Eleanor Stein MD FRCP(C)
Assessment and Treatment of Patients with ME/CFS: Clinical Guidelines for Psychiatrists
Table of Content
1. Abstract
2. What is ME/CFS?
2.1 Clinical Variability
2.2 Comorbidity
2.3 Prevalence
2.4 Etiology
3. ME/CFS is NOT a Psychiatric Disorder
3.1 Rates of Psychiatric Disorder in CFS Are Similar to Rates in Other Chronic Medical Conditions
3.2 Rates of Personality Disorder in ME/CFS Are Not Elevated
3.3 Genetics of Depression and ME/CFS Are Independent
3.4 Physiological Measures Between ME/CFS and Depression Differ
3.5 Illness Severity and Not Psychological Factors Predict Outcome
4. Diagnosing and Treating Depression
4.1 Four Types of Affective Disorder Commonly Seen in ME/CFS
4.2 Diagnosing Major Depression in the Presence of ME/CFS
5. Diagnosing and Treating Anxiety
5.1 Four Types of Anxiety Commonly Seen in ME/CFS
5.2 Diagnosing Generalized Anxiety Disorder in the Presence of ME/CFS
6. Psychological Issues
6.1 Grief
6.2 Coping
6.3 Empowerment
6.4 Stress Management
7. Special Classes: Children and Adolescents
8. Treatment Issues
8.1 Drug Dosage and Drug Sensitivity
8.2 Utility of CBT/Graded Exercise in ME/CFS
9. Conclusion
Acknowledgements
References
1. Abstract
This paper will:
Define ME/CFS
Explain why ME/CFS is not a psychiatric disorder despite that a significant subgroup of patients have psychiatric diagnoses.
Outline how to differentiate the symptoms of ME/CFS from those of depression and anxiety.
Suggest a treatment approach for common psychiatric symptoms in patients with ME/CFS.
Summarize psychological treatment issues in patients with ME/CFS.
Explain issues relevant to children and adolescents with ME/CFS.
Discuss the treatment issues of drug sensitivity and the utility of Cognitive Behavior Therapy and Graded Exercise in patients with ME/CFS.
2. What Is ME/CFS?
Myalgic Encephalomyelitis (ME) was first defined by Acheson in 1959 based on 14 docu- mented outbreaks in several countries and hundreds of sporadic cases of illness charac- terized by: headache, myalgia, paresis, mental symptoms, low or absent fever and no mortality (Acheson, 1959). This was in contrast to polio and other paralyzing conditions prevalent at the time. The disorder was later operationalized by Ramsay to include the triad of: muscle weakness and fatigability, CNS involvement and symptom fluctuation. In early reports, lability of emotions was an almost constant feature ranging from slight irri- tability to violent manifestations.
In 1988 after an outbreak at Incline Village Nevada, the CDC formed a committee that named the disorder “Chronic Fatigue Syndrome” and suggested criteria for a research definition (Holmes et al, 1988). These criteria were found clinically problemat- ic and in 1994 the CDC revised their definition publishing what is commonly referred to as the “Fukuda criteria” (Fukuda et al, 1994). The 1994 definition requires fewer physi- cal signs than the 1988 definition and therefore selects less severely ill patients (De Becker et al, 2001). The Fukuda criteria require only one mandatory symptom: disabling fatigue of greater than 6 months duration. In addition there must be at least 4 of: impaired memory/concentration, sore throat, tender lymph nodes, muscle pain, multi- joint pain, new headache, unrefreshing sleep and post-exertional fatigue. This definition lacks specificity because common symptoms such as autonomic and endocrine symptoms were not included. The Fukuda criteria have also been criticized for not requiring muscle fatigability as mandatory. Muscle fatigue is necessary for the diagnosis of ME.
Cooperation between the National ME-FM Action Network of Canada and Health Canada resulted in the 2003 publication of what is referred to as the “Canadian Consensus Guidelines for ME/CFS” (Carruthers et al, 2003). The Guidelines describe a clinical case definition, clinical evaluation, prognosis, occupational disability and treat- ment protocol for patients with ME/CFS. The full document may be viewed at:
http://www.mefmaction.net/documents/journal.pdf. The Canadian Consensus definition requires the concurrent presence for at least 6 months of five major criteria: disabling fatigue, post exertional malaise and/or fatigue, sleep dysfunction, pain and two or more neurological/cognitive symptoms. In addition there must be two of: autonomic, neu- roendocrine and immune manifestations (Carruthers et al, 2003). The inclusion of auto- nomic, neuroendocrine and immune symptoms as minor criteria seems to increase speci- ficity as this definition selects fewer patients with psychiatric disorder and more patients with severe physical symptoms than the Fukuda criteria (Jason et al, 2005).
There are two other definitions in the literature: the Oxford Criteria (Sharpe et al, 1991) and the Australian Criteria (Lloyd et al, 1990). Both of these are so broad as to make it impossible to ensure a homogeneous group. Both fail to exclude patients with primary psychiatric diagnoses in the absence of physical symptoms. Neither are often used in research.
Patients who suffer from symptoms consistent with CFS dislike the name because it trivializes the severe, incapacitating mental and muscle fatigue that is experienced. Though ME and CFS differ in definition, many groups including the group of international researchers who published the Canadian Guidelines refer to the disorder as: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) encompassing patients with both epidemic and sporadic onsets and patients with mild to extremely severe symptoms. The term ME/CFS will be used in this paper.
2.1 Clinical Variability
The clinical profile of ME/CFS is of unremitting and fluctuating mental and physical fatigue, non restorative sleep, cognitive dysfunction and other symptoms. The severity can be
mild - still able to work/study full time though with effort and rest on weekends,
moderate - able to work or study part time with effort,
severe - unable to work/study and requires assistance to live independently,
extreme – unable to live independently, virtually house and sometimes bedbound.
The course of ME/CFS is variable. The hallmark feature of the disease is debilitat- ing physical and cognitive malaise and/or fatigue and worsening of other symptoms fol- lowing exertion which show prolonged reactive exacerbations following activities.
2.2 Comorbidity
In the largest epidemiological study to date, it was shown by Jason and colleagues in Chicago that only 40% of the community CFS cohort had pure CFS (Jason et al, 1999). 15.6% of the cohort also had Fibromyalgia Syndrome (FM), a disorder of chronic gener- alized muscle pain and joint stiffness with the presence on physical exam of at least 11/18 designated tender points. Forty-one percent had Multiple Chemical Sensitivity (MCS), a disorder defined as a chronic condition with symptoms that recur reproducibly in response to low levels of exposure to multiple unrelated chemicals. The symptoms improve or resolve when the incitants are removed. The symptoms of ME/CFS occur in multiple organ systems and no other disorder can account for the symptoms (1999). The disabil- ity found in patients with ME/CFS is often aggravated by the comorbidity of ME/CFS with FM and MCS as well as other medical and psychiatric disorders if present. A full history must be taken to identify all of the symptoms which impact on function and health.
