Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Introduction:
Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are chronic, complicated disorders that involve multiple sites and organ systems throughout the body.  This condition is one of the most difficult to diagnose and treat because little is known about its etiology. Additionally, no tests have been proven to diagnose it consistently and effectively. This condition is so complex even its name portrays its ambiguity. “ME has not been proven to include myelitis (spinal cord inflammation) or encephalitis (brain inflammation)” (Scott et. al, 1995), yet the name “myalgic encephalomyelitis” remains.

There are many symptoms that can be associated with ME/CFS.  Muscular fatigue is the most common and widely recognized symptom associated with ME/CFS, as indicated by the name “chronic fatigue syndrome”.   Some of the other common symptoms displayed are cognitive diminution, depression, musculoskeletal pain, and sleep abnormalities.  While these deficits are typical symptoms, they are not necessary to diagnose ME/CFS and also do not represent all of the possible symptoms associated with the illness.  Furthermore, the spectrum of ME/CFS ranges greatly from mild to severe.  Mild cases typically exhibit discomfort after exertion.  In extremely severe cases, “patients may be confined to bed or a wheelchair” (Chambers et. al, 2006).
Although much research has been done, the etiology of ME/CFS remains largely unknown.  Possible causes include “neurological, endocrine, immunological, genetic, psychiatric, and infectious” (Baker et. al, 2007) problems.  This is precisely what makes ME/CFS so hard to diagnose and even more difficult to treat.  Most treatments target the source or root of a condition. ME/CFS treatment is more palliative than curative because of its unknown etiology. There are many theories as to how ME/CFS manifests itself, however there is no “accepted disease model that can explain signs and symptoms in terms of specific pathophysiological abnormalities” (White et. al, 2000).
Physicians are often hesitant to diagnose ME/CFS since there is no proven etiology, no definitive set of symptoms, and little guidance for treatment.  It should seem evident that “problems in doctor-patient relationships may be a factor in persistent disability in fatigue states” (Scott et. al, 1995).  In fact, studies have shown that half of physicians do not even believe the condition exists (Thomas et. al, 2005).  While it is apparent that this trend of disbelief is changing for the better, it is crucial that all primary care physicians realize this is a prevalent illness. The point prevalence of chronic fatigue in 1997 was 2.6%, “falling to 0.5% if co-morbid psychological disorders were excluded” (Wessely et. al, 1997). Even excluding chronic fatigue cases coupled with psychological disorders, 0.5% prevalence indicates a very significant condition that should be taken seriously by primary care physicians. The most important step to improve the treatment and quality of care of patients with ME/CFS revolves around the primary care physician. Physicians need to recognize that ME/CFS is a very real and highly debilitating condition affecting patients drastically. Until physicians realize the impact of ME/CFS, patients will continue to suffer by not receiving the same dedication and standard of care as someone with a similar widely-recognized condition, such as Duchenne muscular dystrophy.
The complexity of ME/CFS is portrayed by the 7 different subtypes used to classify a patient with ME/CFS.  While there is no need to explain all 7 subtypes, it is important to note the huge range of symptoms and severity that are displayed by the different subtypes.  For example, subtype 7, the most severe, includes “pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, and anxiety/depression” (JR Kerr et. al, 2007) issues.  On the other hand, subtype 4 is purely cognitive and subtype 5 patients display only musculoskeletal and gastrointestinal problems (JR Kerr et. al, 2007).  This huge discrepancy in the classification of ME/CFS sheds light on the huge range and variation of symptoms that can occur.  Given that ME/CFS has no known etiology, this variation of symptoms compounds the complexity of trying to diagnose and treat the condition.
