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Fatigue can be considered the final common pathway of a multitude of biological, psychological, and social disturbances that are often not clearly distinguishable from one another. A biopsychosocial approach is, therefore, in order, and it should be borne in mind that, frequently, more than one mechanism is at work.
Patients seen in general medical practice with primarily unexplained fatigue have the following conditions in the following frequencies (means and 95% confidence intervals, from a systematic review) ( 11 ): anemia, 2.8% [1.6; 4.8]; cancer, 0.6% [0.3; 1.3]; serious somatic disease (including anemia and cancer, because the studies are highly variable in the clinical definitions and methods employed), 4.3% [2.7; 6.7]; depression, 18.5% [16.2; 21.0]. Further relevant conditions include sleep disturbances and sleep-related breathing disturbances, post-infectious states, and substance abuse, particularly alcohol abuse, as has been shown in other studies as well ( 29 , e38 ).
Fatigue can be considered the final common pathway of many biological, psychological, and social disturbances that are often not clearly distinguishable from one another. A biopsychosocial approach is, therefore, in order, and often more than one mechanism is at work.
Relevant conditions include sleep disturbances and sleep-related breathing disturbances, post-infectious states, and substance abuse, particularly alcohol abuse, as has been shown in other studies as well.
The recommended basic test battery ( table 2 ) comprises, independently of the age of the patient: history-taking and physical examination focused on potential causes of fatigue, particularly sleep disturbances, major changes in body weight, dysfunction of the cardiac, respiratory, gastrointestinal, urogenital, and central nervous systems, intake of drugs and psychoactive substances, problems in the patient’s social, familial, or occupational setting, chemical exposures or excessive exposure to noise, similar symptoms in family members or co-workers, snoring, falling asleep at the wheel, and (habitual) sleep deficit. Targeted laboratory testing should include blood sugar, complete blood count, erythrocyte sedimentation rate/CRP, transaminases or γ-GT, and TSH. The patient should also fill out a fatigue questionnaire, such as the one found in the accompanying information for patients in the DEGAM guideline on fatigue ( e39 ). In particular, the question about the patient’s own ideas about the cause of fatigue ( e40 ) often yields plausible explanations and important information about the patient’s expectations and fears, which the physician must know in order to establish effective communication with the patient. If the basic evaluation yields evidence of a specific illness, further testing is indicated. In premenopausal women whose basic evaluation is negative, the ferritin concentration should be measured as well.
● symptom characteristics, differentiation from somnolence ● associated complaints ● fatigue new/unusual ● impairment in everyday life ● the patient’s own conception of the cause and treatment of fatigue ● symptoms of depression and anxiety | ● somatic history ● sleep: duration, quality, changes from personal norm, (habitually) insufficient sleep ● body weight, changes in weight ● cardiac, respiratory, gastrointestinal, urogenital, and central nervous system function ● drugs, psychotropic substances ● post-infectious state, chronic disease | ● social, familial, occupational situations ● exposure to chemicals or noise ● similar symptoms in family members, friends, or coworkers ● snoring, falling asleep at the wheel |
● depending on positive findings in the history | ● if the history does not arouse suspicion of any particular physical illness: abdomen, heart, circulation, airways, skin and mucous membranes, lymph nodes; muscle bulk, strength, and tone; proprioceptive reflexes | |
● depending on positive findings in the history and physical examination | ● if there is no evidence of any particular physical illness: fasting blood sugar, complete blood count, erythrocyte sedimentation rate/CRP, transaminases/γ-GT, TSH (creatinine only if there is evidence of renal disease, or in the presence of risk factors such as hypertension, diabetes, nephrotoxic drugs) | ● further laboratory testing only if the history or physical examination arouses suspicion of a particular condition ● ferritin measurement in premenopausal women with normal history, physical examination, and basic laboratory tests |
* These recommendations are also given in the DEGAM guideline.
Many patients presenting with fatigue as their chief complaint suffer from depression or anxiety disorders or have a history of infection. These conditions should be asked about specifically. Screening questions for current depression are: In the last four weeks, have you felt dejected, melancholic, or hopeless? Have you had less interest in, or enjoyment from, activities that you are ordinarily interested in or enjoy ( e42 )?
In premenopausal women whose basic evaluation is negative, the ferritin concentration should be measured as well.