2.3 Prevalence
The prevalence of CFS in population based epidemiological studies using the Fukuda cri- teria is 0.24 - 0.42% (Reyes et al, 2003) (Jason et al, 1999). This means that in Canada there are approximately 125,000 people meeting the CDC criteria for CFS. Based on American estimates, the annual lost productivity is $20,000 per person. In Canada annual lost productivity is estimated at $2.5 billion (Reynolds et al, 2004). This is a huge bur- den on the economy and suggests that more research funding should be directed towards understanding the prevention, diagnosis and management of ME/CFS.
2.4 Etiology
Despite 20 years of research and over 3000 published peer reviewed papers, the etiolo- gy of ME/CFS remains unclear. It is now generally accepted that ME/CFS is an umbrella term for a heterogeneous group of disorders and that one etiology or mechanism may not be found. This has led for a call for careful subtyping using known correlates if future research (Jason et al, 2005).
Nevertheless, certain abnormalities are consistently reported. These include: autonomic nervous system dysfunction using the objective measure of heart rate vari- ability (Cordero et al, 1996) or tilt table testing (Rowe & Calkins, 1998). Several studies have shown deficiency in natural killer cell function (Whiteside & Friberg, 1998;Ogawa et al, 1998) in ME/CFS.
Studies of cytokine profiles have generally suggested a Th1 to Th2 shift. Th1 is the aspect of the immune system that controls intracellular infection. An intriguing finding is that of increased levels of 37 kDa RNase L in patients with ME/CFS but not in healthy controls or patients with depression (Suhadolnik et al, 2004;Suhadolnik et al, 1994;2002). This is an abnormal variant of the enzyme normally produced by cells to kill RNA viruses. This variant is not found in healthy people and is not subject to the normal cellular control mechanisms. Further supporting relevance to clinical presentation is that 37 kDa Rnase L levels correlate with exercise capacity in patients with ME/CFS (Snell et al, 2002).
Many intracellular infections have been shown to be more prevalent in ME/CFS compared with healthy controls. These include the Human Herpes viruses: EBV (Lerner et al, 2004), CMV (Lerner et al, 2004), HHV6 (Ablashi et al, 2000) and HHV7. Other intra- cellular pathogens including: mycoplasma (Choppa et al, 1998), chlamydia (Nicolson et al, 2003) and coxiella (Wildman et al, 2002) (Ayres et al, 1998)have also consistently been found in high proportions. Finding so many intracellular infections suggests that the infections are secondary to an immune dysfunction. Cognitive function (DeLuca et al, 1997;Michiels et al, 1999;Tiersky et al, 2003), brain blood flow on SPECT (Ichise et al, 1992;Costa et al, 1995;Fischler et al, 1996) and quantitative EEG are all abnormal (Flor- Henry et al, 2003). Hormonal studies show hypo function at the level of the hypothala- mus. It has recently been suggested that this may be secondary to chronic illness rather than causative (Cleare, 2004).
3. ME/CFS Is NOT a Psychiatric Disorder
The first question in the minds of many psychiatrists will be whether ME/CFS is a psy- chiatric disorder. If so why isn’t it in the DSM? If not why are guidelines being written for psychiatrists?
The research is increasingly clear that CFS is not a primary psychiatric disorder though psychiatric symptoms may be prominent, The World Health Organization has classified ME/CFS as a neurological disorder. Early hypotheses of psychological causation such as the quote below by Abbey and Garfinkel have been countered by growing research showing biological correlates of ME/CFS not found in depression or any other psychiatric disorder. They stated: “majority of its sufferers are experiencing primary psy- chiatric disorders or psychophysiological reactions and that the disorder is often a cultur- ally sanctioned form of illness behavior” (Abbey & Garfinkel, 1991).
3.1 Rates of Psychiatric Disorder in CFS Are Similar to Rates in Other Chronic Medical Conditions
If ME/CFS were a psychiatric disorder, psychiatric symptoms should be universal. However when the stricter Fukuda criteria are used for patient selection, the prevalence of known psychiatric disorders among patients with ME/CFS is similar to the rates in patients with other chronic, disabling medical conditions such as rheumatoid arthritis; approximately 30 - 40% (Thieme et al, 2004;Hickie et al, 1990;Fiedler et al, 1996). Jason’s recent comparison study of the Canadian and Fukuda criteria for ME/CFS indi- cated that the Canadian criteria selected patients who were more physically ill, had greater physical functional impairment, greater fatigue/weakness, and more neurocog- nitive, neurological and cardiopulmonary abnormalities, and less current or lifetime psy- chiatric impairment (Jason et al, 2004). This adds to the evidence that diagnostic crite- ria influence patient selection. Studies which have reported higher prevalence rates of psychiatric disorder have had sampling biases eg. selecting those who seek treatment at specialty centers or use of inappropriate survey instruments (Thieme et al, 2004). Jason has shown that the type of questionnaire used in a study can significantly affect the prevalence (50% using the DIS vs 25% using the SCID) of psychiatric disorders reported in ME/CFS populations (Jason et al, 2003). For research purposes the Structured Clincial Interview for DSMIV developed by Spitzer et al is recommended in ME/CFS studies (Spitzer et al, 1992;Williams et al, 1992).
3.2 Rates of Personality Disorder in ME/CFS Are Not Elevated
If ME/CFS were a psychiatric disorder one would expect that rates of personality disor- der would be elevated as they are in psychiatric samples. However people with CFS have similar rates of personality disorder (approx 10%) as the general population and lower rates that that found in depression (Thieme et al, 2004) (Pepper et al, 1993;Saltzstein et al, 1998;Chubb et al, 1999). There are studies which report higher rates of psychological distress using the MMPI (Blakely et al, 1991) in CFS as compared with healthy controls however it has been argued that the MMPI is not an accurate assessment in people with chronic medical conditions because the items were derived and normed based with physical healthy subjects. When used in cohorts with chronic illness, the physical symptoms load to the “hyperchondriasis” and “hysteria” scales resulting in false positives (Pincus et al, 1986;Goldenberg, 1989).
Despite the preponderance of research to the contrary, a group of primarily British psychiatrists continue to publish that ME/CFS is caused and exacerbated by faulty self- perception and avoidance behavior. The faulty beliefs are described as: ”the belief that one has a serious disease; the expectation that one's condition is likely to worsen; the "sick role," including the effects of litigation and compensation; and the alarming por- trayal of the condition as catastrophic and disabling” (Barsky & Borus, 1999). It should be noted that neither this paper written by Barsky nor any of the others with similar views are evidence based, they are the personal opinions of the authors.