Diagnosis:
Diagnosing ME/CFS is extremely difficult.  “CFS/ME is diagnosed clinically as insufficient evidence exists for routinely using diagnostic tests (Baker et. al, 2007). A few diagnostic exams have shown promise but have not yet proven to be reliable in diagnosing the general population. For example, the head-up tilt test proved to be predictive in a small subset of patients with clinically diagnosed CFS. However, in the general population a person presenting with fatigue that displayed a positive head-up tilt test exhibited a positive predictive value of “only 0.37 – 1.15” (Ghosh et. al, 2003). Similarly, a study “showed that the stapedial reflex together with the auditory brainstem response test could be useful” in the diagnosis of ME/CFS (Neri et. al, 1996). However, the study was performed in a specific subset of patients with clinically diagnosed ME/CFS and its utility in the general population is very questionable.
In the absence of diagnostic exams, a physician must conduct a method of “process of elimination” to truly derive a confident clinical diagnosis of ME/CFS.  A multitude of symptoms are associated with ME/CFS as well as many other illnesses.  No symptoms are found exclusively in ME/CFS. In addition, each symptom may or may not be present in ME/CFS due to the extreme variation among inflicted patients. The most common symptoms associated with ME/CFS are muscular fatigue, impaired concentration and memory, depression, sleep abnormalities, and musculoskeletal pain.  A final diagnosis of ME/CFS can be reached with a relative degree of certainty only after all pertinent common conditions with similar symptoms have been ruled out. There are many diagnostic exams that are extremely useful in ruling out these other conditions.
                 Urine analysis is one exam that should be conducted to exclude other conditions before a diagnosis of ME/CFS is made.  Urinalysis for protein, blood, and glucose can indicate many conditions with similar symptoms to ME/CFS.  While it is normal for small amounts of protein to be found in the urine of children or after strenuous exercise, proteinuria in high levels in adults may indicate kidney disease.  Blood in the urine, hematuria, may also indicate problems other than ME/CFS.  Hematuria can result from numerous causes, such as urinary tract infections, kidney stones, medications, or even cancer.  Similarly, glucose in the urine can indicate a potential for diabetes mellitus. Anything more than trace amounts should be followed up with further testing for a possible diagnosis of diabetes.  Urinalysis is conducted to exclude ME/CFS from other diagnoses because kidney problems, diabetes, and many other conditions convey very similar symptoms to ME/CFS, especially fatigue.  A positive exam will allow a physician to focus on diagnosing and treating these other conditions, which generally have approved methods of treatment. Urinalysis should always be performed before clinically diagnosing ME/CFS.
A complete blood count (CBC) should be conducted to rule out other conditions with associated symptoms similar to ME/CFS.  High white blood cell numbers in CBC results can detect infections. Similarly, anemia and leukemia can be detected through CBC’s.  Erythrocyte sedimentation is also a useful blood exam because of its ability to detect inflammation in the body.  Rheumatoid arthritis, a degenerative inflammation of joints and surrounding tissue, can be discovered through this sedimentation process. Infections, anemia, leukemia, and arthritis can all provide symptoms of chronic fatigue and musculoskeletal pain.  These conditions should be confidently excluded before a presumptive diagnosis of ME/CFS is made.
C reactive protein (CRP) is another valuable laboratory exam used to rule out illnesses that present similarly to ME/CFS. CRP is similar to erythrocyte sedimentation in that it signals the presence of inflammation in some portion of the body.  CRP is often thought to be a good predictor of coronary heart disease, although it is unable to pinpoint the exact location of inflammation.  High levels of CRP in the absence of a coronary emergency can indicate an array of other conditions including but not limited to cancer, infection, lupus, fever, and tuberculosis (Danesh et. al, 2004).  These illnesses have all been shown to be associated with muscle aches and pains as well as many other symptoms commonly associated with ME/CFS.
Testing the serum for various elements such as creatinine, electrolytes, calcium, and urea is useful to ensure other conditions are not bringing about symptoms commonly seen in ME/CFS.  Serum creatinine exams can reveal underlying renal function problems, nephritis, or muscle diseases.  Serum electrolyte counts can signal a disruption in patients’ intrinsic homeostatic mechanisms. Serum calcium is a very tightly controlled substance and can often indicate thyroid conditions. Thyroid problems are linked to abnormal energy metabolism and irregular baseline activity levels of the body, commonly perceived as chronic fatigue. Serum urea, or BUN, is used as another indicator of kidney function. Abnormal amounts should not be present unless someone has recently undergone rigorous exercise. All of these conditions can exhibit symptoms similar to ME/CFS. Consequently, only after excluding all of these possible ailments through serum analysis should a diagnosis of ME/CFS be made.