Analogous screening questions for anxiety disorders are: In the last four weeks, have you suffered from nervous tension / fearfulness / a feeling of being emotionally out of balance? Have you been worried about many different things, or suffered from anxiety attacks ( e43 )? Positive answers to any of these questions call for further evaluation, and, in depressed patients, the potential risk of suicide must be assessed.
In patients with evidence of sleep disturbances, the following things should be determined: Does the patient have greater difficulty falling asleep, or a worse quality of sleep, than in the normal situation for him or her? Is sleep hygeine inadequate, does the patient have too little time to sleep, or is sleep prevented by situational factors (pain, psychosocial stress, noise, shiftwork)? The suspicion of a sleep-related respiratory disorder (SRRD) is aroused if the patient reports snoring, respiratory pauses in sleep observed by others, and falling asleep at the wheel of a car or any other manifestation of unavoidable, involuntary falling asleep in the daytime. If the patient also has a high STOP-BANG score (number of items from a list of eight: snoring, tiredness, observed apnea, high blood pressure or body-mass index [BMI], age, neck circumference, and gender) ( e44 ), or a high score on the somewhat more practical and probably equally useful GOAL questionnaire (which has only four items: male gender, obesity with a BMI ≥ 30, age ≥ 50 years, loud snoring) ( 30 ), evaluation by a specialist in sleep medicine is indicated. A STOP-BANG score of 0–2 implies a low probability of moderate to severe obstructive sleep apnea, while a score of 5–8 implies a high probability. In the intermediate range (3–4 points), further criteria are needed. A GOAL score of 2 or above implies a high probability of sleep apnea.
The history and physical examination enable classification into the following three categories ( figure 1 ) :
Thinking traps and fallacies about fatigue as the chief complaint
The suspicion of a sleep-related respiratory disorder (SRRD) is aroused if the patient reports snoring, respiratory pauses in sleep observed by others, and falling asleep at the wheel of a car or any other manifestation of unavoidable, involuntary falling asleep in the daytime.
A high STOP-BANG score (snoring, tiredness, observed apnea, high blood pressure or BMI, age, neck circumference, and gender) or GOAL score (male gender, obesity with a BMI ≥ 30, age ≥ 50 years, loud snoring) indicates that evaluation by a specialist in sleep medicine is indicated.
If the cause of fatigue remains unknown after initial laboratory testing and (possibly) further technical studies, the strategy from then on is one of expectant observation, with regular follow-up every four to six weeks. A ferritin level should be measured in premenopausal women, but other additional laboratory tests or ancillary studies further on in the patient’s course are indicated only if there are positive findings or specific clinical evidence. The risk of an underlying illness in an early stage is not completely ruled out, but is thought to be no higher in such patients than in the population at large ( 11 , 29 , e16 ), and the low diagnostic yield must be weighed against the stress and risk of diffuse, untargeted diagnostic testing. Current evidence suggests that such testing does not, in general, improve patient outcomes. Rather, it elevates the risk of false-positive findings, overdiagnosis, which can derail the proper care of the patient. The risk of the patient’s focusing or fixating on a putative somatic disease as the cause of fatigue ( e45 , 31 ) is also increased if prolonged diagnostic efforts are made—perhaps lasting several weeks—to rule out somatic causes, while psychological matters are not discussed at all. Dreibholz describes somatic fixation as “a cyclic process in which all the patient’s symptoms, signs, problems, and illnesses are considered purely somatic processes by the patient and/or the primary care physician, while the psychosocial aspects of the symptoms or illnesses are overlooked and disregarded, whether consciously or not” ( e46 ) ( figure 2 ).
Diagnostic pathways for patients with fatigue as the chief complaint
A further risk is that irrelevant changes will be assigned too much importance and labeled the cause of fatigue. Deceptive associations of this kind are most likely in patients who suffer from a known underlying disease, manifest isolated laboratory changes such as mild iron deficiency or subclinical hypothyroidism, or are subject to dubious environmental influences. Conversely, the overall clinical picture must always be borne in mind so that a relevant disease will not be overlooked in the presence of only mild laboratory abnormalities.
Laboratory tests.
Patients whose initial laboratory tests and ancillary studies do not reveal the cause of their fatigue are treated with a watchful waiting strategy, with follow-up every four to six weeks.