3.3 Genetics of Depression and ME/CFS Are Independent
The genetics of CFS vary independently from those of depression suggesting that the two disorders do not have a similar genetic risk (Thieme et al, 2004) (Hickie et al, 1999).
3.4 Physiological Measures Between ME/CFS and Depression Differ
In depression the hypothalamic-pituitary-adrenal axis is stimulated and difficult to sup- press with dexamethasone, whereas the opposite is true in ME/CFS. Urinary cortisol levels are low, serum cortisol levels decrease sharply and for long periods of time with oral dexamethasone (Scott & Dinan, 1998). It is unclear whether these changes in hypothalamic-pituitary-adrenal axis function are primary or secondary(Cleare, 2004). Electrodermal skin response and digital skin temperature are different in ME/CFS than in depression Pazderka-Robinson et al, 2004. Quantitative EEG profiles discriminate between ME/CFS, depression and healthy controls (Flor-Henry et al, 2003).
3.5 Illness Severity and Not Psychological Factors Predict Outcome
If ME/CFS were a psychiatric disorder, one would expect psychological symptoms to predict outcome. However this is not the case. Studies consistently show that symp- tom severity at onset and whether one meets full criteria for CFS predict prognosis in ME/CFS (Darbishire et al, 2005) but psychological symptoms and cognitive beliefs do not (Deale et al, 1998;Jones et al, 2004a). (Darbishire et al, 2005;White et al, 1998)
As the research data builds that ME/CFS is in fact a serious, often disabling condi- tion, the abandonment of the psychological model or primary causation is understand- able. As the following data show, psychiatric disorder in ME/CFS is most often secondary to the loss of health, lifestyle, social role and financial means as well as the social stigma of having a serious disabling but poorly understood illness.
4. Diagnosing and Treating Depression
4.1 Four Types of Affective Disorder Commonly Seen in ME/CFS
1. Reactive grief due to loss of health, social connections, family support, financial capability, career and uncertainty re all of these
2. Biological change in mood/cognition as part of the disorder of ME/CFS (similar to mood change in MS or Parkinson’s disease and as reported in epidemic ME)
3. Comorbid depressive disorder
4. Mood change due to medication or food or withdrawal from either
Consider a diagnosis of comorbid depression when:
The depressive symptoms predated the physical disorder
Pessimism is generalized beyond health and illness related issues
The patient is stuck in depression and it is having a negative effect on treatment.
Teaching the patient careful self observation skills and using daily ratings of mood and other symptoms can help distinguish patients whose mood problems are biological and associated with ME/CFS and other types of mood changes. Biological mood changes vary in parallel with physical symptoms, while other types of mood problems are more independent. Ask the patient: “does it ever happen that you are having a good day with respect to energy but a bad day with respect to mood”. If the patient says “yes” then the mood disorder is independent of the ME/CFS. If the answer is “no” the conditions covary and the depression is likely a biological concomitant of ME/CFS
4.2 Diagnosing Major Depression in the Presence of ME/CFS (Must tick all four boxes for diagnosis)
Does the subject currently have:
- 5 or more of following symptoms:
depressed mood (sad or empty) most of the day nearly every day
decreased interest or pleasure in most activities nearly all the time
significant (>5% change) weight loss or weight gain not due to dieting and/or change in appetite (up or down)
insomnia or hypersomnia nearly every day
objective (notable by others) psychomotor agitation/retardation nearly all the time fatigue or loss of energy nearly every day
feelings of worthlessness or excessive guilt nearly every day
decreased ability to think or concentrate or indecisiveness nearly every day
Duration of > 2 weeks
Level of functioning decreased from before
Must have either
depressed mood or
loss of interest or pleasure
The last point should prevent patients with physical symptoms only being classi- fied as depressed. According to DSM IV if the subject has physical symptoms only i.e. items 3,4,5,6,8 only the diagnosis of depression cannot be made. If the subject has symptoms 3,4,5,6,8 AND has items 1,2 or 7 then the criteria are met.
The following chart identifies some of the keys in differentiating ME/CFS from Depression. Of course none of these area globally true. There are always exceptions.
CFS
- Clinical Presentation
- Infectious onset in > 80% of cases Fatigue is necessary for diagnosis
- Muscle and/or joint pain and significant headaches
- Diurnal variation with pm the worst time of day
- Orthostatic intolerance, tachycardia and other autonomic dysfunctions are common (Rowe & Calkins, 1998)
- Immune manifestations including tender lymph nodes, sore throat, chemical and food sensitivities
- Loss of body thermostatic stability, intoler- ance to extremes of temperature
- Fatigue worsened by physical or mental exertion (Blackwood et al, 1998b)
- Decreased positive affect (energy, enthusiasm, happiness)
- Children have a better prognosis than adults
DEPRESSION
- Rarely follows infectious illness
- Mood change is necessary for diagnosis
- Not usually associated with pain symptoms
- Diurnal variation with am the worst time of day
- No association with autonomic symptoms
- No association with immune symptoms
- No association with thermostatic instability
- Fatigue and mood improve with exercise
- Increased negative affect (apathy, hoplessness, suicidal ideation, self reproach)
- Children have a worse prognosis than adults
Additional Pointers
The sine qua non of clinical depression is a persistent low or irritable mood and anhedonia, guilt or self blame
The sine qua non of CFS is severe, prolonged fatigue post-exertional malaise, sleep dysfunction, pain, neurological/cognitive, autonomic, neuroendocrine and immune manifestations.
Ask which activities the patient enjoys when s/he feels well or better. If s/he can’t think of anything, consider depression.
Those who think of ME/CFS as “fatigue” and forget the importance of the other symp- toms will be risk of misdiagnosing patients with depression leading to inappropriate treatment recommendations.
Management of Depressive Reactions to ME/CFS and its Effects
The best antidepressant for patients with ME/CFS is improved physical health & quali- ty of life.
Validation by physician of life circumstances is NB.
Ask about suicidal ideation. Anecdotally, suicide is the #1 cause of death in CFS
Supportive counseling/therapy regarding career, peer group and family issues. Lack
of social support is reported in patients with ME/CFS and lack of social support is cor-
related with poorer quality of life (Schoofs et al, 2004).
Active support of patient obtaining sustainable school/work conditions or leave of
absence from school or work, disability insurance, etc.
Treatment of Comorbid Depression in CFS
Treat similarly to depression in the absence of CFS
No antidepressant has been shown to improve the core symptoms of ME/CFS (White
& Cleary, 1997;Vercoulen et al, 1996)
Low dose tricyclics are often useful for sleep rehabilitation and pain management but
rarely have antidepressant effect.
Psychotropic medication may be tried if symptoms are interfering with sleep and
rehabilitation
Antidepressant doses usually need to be lower that in other patients. Some patients
will be unable to tolerate any antidepressant
CBT to help a patient with unrealistic assumptions cope can be helpful
CBT to convince a patient that s/he does not have a physical disorder is disrespectful
and inappropriate.