Random blood glucose is another exam useful in ruling out conditions other than ME/CFS.  It is well known that blood glucose can identify problems in the body’s mechanisms of controlling energy storage and production.  Diabetes is the most common condition that can be diagnosed from abnormal blood glucose results.  Improper sugar balance in the body can lead to many symptoms very similar to ME/CFS such as fatigue, headaches, and even cognitive impairments when glucose levels become too low.
Creatine kinase is an exam that monitors if there has been a recent traumatic event to a muscle or group of muscles in the body.  CK is specifically used to help diagnose a myocardial infarction (MI). In the absence of an MI, abnormal results can indicate that there has been some other muscle deterioration.  Muscle deterioration and weakness present similarly to symptoms commonly associated with ME/CFS, particularly chronic fatigue and musculoskeletal pain. A diagnosis of ME/CFS should only be made after other muscular conditions are ruled out.
A liver panel is a useful laboratory exam to rule out many liver conditions that have like symptoms with ME/CFS.  A standard liver panel should include total protein, bilirubin, albumin, alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase.  All of these individual tests in concert can produce a holistic view of liver function.  Hepatitis, hemolytic anemia, and pancreatic cancer are some of the many conditions with symptoms similar to ME/CFS that can be diagnosed using this liver panel. Each of these conditions can produce one or more symptom(s) commonly associated with ME/CFS.
Thyroid function should be analyzed through T3, T4, and TSH testing before a diagnosis of ME/CFS is made.  The thyroid gland is crucial for basal metabolic rate and activity levels. Disruptions can mirror many of the symptoms of ME/CFS.  Some of the most common symptoms associated with thyroid disorders are fatigue and weakness, lowered basal body temperature, and cognitive impairments such as forgetfulness or even dementia.  By testing the T3, T4, and TSH levels in blood, one can properly assess thyroid function and rule thyroid abnormalities out before proceeding to a diagnosis of ME/CFS.
In children and young adults, serum ferritin is a valuable exam used to rule out issues of iron homeostasis.  Serum ferritin reveals how much iron is carried in the blood and can be an indicator of conditions such as anemia or hemochromatosis (Jacobs et. al, 1972).  Anemia is simply a lack of adequate red blood cells. It is very common for patients with this condition to feel extremely tired and to also display cognitive problems due to the lack of proper oxygen transport. Hemochromatosis is a condition in which the body stores and absorbs too much iron. Iron overload often damages organs in the body such as the liver, pancreas, or thyroid. This leads to conditions that typically display symptoms similar to ME/CFS.
Finally, to correctly diagnose ME/CFS one must attempt to distinguish ME/CFS from fibromyalgia (FM), the most similar condition.  Symptoms commonly associated with FM are extremely similar to ME/CFS.  These symptoms include chronic pain, sleep abnormalities, psychological impairment, and debilitating muscle fatigue.  The striking similarities in the clinical presentation of CFS and FM “suggest that these conditions have extensive overlap or may even be different presentations of the same condition” (Buchwald, 1996). Like ME/CFS, there is currently no way to diagnose FM through biological markers.  It is highly debatable whether the two conditions can be clinically separated because of their similar symptoms as well as the broad range of severity displayed by both.  Some experts believe the defining characteristic is that “only persons with FM alone exhibit abnormal pain responses to mild levels of stimulation, or allodynia” (Bradley et. al, 2000).  However, definition criteria of both ME/CFS and FM put a large emphasis on severity instead of focusing on actual characteristics, which allows for the extensive overlap between the two.  In fact, a recent study has shown that “70-80% of patients with CFS/ME also fulfill the 1990 criteria for FM” (Garcia-Fructuoso et. al, 2008).