Disease-specific treatment should be given if such a treatment is possible and indicated, and its effect on fatigue should be documented: for example, antidepressant therapy and the treatment of anemia, heart failure, diabetes mellitus, neurological diseases, sleep disturbances, and pain. If fatigue remains unexplained, or if there is evidence of relevant psychosocial stress, the clinical approach should be one of expectant observation for somatic and psychological causes, with regular follow-up at four- to six-week intervals, as appropriate for the individual patient. The physician should counsel the patient empathetically and communicate openly, so that the patient can be motivated to change his or her behavior in order to modify unmanageable (or, in some cases, insufficient) physical and psychosocial challenges. Problem-oriented cognitive behavior therapy is useful in some cases as well. Keeping a symptom diary can be useful ( 32 ) as a basis for discussions about symptoms, impairments, and the associated feelings and conceptions. This therapeutic approach accords with the recommendations of the DEGAM guideline on fatigue cited above; the corresponding evidence levels and recommendation strengths can be found in the guideline.
Psychoeducative measures to inform the patient about the disease process and the appropriate way of dealing with it by assuming personal responsibility, thus strengthening patient resources ( e47 ), with the aid of accompanying materials ( e39 ), are useful for dealing with excessive (or insufficient) challenges in everyday life, as well as for patients with sleep disturbances or cancer ( 33 ). For patients with many different types of underlying condition or disease, behavior therapy ( 34 ) or symptom-oriented activating measures lessen fatigue and improve overall well-being ( 35 , 36 ). An appropriately adapted program of physical activation lessens fatigue and counteracts physical deconditioning ( table 3 ) , as discussed in the Case Illustration ( ebox 2 ).
[95% confidence intervals] | |
SSRI and SNRI ( , ) | As first-line therapy, vs. placebo: SSRI: g = 0.33 (limits: 0.26–0.39), SNRI: g = 0.36 (limits: 0.29–0.42) ( ); Pp d: SSRI: 3.48 [3.18; 3.78], SNRI: 2.47 [2.09; 2.84]) ( ) |
CBT ( , ) | Strong effect compared to waiting list: d = 1.23 [1.02; 1.45], weak to moderate effect compared to routine treatment and placebo: d = 0.57 [0.20; 0.94] (effect strengths of individual CBT pooled over all anxiety disorders) ( ) |
CBT and psychodynamic therapy ( , ) | Best long-term treatment outcome of all psychological therapies. Pp individual CBT: d = 1.24 [1.10; 1.39]; Pp psychodynamic therapy: d = 0.97 [0.58; 1.36] ( ) |
Antidepressants ( ) | More effective than placebo against major depression: odds ratios of 21 antidepressants vs. placebo range from 1.37 [1.16; 1.63] to 2.13 [1.89; 2.41] ( ) |
Exercise therapy ( ) | Only moderate effect: SMD compared to no treatment –0.62 [–0.81; –0.42], no significant effect in high-quality studies: –0.18 [−0.47; 0.11] ( ) |
Behavior therapy ( ) | Similar efficacy to other forms of psychotherapy: response rate of BT vs. all other forms of psychotherapy: risk reduction 0.97 [0.86; 1.09] ( ) |
Antidepressants ( ) | Doxepin pooled with imipramine vs. placebo, for improved sleep quality: SMD −0.39 [−0.56; −0.21) ( ) |
Antihistamines ( ) | Inadequate evidence |
Antipsychotic drugs ( ) | Inadequate evidence |
Benzodiazepines and benzodiazepine receptor agonists ( )* | Improvement of sleep parameters: benzodiazepines: g for TST: 0.64 [0.12; 1.16], for SOL: –0.76 [−1.28; −0.24] benzodiazepine receptor agonists: g for TST: 0.52 [0.33; 0.71], for SOL: −0.46 [−0.61; −0.31] ( ) |
Melatonin ( ) | Generally not recommended because of low efficacy |
Phytotherapeutic drugs ( ) | No improvement to moderate improvement of sleep quality |
CBT ( )* | CBT is recommended as the first line of treatment for adults of any age. CBT vs. placebo: Hedges’ g: 1.07 [0.10; 2.05] ( ) |
Complex rehabilitation (exercise training and psychological counseling) after a COPD exacerbation ( ) | Good evidence for improvement of fatigue-related quality of life Fatigue domain: mean difference 0.81 [0.16; 1.45] ( ) |
Exercise training ( , ) | Questionable improvement of quality of life |
Behavior therapy (relaxation, meditation, and guided imagery) ( , ) | Potential benefit with regard to quality of life |
Exercise training ( , ) | May lessen fatigue |
CBT ( , ) | May lessen fatigue |