5. Diagnosing and Treating Anxiety
5.1 Four Types of Anxiety Commonly Seen in ME/CFS
1. Anxiety about health e.g. prognosis, cause of symptoms or unpredictability of symp- toms
2. Anxiety as a result of the impact of having ME/CFS e.g. loss of social connections, loss of family support, financial hardship, loss of career. Anxiety about being denied disability payments is common.
3. Biological anxiety as part of the physical disorder of ME/CFS
4. Comorbid anxiety disorder; GAD and social anxiety being the most common
5. In the proportion of patients with ME/CFS who also have Multiple Chemical
Sensitivity, anxiety can be in reaction to drug or volatile organic exposure or fear of such exposures.
Consider comorbid anxiety disorder when:
Anxiety predated the physical disorder
Anxiety is generalized and not limited to health and health care related issues Patient is unable to cope with or resolve anxiety over the long term
5.2 Diagnosing Generalized Anxiety Disorder in the Presence of ME/CFS (must tick all 6 boxes for diagnosis)
Does the subject have:
Excessive worry on most days (about many things, not just illness Duration > 6 months
Difficulty controlling worry
Must have 3 or more of the following symptoms:
feeling restless or keyed up
easily fatigued
difficulty concentrating/mind going blank
irritability
muscle tension
sleep disturbance (difficulty falling asleep or unrefreshing sleep)
Symptoms cause clinically significant distress/impairment
Symptoms are NOT due to direct physiological effects of a medical condition (eg. ME/CFS)
Most subjects with ME/CFS will have 3 or more of the physical symptoms of GAD and many are worried about their health and related problems. However most will not be excessively worried about life every day and/or have difficulty controlling their worry. Therefore the necessary inclusion of items 1, 3 and 6 differentiates ME/CFS patients from psychiatric cases.
Management of Anxiety Reactions to ME/CFS and its Effects
Validation of ME/CFS diagnosis by physician is therapeutic.
Spend time listening to patient’s worries and explaining why certain diagnoses may or
may not be relevant.
Undertake appropriate investigation and referral to rule out feared diagnoses such as
cancer, MS or heart disease.
The best antidote to anxiety is improvement in physical health.
Institute appropriate management e.g. ensuring adequate sleep, adequate diet, ade-
quate rest, treatment of other syndrome components such as postural hypotension, tachycardia, reactive hypoglycemia, irritable bladder and bowel which can be very anxiety provoking.
Offer supportive counseling/therapy regarding career, peer group and family.
Offer active support of patient obtaining sustainable school/work conditions or leave
of absence from school or work, disability, insurance etc.
Treatment of Comorbid Anxiety Disorder in CFS
Treat similarly to anxiety in the absence of CFS
CBT to help patient cope with unrealistic fears can be helpful; CBT to convince patient
that s/he does not have a physical disorder is disrespectful and inappropriate
Patient’s energy level, cognitive dysfunction and sensitivity to medication must be
taken into account.
Psychotropic medication may be required to ensure sleep and prevent excess energy
drain.
Use low doses of SSRI's and avoid benzodiazepines if at all possible.
Benzodiazapines are useful in patients who have anxiety as well as movement disor-
ders such as restless legs syndrome.
6. Psychological Issues
6.1 Grief
Grief is a universal issue for people with ME/CFS. The losses are numerous and individ- ual. People should be asked about how their lives have changed since becoming ill and be given a chance to describe the process of adjustment. Primary losses are of finan- cial independence, in some cases physical independence, role in family, role as a worker and bread winner, loss of support from family and friends who do not understand the illness and loss of self esteem from all of the above.
6.2 Coping
Patricia Fennell describes four phases of coping with chronic illness: Her model is used widely by therapists working with patients with ME/CFS. Fennell stresses that the four phases are not followed in linear fashion and that people move between phases and aspects of more than one phase may be evident at one time. Given the fluctuant nature of ME/CFS there are always new challenges and maintaining a “phase 4” position is not a realistic goal. The goal is to be flexible enough to adapt to the significant changes imposed by chronic illness with ME/CFS.
PHASE 1: CRISIS
This occurs whether onset is sudden or gradual. Crisis develops when one’s values, self concept, and life goals are called into question i.e. you are too sick to function as you used to. The action goal of phase one is to batten down the hatches, take stock of resources, adjust expenditure and try to minimize immediate pain. A tool of phase one is to begin a personal narrative. The spiritual goal of phase one is to learn to allow one’s suffering.
PHASE 2: STABILIZATION
One reaches phase two when one’s physical condition has stabilized somewhat due to the lifestyle changes one has made. However people in phase 2 continue to think they can function as they used to and continue to overestimate their personal resources. They have relapses as a result. The action goal of phase two is to focus on what one really needs. The tools of phase two are learning, restructuring and educating others. The spiritual goal of phase two is to learn to regard your suffering with compassion.
PHASE 3: RESOLUTION
The work of Phase 3 is grief work, the challenge to obtain insight and develop meaning in the face of huge losses. In phase three patients are becoming more self reliant and self trusting with regard to health decisions. Humor and play become possible again. The action goal of phase three is to stand for oneself without apology. The spiritual goal of phase three is to meet one’s suffering with respect.
PHASE 4: INTEGRATION
Becoming more than one’s illness frees up emotional energy for other meaningful tasks and interactions. One begins to connect the personal to the world view and embrace the mystery and unknown of life. The spiritual goal of phase four is to integrate your suffering into a whole life.
6.3 Empowerment
AS in all chronic medical conditions, long term health status for patients with ME/CFS depends upon patients learning to observe and trust their body’s reactions to psycho- logical and physical stressors, experiment to see what works best for them and then make changes accordingly. Self management is accepted as the most cost effective and successful approach to chronic illness (Lorig et al, 2000) and the Stanford model of self management is widely used. From a psychotherapeutic perspective one can observe a change in emotional status when the patient has the moment of realization that that his/her opinions are as valid as anyone else’s, that s/he is not to blame for his/her dis- order and that s/he has value and rights despite being ill. From that point onwards patients cope better even if their physical condition or life circumstances do not improve.
6.4 Stress Management
One neuroendocrine manifestation of ME/CFS is “loss of adaptability and worsening of symptoms with stress”. This indicates that homeostatic failures occur among patients with ME/CFS. Small physical stressors such as walking up a flight of stairs or being in a cold room can cause exhaustion, pain and other symptoms. Psychological stressors such as interpersonal issues which were easily managed before becoming ill can feel monumental. In part this reaction may be due to the stress of altered lifestyle, occupa- tional, and financial circumstances over which the patient has little control and which may not be easily resolved. Many problems in life can be solved by more effort or more money and patients with ME/CFS cannot increase either sufficiently to manage ordinary stressors. The need for basic stress management skills becomes greater than for healthy people who have more reserve capacity.