While differentiating between these two very similar conditions may not be of utmost importance, there are current studies looking to objectively distinguish ME/CFS and FM.  A recent study has shown that predictor single nucleotide polymorphism (SNP) mapping can make a distinction between these two conditions.  It was found that “from the [20] SNPs analysed, a combination of 15 were found that could very efficiently discriminate between FM and CFS/ME patients” in the subset of patients studied (Garcia-Fructuoso et. al, 2008).   Since both ME/CFS and FM have no proven method of treatment, this absolute diagnosis between the two is not nearly as important as ruling out the other diagnoses noted above.
Once all other options have been exhausted, a diagnosis of ME/CFS can be made.  According to the National Institute for Health and Clinical Excellence, “CFS/ME should be diagnosed in an adult only after symptoms have persisted for four months and after exclusion of other likely causes of the symptoms” (NICE, 2007).
Treatment:
There are no clinically proven methods to treat ME/CFS.  Consequently, treatment of ME/CFS becomes less important than treatment of the actual patient. After diagnosis, a physician must conduct “patient-centered medicine” and focus on a treatment plan that is individually tailored to that patient’s precise needs.  In reality, even if a diagnosis of ME/CFS is not made for any particular reason, the treatment of individual symptoms will remain virtually the same.  A patient may benefit from the relief of a diagnosis instead of the apprehension of an unknown affliction if no diagnosis is made. However, the real focus now shifts away from the diagnosis and directly to the individualized treatment of symptoms. If a patient is suffering from muscular fatigue and pain, the primary care physician must treat the muscular fatigue and pain.  If a patient is suffering from psychological problems such as depression, the physician must treat the depression through psychological care.  To this date, there is no proven standard of care for ME/CFS. Thus, a primary care physician’s most important resource in treating a patient with ME/CFS is the patient himself/herself. A collaborative approach between the care team and patient can most effectively provide reprieve to all or most of a patient’s symptoms.
Holistic methods of treating ME/CFS require a large amount of collaboration between a primary care physician, the patient, the care team, and oftentimes a group of specialists. This can include but is certainly not limited to “neurologists, immunologists, specialists in infectious disease, pediatricians, nurses, clinical psychologists, liaison psychiatrists, dietitians, physiotherapists, and occupational therapists” (NICE, 2007). The extensiveness of this list portrays the wide variety of treatments that can be incorporated into a patient’s regimen to combat ME/CFS. It is crucial to note that these forms of treatment are not intended to cure ME/CFS, but rather only to alleviate the symptoms. Some of the most common methods of treating ME/CFS include exercise therapy, pharmacotherapy, dietary changes, and cognitive behavior therapy.
There are two main forms of treatment for dealing with physical exertion problems in ME/CFS: exercise therapy and rest.  Exercise therapy typically consists of graded exercise treatment.  Graded exercise treatment involves beginning to exercise at a slow, minimal exertion level and slowly progressing to more demanding and longer workouts.  This means strictly adhering to a program mapped out specifically by a physiologist. The most important part of these graded programs is not overexerting or exercising more than planned on “good days”, as this can incur large setbacks. The graded exercise program will allow the body ample time to recuperate and adjust to activity changes in a slow and progressive manner.  In numerous studies, graded exercise therapy was found to be more beneficial than rest alone (Fulcher et. al, 1997, Moss-Morris et. al, 2005).  Many studies note the simple effect of distracting the patient from their symptoms and focusing on exercise as a goal.   “A decrease in symptom focusing rather than an increase in fitness mediated the treatment effect” (Moss-Morris et. al, 2005) in a study based on self-surveys.  This is not to say that exertion levels and overall fitness are not inherently improved as well in graded exercise therapy.  On the contrary, “fatigue, functional capacity, and fitness were significantly better after exercise” in an objective study (Fulcher et. al, 1997).  Therefore, an exercise program can have multiple modes of improvement in the symptoms of ME/CFS.  Graded exercise appears to be a multi-faceted approach for ME/CFS because “it operates in part by reducing the degree to which patients focus on their symptoms” (Moss-Morris et. al, 2005) as well as improving overall fitness.
