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Key Clinical Updates in Fatigue & Systemic Intolerance Disease (Chronic Fatigue Syndrome)

Pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effect, may reduce daytime sleepiness in patients with moderate to severe obstructive sleep apnea who do not want continuous positive airway pressure treatment.

Dauvilliers Y et al. Am J Respir Crit Care Med. [PMID: 31917607]


  • Weight loss; fever.

  • Sleep-disordered breathing.

  • Medications; substance use.


Fatigue, as an isolated symptom, accounts for 1–3% of visits to generalists. The symptom of fatigue is often poorly described and less well defined by patients than symptoms associated with specific dysfunction of organ systems. Fatigue or lassitude and the closely related complaints of weakness, tiredness, and lethargy are often attributed to overexertion, poor physical conditioning, sleep disturbance, obesity, undernutrition, and emotional problems. A history of the patient’s daily living and working habits may obviate the need for extensive and unproductive diagnostic studies.

Fatigue in older adults increases the risk of developing negative health outcomes (mortality OR, 2.14), the development of disabilities in basic activities of daily living (OR 3.22), or the occurrence of physical decline (OR, 1.42).

A working case definition of chronic fatigue syndrome indicates that it is not a homogeneous abnormality, there is no single pathogenic mechanism (eFigure 2–1), and no physical finding or laboratory test can be used to confirm the diagnosis. The Institute of Medicine (now called the National Academy of Medicine) has recommended using the term systemic exertion intolerance disease. Other conditions identified as causing chronic fatigue include myalgic encephalitis and neurasthenia, each with specific diagnostic criteria creating inconsistent diagnoses and treatment plans.

eFigure 2–1.

Classification of chronic fatigue patients. Ca2+, calcium; PO43–, phosphate.

A systemic search of pooled public databases from 1980 to 2018 found the prevalence of systemic intolerance disease to be 0.89% (using the case definition established by the CDC-1994), with women affected approximately 1.5- to 2-fold higher than men. The diagnosis of systemic intolerance disease remains hotly debated because of the lack of a gold standard.

Persons with systemic intolerance disease who meet specific criteria (such as those from the CDC) report a greater frequency of childhood trauma and psychopathology and demonstrate higher levels of emotional instability and self-reported stress than persons who do not have chronic fatigue. There may be increased tendency to perfectionism if there is also depression and anxiety. Neuropsychological and neuroendocrine studies reveal abnormalities in most patients but no consistent pattern.

Sleep disorders have been reported in 40–80% of patients with chronic fatigue syndrome, but polysomnographic studies have not shown a greater incidence of primary sleep disorders in those with chronic fatigue syndrome than in controls, suggesting that the sleep disorders are comorbid rather than causative. Veterans ...

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