Prioritize energy for solving problems that are solvable and put aside worries about things that cannot be changed.
Use written reminders for tasks and messages to avoid confusion and errors.
Listen to your body and pace activities according to the body’s feedback rather than a
predetermined schedule or activity goal.
Plan rest days between appointments and visits if necessary
Enlist the support of friends and family when needs can be foreseen. Believe in oneself and use self talk to get through hard times.
Note and address thought patterns which are counterproductive.
7. Special Cases: Children and Adolescents
CHILDREN and adolescents do get ME/CFS though the prevalence is lower than in adults (Jones et al, 2004b;Patel et al, 2003;Bell et al, 2001). In young people the onset is typically acute and infectious and the symptoms severe however, as with adults, the onset can be gradual and difficult to diagnose. If children complain of severe pain and fatigue they should be believed rather than assuming that children could not possibly be that ill without objective physical signs or test results. An unfortunate consequence of disbelief by health care professionals is that supportive parents are assumed to be facilitating the child’s avoidance and children have been removed from their families due to assumed medical neglect (Hammond, 1999). This iatrogenic trauma should be avoided.
If managed carefully, the outcome is better for young people with ME/CFS than for adults. Many young patients with ME/CFS are too ill to attend school full time or even part time. Some are limited by mental and physical fatigue, some by pain, some by cog- nitive dysfunction, some by sensory overload, many by a combination of these. Pushing through the symptoms often leads to worsening of symptoms and a longer recovery time. In general if a child is not able to recover from a day’s activity by the next day it will not be sustainable.
Children are less able than adults to describe their symptoms and reactions to tri- als and are more vulnerable to outside pressures. In the absence of obvious secondary gain, children and adolescents with ME/CFS should be encouraged to develop self man- agement skills as appropriate for their developmental age. Just as adults may need work accommodation, children and adolescents may need accommodation at school such as reduced school hours, a quiet place to work and extended time to finish courses and exams. Cognitive dysfunction may be severe and school performance often deteriorates.
8. Treatment Issues
8.1 Drug Dosage and Drug Sensitivity
It is widely accepted that some patients with ME/CFS are more sensitive to the adverse effects of medication than most healthy people. They share this trait with chronic pain and fibromyalgia patients. Tricyclic antidepressants for example are useful for sleep maintenance and to decrease central pain sensitivity. However many patients with ME/CFS benefit from and tolerate only very low doses, an average of 10 – 40 mg qhs. Some patients benefit from as little as 2 – 4 mg per dose. SSRIs which are generally well tolerated for the treatment of depression and anxiety are not tolerated by a sub- group of ME/CFS patients. The mechanism of these reactions is unknown. However to push the dose higher in the face of adverse effects in these patients is to court disaster and to weaken the therapeutic relationship. In the case of severe and/or persistent adverse effects one must lower the dose, add a low dose of a second agent or change drug class. In some cases drug sensitivity can severely hamper the treatment of the subset of these patients who have psychiatric disorders.
8.2 Utility of CBT/Graded Exercise in ME/CFS
Although Cognitive Behavior Therapy (CBT) is widely recommended for patients with ME/CFS, it is far from clear whether cognitive behavior therapy is helpful for most patients. The rationale for using CBT in ME/CFS is that inaccurate beliefs (that etiology is physical) and ineffective coping (activity avoidance) maintain and perpetuate CFS morbidity (Deale et al, 1997;Sharpe et al, 1996). However, it has never been proven that these illness beliefs contribute to morbidity in CFS.
Where correlations do exist it is possible, even likely, that beliefs in physical etiology are correct and that activity avoidance is necessary for the more severely ill (Lloyd et al, 1993;Ray et al, 1995).
Of the 6 reported studies using CBT in “ME/CFS” two selected patients as defined by the Oxford (Deale et al, 1997;Sharpe et al, 1996) one using the Australian criteria (Lloyd et al, 1993) and one using the Fukuda criteria “with the exception of the criterion requiring four of eight additional symptoms to be present” (Prins et al, 2001). These methods of patient selection allow for considerable heterogeneity and inclusion of psy- chiatrically ill patients with fatigue. Therefore, the results may not be applicable to the average Fukuda or Canadian defined patient. Of the remaining two studies using valid selection criteria, one found no benefit of CBT (Friedberg & Krupp, 1994). The only study reporting benefit (improved functional capacity and decreased fatigue) was conducted in adolescents (Stulemeijer et al, 2005).
It is important to note that no CBT study has reported that patients have been improved enough to return to work nor have they reported changes in the physical symp- toms of CFS eg. muscle pain, fever, lymphadenopathy, headache or orthostatic intoler- ance. Furthermore, clinical experience suggests that trying to convince a patient with ME/CFS that s/he does not have a physical disorder and should not rest when tired leads to conflict in the doctor-patient relationship and poor outcome for the patients. Therefore it would be prudent to await further research before recommending this CBT approach.
Despite the fact that worsening of symptoms after exercise is a compulsory crite- ria for diagnosis of ME/CFS, graded exercise programs have often prescribed for such patients. Presumably these recommendations are made on the assumption that exercise will be accompanied by improved aerobic capacity, increased anaerobic threshold and improved exercise tolerance. However, in patients with ME/CFS, neither exercise toler- ance nor fitness has been shown to improve with exercise programs. This may be con- nected with abnormal responses to exercise in people with ME/CFS. The resting heart rate of patients is elevated, and maximum oxygen uptake is reduced compared with healthy sedentary controls (Riley et al, 1990;Farquhar et al, 2002;Fulcher & White, 1997;De Becker et al, 2000). SPECT scan brain analysis indicates worsening of hypop- erfusion (Goldstein, 1993) and decreased cerebral blood flow (Peterson et al, 1994) after exercise. Decreased cognition (Blackwood et al, 1998a;LaManca et al, 1998), decreased pain threshold (Whiteside et al, 2004a;Whiteside et al, 2004b) and reduced maximal muscle contraction (Paul et al, 1999) are also reported.
According to the recent Cochrane Collaboration metanalysis (Edmonds et al, 2004) there are five studies on exercise and ME/CFS that are methodologically sound. However three of these studies used the Oxford criteria for patient selection which requiring only fatigue of 6 months duration for diagnosis. One of these excluded patients with sleep dis- rupted sleep (Fulcher & White, 1997) meaning that virtually all patients seen in clinical practice would be excluded. There are two studies using valid diagnostic criteria and both report improved fatigue by self report (Chalder Fatigue Scale) (Wallman et al, 2004;Moss- Morris et al, 2005). Neither of these report follow-ups past 12 weeks. Neither report on core physical symptoms of ME/CFS such as pain, unrefreshing sleep, infective, autonom- ic, neurological or endocrine symptoms. It is unclear whether these findings are applica- ble to severely ill patients as none of these patients are well enough to participate in stud- ies. It will require more study on a broader group of patients, reporting all symptoms to discern if graded exercise affects the core symptoms of ME/CFS.