Pharmacotherapy ( , ) | Individual decision in the absence of convincing evidence |
Newer-generation antidepressants ( ) | Compared to placebo (with very low study quality) moderately effective against somatic symptoms (SMD −0.91, [−1.36; −0.46]), anxiety (SMD −0.88, [−1.81; 0.05]), depression (SMD −0.56, [−0.88; −0.25]) ( ) * |
Exercise training ( ) | Moderate improvement of CRF: mean weighted effect size (WES) = 0.30 [0.25; 0.36] ( ) |
CBT ( ) | Moderate improvement of CRF: mean weighted effect size (WES) = 0.37 [0.28; 0.47] ( ) |
Psychological interventions overall ( ) | Moderate improvement of CRF: mean weighted effect size (WES) = 0.27 [0.21; 0.33] ( ) |
Pharmacotherapy ( ) | Very little improvement of CRF: mean weighted effect size (WES) = 0.09 [0.00; 0.19] ( ) |
BT, behavior therapy; CRF, cancer-related fatigue; CBT, cognitive behavior therapy; d, Cohen’s d; g, Hedges’ g; SMD, standardized mean difference; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-noradrenaline reuptake inhibitor; TST, total sleep time; SOL, sleep onset latency; WES, weighted effect size; Pp, pre-post
* 1 In general, effect strengths (Cohen’s d, Hedges’ g) of > 0.2 are considered weak, > 0.5 as moderate, and > 0.8 as strong. The effect strengths presented here for COPD, neurological diseases and cancer are with respect to fatigue as a symptom of these conditions; the strengths presented for the other diseases are with respect to the overall disease process.
* 2 This can be offered if CBT is insufficiently effective or not feasible. Beware of the risk of tolerance and dependence, no information on daytime fatigue
* 3 Risk of daytime fatigue and somnolence in sleep restriction therapy
* 4 The potential benefit must be weighed against the risk of side effects.
Mr. F., a 32-year-old barber, complains to his family physician of fatigue and exhaustion of approximately ten weeks’ duration. He states that he no longer even wants to go jogging, despite having been an enthusiastic endurance athlete until now. He has hardly ever been ill before, except for minor injuries. He is experiencing considerable stress at the moment, as he will soon be taking an examination for an important professional qualification that will enable him to set up his own barber shop. His history is otherwise positive only for difficulty falling asleep at night. In response to screening questions about anxiety and depression, he reports having suffered from nervous tension in the past four weeks, but no further symptoms. On physical examination, his blood pressure is 118/76 mmHg, height 188 cm, weight 78 kg. The skin, mucous membranes, heart, lungs, abdomen, renal beds, limbs, and basic neurological examination are normal. In the DEGAM patient questionnaire on fatigue, Mr. F. notes that his symptoms are associated with the above-mentioned stresses in his everyday life. Laboratory findings: hemoglobin 14.2 g%, normal complete blood count, ESR 7/14 mm, TSH 2.3 mU/L, ALT 18 U/L, γGT 20 U/L, fasting blood sugar 96 mg%. Assessment and plan: Discussing the findings, the physician and the patient agree that his fatigue and exhaustion are probably due to the stress of his upcoming professional examination and his plan to go into business for himself in the near future. There is no evidence of any serious somatic or psychological disorder. They determine that Mr. F. will seek help with business planning from the Chamber of Industry and Commerce and resume jogging in order to reduce stress and keep fit. He also obtains a CD from his health insurance company with audio instructions on the Jacobson technique of progressive muscle relaxation. He is told to contact the physician in four weeks to report back on his condition, or at any time until then in case any warning symptoms or signs should arise.
The common causes of fatigue include the following, some of which are both preventable and dangerous: psychosocial problems, depression, anxiety disorders, sleep disorders, and sleep-related respiratory disorders. Patients with an unremarkable history, physical examination, and basic laboratory test battery are highly unlikely to be suffering from anemia, cancer, thyroid dysfunction, or other somatic diseases as the cause of their fatigue.
Aspects that must be considered include known underlying illnesses, drug and substance intake, and health risks. Additional diagnostic studies should only be performed in case of well-founded clinical suspicion. The etiology, course, and optimal treatment of chronic fatigue syndrome are still unclear.