Pharmacotherapy has often been used to treat the psychological symptoms of ME/CFS.  It has been documented that a large number of patients with ME/CFS display symptoms most commonly identified with depression.  In fact, almost half of all patients with ME/CFS express depression-like symptoms (Hickie et. al, 1990).  Patients who have been diagnosed with ME/CFS display similar pre-morbid depression statistics when compared to the general population.  This indicates “psychological disturbance is likely to be a consequence of, rather than an antecedent risk factor to the syndrome” (Hickie et. al, 1990).
Many physicians treat ME/CFS patients with anti-depressants. Currently, the most oft-used anti-depressant is fluoxetine. Fluoxetine is a selective serotonin reuptake inhibitor, which results in more serotonin being available to postsynaptic cells.  Fluoxetine is “recommended in preference to tri-cyclic agents because it has fewer sedative and autonomic nervous system effects” (Vercoulen et. al, 1996).  Its effectiveness has been proven in clinically depressed individuals; therefore, patients with ME/CFS displaying depressive symptoms have often been given fluoxetine.  However, despite this seemingly logical thought process fluoxetine has not proven to be effective in the treatment of depression-like symptoms in ME/CFS.  A study showed that patients with ME/CFS who were given an 8-week treatment of fluoxetine did not show any significant improvements over a placebo control group (Vercoulen et. al, 1996).  No improvements were seen in many aspects including sleep disturbances, activity levels, functional impairment, and neuropsychological function.  This indicates “processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder” (Vercoulen et. al, 1996).
Galantamine hydrobromide has many pharmacological properties that would appear to benefit ME/CFS patients. Galantamine hydrobromide is a cholinesterase inhibitor. It increases acetylcholine activity by down-regulating cholinesterase, the enzyme which breaks acetylcholine down. Galantamine hydrobromide has been proven to be effective in neurological conditions such as Alzheimer’s and mania as well as improving REM sleep density and decreasing REM sleep latency (Blacker et. al, 2004). These positive effects would certainly appear to improve many symptoms associated with ME/CFS. However, a trial in 2004 “did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS” (Blacker et. al, 2004).
To date, there is no evidence that anti-depressant medication such as fluoxetine or galantamine hydrobromide have any benefit on patients suffering from ME/CFS. Until this “virtually unbroken series of failed drug trials for CFS” (Straus, 2004) ends, anti-depressant pharmacotherapy should not be considered a viable option in the treatment of ME/CFS.
Patients with ME/CFS, especially those with documented bowel irritation, often benefit from dietary therapy. Dietary changes and recommendations are one of the least researched forms of treatment for ME/CFS but have shown early signs of utility.  There are two common types of dietary treatment in ME/CFS.  Normal healthy dieting is encouraged in patients with ME/CFS for the obvious reasoning that people who eat healthier generally feel better and have more energy than those with unhealthy (high fat, high calorie) diets.  The other form of ME/CFS treatment involves specific types or categories of food that may have specific methods of improving the symptoms associated with ME/CFS.
There is little dispute that an overall balanced and healthy diet following common guidelines can have great benefits in energy level, weight, and mood. It has been reiterated in the literature that “a diet plan for patients with CFS should be based on sound nutritional principles and common sense” (Morris et. al, 1993).
There have been many specific diet therapies prescribed to patients with ME/CFS that have claimed to be beneficial. However, most of these plans are purely anecdotal and do not stand in the face of clinical research. These treatments include supplements such as megavitamins or royal jelly. Other treatments include general guidelines such as elimination, rotation, and avoidance dieting. These diets are “not supported by clinical evidence and are not practical for patients with CFS” (Morris et. al, 1993). Strict diets and “miracle” supplements are not proven to be effective because of the lack of evidence as well as the unreasonable dietary expectations given to patients with ME/CFS.