9. Conclusion
ME/CFS is a multi-systemic potentially disabling medical disorder. Although a gold standard diagnostic test is not available, the medical literature is clear that ME/CFS is not the same as depression or any other psychiatric disorder. It is important to discern whether a patient has ME/CFS, a psychiatric disorder or both. Using the Canadian Criteria (a clinical diagnostic tool), the signs and symptoms of ME/CFS can clearly be distinguished from psychiatric disorders in most cases. Being knowledgable in both physical and psychological medicine, psychiatry plays an important role in the overall management of ME/CFS both for accurate diagnosis, assessment of the patients’ phase of coping and adaptation and for psychotherapeutic support. Self management is criti- cal in the long term outcome for patients with ME/CFS and empowerment facilitates self management. Comorbid psychological symptoms such as depression and anxiety occur in ME/CFS and are often secondary to loss of health, financial means and role in society. When present, psychiatric symptoms should be treated similarly to any other patient while paying attention to the increased incidence of drug side effects in this population and decreased energy available for therapy. Research on psychosocial inter- ventions is in its infancy. While awaiting further research it is important to first do no harm.
Acknowledgements
The author acknowledges the considered and detailed criticism of this paper by: Dr. Bruce Carruthers, Dr. Pierre Flor Henry, Dr. Ellen Goudsmit, Dr. Alan Gurwitt and Ms. Marj van de Sande
The development of this paper was requested by FM-CFS Canada as part of an educational initiative to create free educational materials for the wide range of health practitioners serving FM & ME/CFS patients. FM-CFS Canada extends it deepest appreciation to the authors, reviewers, and in particular, Dr. Eleanor Stein.
For more information, educational resources, and for links to support groups, visit:
FM-CFS Canada: fm-cfs.ca
National ME/FM Action Network:
www.mefmaction.net
References
(1999) Multiple chemical sensitivity: A Consensus. Arch.Environ.Health, 54, 147-149.
(2002) Chronic Fatigue Syndrome: A biological approach, CRC Press, Boca Raton.
Abbey,S.E. & Garfinkel,P.E. (1991) Neurasthenia and chronic fatigue syndrome: the role of culture in the making of a diagnosis. American Journal of Psychiatry, 148, 1638-1646.
Ablashi,D.V., Eastman,H.B., Owen,C.B., Roman,M.M., Friedman,J., Zabriskie,J.B., Peterson,D.L., Pearson,G.R., & Whitman,J.E. (2000) Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. Journal of Clinical Virology, 16, 179-191.
Acheson,E.D. (1959) The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neurasthaenia. JAMA, 26, 569- 595.
Ayres,J.G., Flint,N., Smith,E.G., Tunnicliffe,W.S., Fletcher,T.J., Hammond,K., Ward,D., & Marmion,B.P. (1998) Post-infection fatigue syndrome following Q fever. QJM., 91, 105-123.
Barsky,A.J. & Borus,J.F. (1999) Functional somatic syndromes. Annals of Internal Medicine, 130, 910-921.
Bell,D.S., Jordan,K., & Robinson,M. (2001) Thirteen-year follow-up of children and ado- lescents with chronic fatigue syndrome. Pediatrics, 107, 994-998.
Blackwood,S.K., MacHale,S.M., Power,M.J., Goodwin,G.M., & Lawrie,S.M. (1998a) Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Journal of Neurology, Neurosurgery & Psychiatry, 65, 541-546.
Blackwood,S.K., MacHale,S.M., Power,M.J., Goodwin,G.M., & Lawrie,S.M. (1998b) Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Journal of Neurology, Neurosurgery & Psychiatry, 65, 541-546.
Blakely,A.A., Howard,R.C., Sosich,R.M., Murdoch,J.C., Menkes,D.B., & Spears,G.F. (1991) Psychiatric symptoms, personality and ways of coping in chronic fatigue syndrome. Psychological Medicine, 21, 347-362.
Carruthers,B.M., Jain,A.K., De Meirleir,K., Peterson,D.L., Klimas,N., Lerner,A.M., Bested,A.C., Flor-Henry,P., Joshi,P., Powles,A.C.P., Sherkey,J.A., & van de Sande,M.I. Malgic Encephalitis/Chronic Fatigue Syndrome: Clinical working case definition diagnostic and treatment protocols - A consensus document. Journal of Chronic Fatigue Syndrome 11[1], 7-116. 2003. Ref Type: Journal (Full)
Choppa,P.C., Vojdani,A., Tagle,C., Andrin,R., & Magtoto,L. (1998) Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome. Molecular & Cellular Probes, 12, 301-308.
Chubb,H.L., Sadler,S., Cole,T., Redman,K., & Farmer,A. (1999) Chronic fatigue syndrome- -Personality and attributional style of patients in comparison to healthy controls and depressed individuals. Journal of Mental Health (Uk), 8.
Cleare,A.J. (2004) The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol.Metab, 15, 55-59.
Cordero,D.L., Sisto,S.A., Tapp,W.N., LaManca,J.J., Pareja,J.G., & Natelson,B.H. (1996) Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome. Clinical Autonomic Research , 6, 329-333.
Costa,D.C., Tannock,C., & Brostoff,J. (1995) Brainstem perfusion is impaired in chronic fatigue syndrome. QJM, 88, 767-773.
Darbishire,L., Seed,P., & Ridsdale,L. (2005) Predictors of outcome following treatment for chronic fatigue. Br.J Psychiatry, 186:350-351., 350-351.
De Becker,P., McGregor,N., & De Meirleir,K. (2001) A definition-based analysis of symp- toms in a large cohort of patients with chronic fatigue syndrome. J.Intern.Med., 250, 234-240.
De Becker,P., Roeykens,J., Reynders,M., McGregor,N., & De Meirleir,K. (2000) Exercise capacity in chronic fatigue syndrome. Arch.Intern.Med., 160, 3270-3277.
Deale,A., Chalder,T., Marks,I., & Wessely,S. (1997) Cognitive behavior therapy for chron- ic fatigue syndrome: a randomized controlled trial. American Journal of Psychiatry, 154 , 408-414.
Deale,A., Chalder,T., & Wessely,S. (1998) Illness beliefs and treatment outcome in chronic fatigue syndrome. Journal of Psychosomatic Research, 45, 77-83.
DeLuca,J., Johnson,S.K., Ellis,S.P., & Natelson,B.H. (1997) Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery & Psychiatry, 62, 151-155.
Edmonds,M., McGuire,H., & Price,J. (2004) Exercise therapy for chronic fatigue syn- drome. Cochrane.Database.Syst.Rev., CD003200.