The further management of patients with fatigue as their main symptom is characterized by causally directed as well as symptomatic treatment, empathetic patient counseling, expectant observation, and regularly scheduled follow-up.
Psychoeducative measures to inform the patient about the disease process and how to deal with it by assuming personal responsibility, thus strengthening patient resources, are useful for dealing with excessive (or insufficient) challenges in everyday life.
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Only one answer is possible per question. Please select the answer that is most appropriate.
You decide how to plan your continuing medical education on the basis of the frequency and dangerousness of the reasons your patients come to see you. In your primary care practice, you have approximately 50 direct physician-patient contacts every day.
How many times a day, on average, will you see a patient with fatigue/exhaustion as their chief complaint?
A previously healthy 26-year-old woman studying physical education is working toward the completion of her thesis and expects to be taking her practical and oral final examinations ten weeks from now. She reports having suffered from exhaustion of progressive severity over the past six weeks. In your physical examination, you note very pale conjunctivae.
What serum laboratory test should be obtained in addition to the basic laboratory test battery?
Mr. F., a 22-year-old bank employee who lost his father in a fatal automobile accident six months ago, reports having suffered from marked fatigue and lack of energy for the past four months. You suspect depression as the main cause.
Which of the following, if the patient states he has suffered from it for several weeks, would tend to confirm your preliminary diagnosis?
You are pursuing the differential diagnosis of fatigue in your patient Mr. K., a very obese 65-year-old man.
Which of the following is highly consistent with a sleep-related respiratory disorder?
Mr. O., a 44-year-old warehouse worker, consults you because of severe fatigue. You suspect obstructive sleep apnea as the cause.
Which of the following symptoms or findings is most consistent with your suspicion?
Patients with somatic diseases may suffer from fatigue as a direct result of their underlying condition, or else by way of dysfunctional emotional adaptation processes or treatment side effects.
Approximately 65% of patients with which of the following diseases suffer from fatigue and exhaustion?
You have not been able to find the cause of longstanding fatigue in your patient Ms. K., a 38-year-old single mother, despite comprehensive history-taking, physical examination, basic laboratory testing, and the use of a patient questionnaire.
Which of the following is a reasonable next step?
Ms. S., a 43-year-old kindergarten teacher, complains of fatigue over the past two months, impairing her everyday activities. There is no known underlying disease, and the history and physical examination reveal no evidence of any somatic condition.
Which of the following laboratory tests is a component of the recommended basic battery?
Mr. N. is a 34-year-old software developer who has been suffering from fatigue for four months. You have conducted a diagnostic evaluation according to the basic evaluation program and have come to the conclusion that he has an anxiety disorder.
Which of the following treatments would be appropriate for him?
Question 10
Long-lasting fatigue carries the risk of physical deconditioning.
What measure do you order to prevent this?
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Conflict of interest statement
Prof. Donner-Banzhof has a personal relationship with GSK.
The other authors state that they have no conflict of interest.
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William is a 65 year old retired architect who came to see me for help with fatigue and depression. His energy level had been gradually deteriorating for the previous four years. His doctor had ordered some basic blood tests and couldn’t find anything wrong, therefore concluded his low energy must be a symptom of getting older and being retired.
William wasn’t happy with that explanation. He had a lovely wife and a small group of close friends, who he enjoyed going out with. His friends were the same age and they seemed to be far more energetic and were thoroughly enjoying their retirement.
Depression is a condition that slowly crept up on William in the previous two years. He told me that he was losing enthusiasm for activities that previously excited him. William’s quality of sleep was quite poor. He found it easy to fall asleep; however, would wake 3 or 4 hours later and the rest of the night would be marked by a light, restless, unrefreshing sleep.
I decided to order some of my own blood tests for William. I ordered the following blood tests for William:
I also ordered a stool test for William to check for intestinal parasites. The test is called a PCR test and it checks for genetic material from a wide range of different harmful intestinal bugs. I ordered this test because William told me he regularly suffered with irritable bowel syndrome symptoms – he was usually bloated and his bowel motions alternated between diarrhea and constipation. These are common symptoms of a gut infection. The fatigue and disturbed sleep are also sometimes clues.
William was very happy to discover there are genuine reasons why he hasn’t been feeling well lately. He was very happy to follow the plan I gave him. I expect to see William again in 4 weeks.
The above statements have not been evaluated by the FDA and are not intended to diagnose, treat or cure any disease.
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