Recently, a few studies have discovered a select few dietary supplements that display positive effects on patients with ME/CFS.  For example, lactic acid producing bacteria, like those found in yogurt, have recently been found to have positive effects on symptoms associated with ME/CFS.  One of the many possible causes of ME/CFS includes disturbances in both the intestinal bacterial flora as well as the flora of the immune system of the patient.  Treatments of lactic acid producing bacteria have been proven to “prevent and alleviate gastrointestinal disturbances and to normalize the cytokine profile which might be of an advantage for patients suffering from chronic fatigue syndrome” (Sullivan et. al, 2009).  The study showed that some patients exhibited improvement in both physical and neurocognitive function after a regimen of bacterial flora.  However, some patients showed no improvement through bacterial yogurt therapy.  It appears that “improvement of health is possible to achieve and should encourage further studies with interventions with probiotics in patients with CFS” (Sullivan et. al, 2009).  The future of research in this method of treatment will aim to identify those patients with ME/CFS who will respond to dietary therapy such as this. Dietary therapy appears promising for treatment but it is important to remember that not every patient will respond to the method.
Cognitive behavior therapy (CBT) has been shown to benefit patients with ME/CFS. CBT is a type of psychotherapeutic therapy intended to affect patients’ conscious emotions, behaviors, and attitudes. It requires instructing the patient extensively about ME/CFS, then focusing on effectively coping with the illness. It promotes actively combating the condition rather than inactivity. Studies have shown that any recommendation “to chronic patients to avoid physical and mental activity is counterproductive” (Butler et. al, 1991). It is important to note that “[CBT] for chronic fatigue syndrome can produce some lasting benefits but is not a cure” (Deale et. al, 2001). Patients who received CBT compared to control groups (no therapy) showed many improvements spanning multiple aspects of life. Improvements were seen as a “decline in functional disability correlated with a decrease in mood and anxiety related symptoms and also somatic symptoms” (Butler et. al, 1991).
CBT has also been proven to be more effective than other types of psychotherapy. For example, a study in 2001 concluded “CBT was more effective than guided support groups and the natural course” (Prins et. al, 2001) in over 250 patients. The positive outcomes were seen in both functional impairment as well as fatigue severity categories. Also, CBT has been shown to be more productive than relaxation therapy. Patients with ME/CFS “receiving CBT, in relation to those in relaxation therapy, experienced symptoms that had steadily improved or were consistently mild or absent since treatment ended” (Deale et. al, 2001). Furthermore, these same patients in CBT were working more hours per week than those receiving relaxation therapy. The evidence shows that CBT is a valuable method for combating the symptoms associated with ME/CFS and is more beneficial than other types of psychotherapy.
Conclusion:
In conclusion, ME/CFS is a very complicated disorder that is not well understood.  Its etiology is largely unknown and there are no universally approved treatments that are proven to work.  It is extremely important for primary care physicians to accept that this is a true condition affecting a significant portion of the population.  ME/CFS has physical, cognitive, and psychological effects.  In order to properly diagnose ME/CFS, one has to first eliminate all other possibilities that could display similar symptoms.  Once this has been accomplished, it becomes more important to treat the patient’s precise set of symptoms rather than focusing on a standardized form of treatment.  This individualized “patient-centered medicine” approach will allow a more thorough and precise method of treatment designed to specifically alleviate the patient’s symptoms instead of a generalized list of symptoms commonly associated with ME/CFS.  This individualized and dedicated approach has been shown to improve patients with ME/CFS partly through the extra attention and focus provided by physicians.  It allows patients to shift their focus from their debilitating condition and associated symptoms to a more positive and determined mindset focused on a specific goal or routine.
If nothing else, ME/CFS reminds physicians of the importance of the patient in medicine.  Too often physicians focus on treating an illness instead of treating the patient.  The most effective way to treat ME/CFS is to treat the patient individually. Only through this focused method will symptoms be most effectively reduced.

Jason M Habeck
University of Wisconsin School of Medicine and Public Health

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