Farquhar,W.B., Hunt,B.E., Taylor,J.A., Darling,S.E., & Freeman,R. (2002) Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue. Am.J.Physiol Heart Circ.Physiol, 282, H66-H71.
Fiedler,N., Kipen,H.M., DeLuca,J., Kelly-McNeil,K., & Natelson,B. (1996) A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome. Psychosomatic Medicine, 58, 38-49.
Fischler,B., D'Haenen,H., Cluydts,R., Michiels,V., Demets,K., Bossuyt,A., Kaufman,L., & De Meirleir,K. (1996) Comparison of 99m Tc HMPAO SPECT scan between chronic fatigue syndrome, major depression and healthy controls: an exploratory study of clinical correlates of regional cerebral blood flow. Neuropsychobiology, 34, 175- 183.
Flor-Henry,P., Lind,J., Morrison,J., Pazderka-Robinson,H.R., & Koles,Z. (2003) Psychophysiological and EEG findings in chronic fatigue syndrome. (Abstract).Klinishe Neurophysiologie, 36, 46-65.
Friedberg,F. & Krupp,L.B. (1994) A comparison of cognitive behavioral treatment for chronic fatigue syndrome and primary depression. Clinical Infectious Diseases, 18 Suppl 1, S105-S110.
Fukuda,K., Straus,S.E., Hickie,I., Sharpe,M.C., Dobbins,J.G., Komaroff,A., & International Chronic Fatigue Syndrome Study Group (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953-959.
Fulcher,K.Y. & White,P.D. (1997) Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ, 314, 1647-1652.
Goldenberg,D.L. (1989) Psychological symptoms and psychiatric diagnosis in patients with fibromyalgia. J.Rheumatol.Suppl, 19:127-30., 127-130.
Goldstein,J. (1993) Chronic Fatigue Syndrome: The Limbic Hypothesis, Howarth Medical Press.
Hammond,P. Sick girl seized from mother in medical row. Courier Mail . 3-5-1999. Brisbane. Ref Type: Newspaper
Hickie,I., Kirk,K., & Martin,N. (1999) Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychological Medicine, 29, 259-268.
Hickie,I., Lloyd,A., Wakefield,D., & Parker,G. (1990) The psychiatric status of patients with the chronic fatigue syndrome. British Journal of Psychiatry, 156, 534-540.
Holmes,G.P., Kaplan,J.E., Gantz,N.M., Komaroff,A.L., Schonberger,L.B., Straus,S.E., Jones,J.F., Dubois,R.E., Cunningham-Rundles,C., & Pahwa,S. (1988) Chronic fatigue syndrome: a working case definition. Annals of Internal Medicine, 108, 387-389.
Ichise,M., Salit,I.E., Abbey,S.E., Chung,D.G., Gray,B., Kirsh,J.C., & Freedman,M. (1992) Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nuclear Medicine Communications, 13, 767-772.
Jason,L.A., Corradi,K., Torres-Harding,S., Taylor,R.R., & King,C. (2005) Chronic Fatigue Syndrome: The need for subtypes. Neuropsychology Review, 15, 29-58.
Jason,L.A., Helgerson,J., Torres-Harding,S.R., Carrico,A.W., & Taylor,R.R. (2003) Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. Eval.Health Prof., 26, 3-22.
Jason,L.A., Richman,J.A., Rademaker,F., Jordan,K.M., Plioplys,A.V., Taylor,R.R., McCready,W.C.-F.H., & Plioplys,S. (1999) A community-based study of chronic fatigue syndrome. Archives of Internal Medicine , 159.
Jason,L.A., Torres-Harding,S., Jurgens,A., & Helgerson,J. (2004) Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome, 12, 37-52.
Jones,J., Hickie,I., Wakefield,D., Davenport,T.A., Vollmer-Conna,U., & Lloyd,A. (2004a) The Dubbo INfgection Outcomes Study: Post-infective Fatigue as a model for CFS.
Jones,J.F., Nisenbaum,R., Solomon,L., Reyes,M., & Reeves,W.C. (2004b) Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a population-based study. J Adolesc.Health, 35, 34-40.
LaManca,J.J., Sisto,S.A., DeLuca,J., Johnson,S.K., Lange,G., Pareja,J., Cook,S., & Natelson,B.H. (1998) Influence of exhaustive treadmill exercise on cognitive func- tioning in chronic fatigue syndrome. American Journal of Medicine, 105, 59S-65S.
Lerner,A.M., Beqaj,S.H., Deeter,R.G., & Fitzgerald,J.T. (2004) IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo, 18, 101-106.
Lloyd,A., Hickie,I., Brockman,A., Hickie,C., Wilson,A., Dryer,J., & Wakefield,D. (1993) Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double blind, placebo controlled trial. American Journal of Medicine, 94, 197- 203.
Lloyd,A., Hickie,I., Wakefield,D., Boughton,C., & Dwyer,J. (1990) A double-blind, place- bo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome [see comments]. American Journal of Medicine, 89, 561-568.
Lorig,K., Halsted,H., Sobel,D., Laurent,D., Gonzalez,V., & Minor,M. (2000) Living a Healthy Life with Chronic Conditions, 2nd edn, Bull Publishing, Boulder CO.
Michiels,V., de,G., V, Cluydts,R., & Fischler,B. (1999) Attention and information process- ing efficiency in patients with Chronic Fatigue Syndrome. Journal of Clinical & Experimental Neuropsychology, 21, 709-729.
Moss-Morris,R., Sharon,C., Tobin,R., & Baldi,J.C. (2005) A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J.Health Psychol., 10, 245-259.
Nicolson,G.L., Gan,R., & Haier,J. (2003) Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS, 111, 557-566.
Ogawa,M., Nishiura,T., Yoshimura,M., Horikawa,Y., Yoshida,H., Okajima,Y., Matsumura,I., Ishikawa,J., Nakao,H., Tomiyama,Y., Kanayama,Y., Kanakura,Y., & Matsuzawa,Y. (1998) Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome. Eur.J Clin.Invest, 28, 937-943.
Patel,M.X., Smith,D.G., Chalder,T., & Wessely,S. (2003) Chronic fatigue syndrome in chil- dren: a cross sectional survey. Arch.Dis.Child, 88, 894-898.
Paul,L., Wood,L., Behan,W.M., & Maclaren,W.M. (1999) Demonstration of delayed recov- ery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology, 6, 63-69.
Pepper,C.M., Krupp,L.B., Friedberg,F., Doscher,C., & Coyle,P.K. (1993) A comparison of neuropsychiatric characteristics in chronic fatigue syndrome, multiple sclerosis, and major depression. Journal of Neuropsychiatry & Clinical Neurosciences, 5, 200-205.
Peterson,P.K., Sirr,S.A., Grammith,F.C., Schenck,C.H., Pheley,A.M., Hu,S., Chao, & CC. (1994) Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. Clinical & Diagnostic Laboratory Immunology, 1, 222- 226.
