearly half the veterans who suffered from Gulf War syndrome, and one scientist speculated that it might have been developed from biological warfare.
- Some experts suspect that post-traumatic stress disorder (PTSD) may be responsible for the symptoms in some cases. A 2002 analysis reported various syndromes of unexplained medical symptoms during earlier wars and campaigns, which included those of the Victorian era, the Boer War, World War I, and World War II. The researchers did not observe that such symptoms in Gulf War veterans differed in any significant way. (In response to the report, however, some writers pointed out that each of these wars exposed soldiers to infections and chemicals that could also have had long-lasting physical effects. And the Gulf War was the most toxic of all. Other studies have also indicated that PTSD does not fully explain Gulf war syndrome.)
- Researchers have discovered a higher than average incidence of the rare and fatal nerve disorder amylotrophic lateral sclerosis (ALS) among the veterans. It is not know if this is meaningful.
Interestingly, in one survey, mental health workers were more likely to believe that the syndrome is a physical disorder, while most primary care physicians thought it was due to psychologic factors.
Severity of Gulf War Syndrome. In studying mortality rates among Gulf War veterans, a seven-year study in 2001 reported that they actually had a lower mortality rate than the general population's. An earlier study also reported that the incidence of hospitalization and death was no higher in these veterans than in soldiers who had not been stationed in the Persian Gulf, but this only proves that the symptoms are not fatal or severe enough to send a patient to the hospital. Neither study disproves the existence of the condition itself.
Treatments. Treatments are generally those used for any patients with chronic fatigue or fibromyalgia, although success rates have been very modest. In one study, for example, slightly over 18% of veterans improved with cognitive behavioral therapy alone or with graded exercise.