Pincus,T., Callahan,L.F., Bradley,L.A., Vaughn,W.K., & Wolfe,F. (1986) Elevated MMPI scores for hypochondriasis, depression, and hysteria in patients with rheumatoid arthritis reflect disease rather than psychological status. Arthritis Rheum., 29, 1456-1466.
Prins,J.B., Bleijenberg,G., Bazelmans,E., Elving,L.D., de Boo,T.M., Severens,J.L., van der Wilt,G.J., Spinhoven,P., & van der Meer,J.W. (2001) Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet, 357, 841-847.
Ray,C., Jefferies,S., & Weir,W.R. (1995) Coping with chronic fatigue syndrome: illness responses and their relationship with fatigue, functional impairment and emotional status. Psychological Medicine, 25, 937-945.
Reyes,M., Nisenbaum,R., Hoaglin,D.C., Unger,E.R., Emmons,C., Randall,B., Stewart,J.A., Abbey,S., Jones,J.F., Gantz,N., Minden,S., & Reeves,W.C. (2003) Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch.Intern.Med., 163, 1530-1536.
Reynolds,K.J., Vernon,S.D., Bouchery,E., & Reeves,W.C. (2004) The economic impact of chronic fatigue syndrome. Cost.Eff.Resour.Alloc., 2, 4.
Riley,M.S., O'Brien,C.J., McCluskey,D.R., Bell,N.P., Nicholls, & DP. (1990) Aerobic work capacity in patients with chronic fatigue syndrome. BMJ, 301, 953-956.
Rowe,P.C. & Calkins,H. (1998) Neurally mediated hypotension and chronic fatigue syn- drome. American Journal of Medicine, 105, 15S-21S.
Saltzstein,B.J., Wyshak,G., Hubbuch,J.T., & Perry,J.C. (1998) A naturalistic study of the chronic fatigue syndrome among women in primary care. General Hospital Psychiatry, 20 , 307-316.
Schoofs,N., Bambini,D., Ronning,P., Bielak,E., & Woehl,J. (2004) Death of a lifestyle: the effects of social support and healthcare support on the quality of life of persons with fibromyalgia and/or chronic fatigue syndrome. Orthop.Nurs., 23, 364-374.
Scott,L.V. & Dinan,T.G. (1998) Urinary free cortisol excretion in chronic fatigue syn- drome, major depression and in healthy volunteers. Journal of Affective Disorders, 47, 49-54.
Sharpe,M., Hawton,K., Simkin,S., Surawy,C., Hackmann,A., Klimes,I., Peto,T., Warrell,D., & Seagroatt,V. (1996) Cognitive behaviour therapy for the chronic fatigue syn- drome: a randomized controlled trial. BMJ, 312, 22-26.
Sharpe,M.C., Archard,L.C., Banatvala,J.E., Borysiewicz,L.K., Clare,A.W., David,A., Edwards,R.H., Hawton,K.E., Lambert,H.P., Lane,R.J., McDonald,E.M., Mowbray,J.F., Pearson,D.J., Peto,T.E., Preedy,V.R., Smith,A.P., Smith,D.G., Taylor,D.J., Tyrrell,D.A., Wessely,S., & White,P.D. (1991) A report - chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine, 84, 118-121.
Snell,C.R., Vanness,J.M., Strayer,D.R., & Stevens,S.R. (2002) Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. (Abstract).In Vivo, 16, 107-109.
Spitzer,R.L., Williams,J.B., Gibbon,M., & First,M.B. (1992) The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Archives of General Psychiatry, 49, 624-629.
Stulemeijer,M., de Jong,L.W., Fiselier,T.J., Hoogveld,S.W., & Bleijenberg,G. (2005) Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: ran- domised controlled trial. BMJ, 330, 14.
Suhadolnik,R.J., Peterson,D.L., Reichenbach,N.L., Roen,G., Metzher,M., McCahan,J., O'Brien,K., Welsch,S., Gabriel,J., Gaughan,J.P., & McGregor,N.R. (2004) Clinical and biochemical characteristics differentiating Chronic Fatigue Syndrome from Major Depression and healthy control populations: relation to dysfunction of RNase L pathway. Journal of Chronic Fatigue Syndrome, 12, 5-35.
Suhadolnik,R.J., Reichenbach,N.L., Hitzges,P., Sobol,R.W., Peterson,D.L., Henry, B, Ablashi,D.V., Muller,W.E., Schroder,H.C., & Carter,W.A. (1994) Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syn- drome. Clinical Infectious Diseases, 18 Suppl 1, S96-104.
Thieme,K., Turk,D.C., & Flor,H. (2004) Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom.Med., 66, 837-844.
Tiersky,L.A., Matheis,R.J., DeLuca,J., Lange,G., & Natelson,B.H. (2003) Functional status, neuropsychological functioning, and mood in chronic fatigue syndrome (CFS): relationship to psychiatric disorder. J.Nerv.Ment.Dis., 191, 324-331.
Vercoulen,J.H., Swanink,C.M., Zitman,F.G., Vreden,S.G., Hoofs,M.P., Fennis,J.F., Galama,J.M., van der Meer,J.W., & Bleijenberg,G. (1996) Randomised, double- blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet, 347, 858-861.
Wallman,K.E., Morton,A.R., Goodman,C., Grove,R., & Guilfoyle,A.M. (2004) Randomised controlled trial of graded exercise in chronic fatigue syndrome. Med.J Aust., 180, 444-448.
White,P.D. & Cleary,K.J. (1997) An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome. International Clinical Psychopharmacology, 12, 47-52.
White,P.D., Thomas,J.M., Amess,J., Crawford,D.H., Grover,S.A., Kangro,H.O., & Clare,A.W. (1998) Incidence, risk and prognosis of acute and chronic fatigue syn- dromes and psychiatric disorders after glandular fever. British Journal of Psychiatry, 173, 475-481.
Whiteside,A., Hansen,S., & Chaudhuri,A. (2004a) Exercise lowers pain threshold in chronic fatigue syndrome. Pain, 109, 497-499.
Whiteside,T.L. & Friberg,D. (1998) Natural killer cells and natural killer cell activity in chronic fatigue syndrome. American Journal of Medicine, 105, 27S-34S.
Wildman,M.J., Smith,E.G., Groves,J., Beattie,J.M., Caul,E.O., & Ayres,J.G. (2002) Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort. QJM., 95, 527-538.
Williams,J.B., Gibbon,M., First,M.B., Spitzer,R.L., Davies,M., Borus,J., Howes, MJ, Kane,J., Pope,H.G., Jr., & Rounsaville,B. (1992) The Structured Clinical Interview for DSM- III-R (SCID). II. Multisite test-retest reliability. Archives of General Psychiatry, 49, 630-636.
Apañados vamos
