Chronic fatigue syndrome/Myalgic encephalitis

Now referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Relapsing or relapsing unexplained fatigue, of new or definite onset and lasting for at least 6 months.

Characterized by persistent or relapsing fatigue of a debilitating nature, which is present for at least six months, in addition to at least 4 symptoms from a range including memory loss, poor concentration, joint pain, and tender glands.

By definition patients with chronic fatigue syndrome are free of major medical and psychiatric disorders leading to prolonged fatigue.

ME/CFS initially thought to arise from Epstein-Barr virus, and it’s still believed to be a result of a viral or bacterial infection.

It is characterized by continuing and extreme fatigue without any other diagnosed cause.

Affects as many as 420 people per 100,000 population, with adults and women more commonly affected.

Incidence is reported to be a rate of 180 per 100,000 persons (Reyes M et al).

Affects up to an estimated 2.5 million people in the US.

Generates direct and indirect expenses of approximately 17-$24 billion annually.

Wide differences in prevalence estimates are related to study designs, illness definition and study populations.

The most common exclusionary conditions are obstructive sleep apnea, restless leg syndrome, and substance-abuse.

The core symptoms needed for diagnosis include: reduced ability to do regular activities for more than six months, serious fatigue that doesn’t improve with rest, post exertional malaise with an exaggerated and disabling response to physical or mental activity, unrefreshing, or disrupted sleep.

in addition, patients must have problems with memory/thinking, orthostatic intolerance, or both to receive a diagnosis.

Some patients with ME/CFS experience headaches, muscle pain, shortness of breath.

Commonly associated with somatic disorders, insomnia, and comorbid psychiatric conditions: suggesting that physiologic dysregulations may overlap in these disorders.

Associated with impairment of several limbic-hypothalamus-pituitary axes involving cortisol, prolactin, and growth hormone end products.

Associated with the general down regulation of the hypothalamus-pituitary-adrenal axis.

The COVID-19 pandemic added millions of people with long Covid; about half meet the duration and symptom severity criteria for ME/CFS.

Studied patients with ME/CFS are found to have increased naiive B cells and switch memory. B cells were decreased in their blood, suggesting chronic antigen stimulation, Programmed cell death markers of immune exhaustion were increased on CD8 T cells in the CSF, stool, samples has less  microbial diversity, dopamine metabolism is significantly lower in the CSF, and associated with worse motor performance and cognitive symptoms.

In addition, the resting heart rate was higher, while the drop in nighttime heart rate and ambulatory heart rate variability were lower during exercise, their peak, heart rate and aerobic capacity wad lower, after exercise.

These patients had a diminished cortisol response, and decreased force during repetitive grip testing correlating with imaging of decreased activity in the brain’s right temporal parietal junction.

Autonomic  nervous system dysfunction is present with higher resting heart rate with drop in nighttime heart rate and ambulatory heart rate variability is lower than controls, during exercise, peak, heart rate in the aerobic capacity or lower, and after exercise, they have diminished cortisol response, individuals pace themselves to limit exertion and associated feelings of discomfort, individuals had trouble maintaining force, doing repetitive grip testing  correlating with decreased activity in the brain’s right temporal parietal junction.


There is a decreased activation in response to reward in the  basal ganglia of individuals having chronic fatigue syndrome.

Conditions impacting basal ganglia are frequently linked to fatigue.

Associated with slowed cognition, information processing speed, impaired memory and attention.

Physical, orthostatic postural, and cognitive challenges often produce a flare in symptomatology, typically after 12-48 hour delay, with the condition called postexertional malaise.

During exercise the tissues of patients with ME/CFS feel worse and make biologic abnormalities worse.

During exercise, tissues of patients with ME/CFS have difficulty extracting oxygen, leading to a lower anaerobic threshold.

With exercise patients also have a lower heart rate, blood pressure, and preload, several of which are more prominent during a second exercise test repeated 24 hours after the first.

MRI has revealed increased numbers of punctate areas of high signal in white matter.

PET scans and MRI spectroscopy have demonstrated widespread states of neuroinflammation and increase ratios of choline-creatinine and increased levels of lactate correlate with levels of fatigue.

Spinal fluid contains increased levels of proteins involved in tissue injury and repair.

Cellular energy generation is impaired, including energy from oxygen, sugars, lipids, and amino acids.

It is felt patients feels the lack of energy because its cells have a problem generating and possibly using energy.

Studies have reported markers are both oxidative stress and nitrosative stress with increased levels of inducible nitric oxide synthase.

Associated with increased numbers of activated cytotoxic CD8 T cells and poorly functioning natural killer cells.

Blood levels of many cytokines are significantly higher in patients with chronic fatigue syndrome, especially in the first three years of illness.

Levels of many circulating cytokines correlate positively with severity of symptomatology.

Abnormal levels of several cytokines in spinal fluid also has been reported.

Autonomic nervous system abnormalities have been demonstrated, particularly altered systemic and cerebral hemodynamics that correlate with symptoms.

The prolonged upright posture, abnormal increases heart rate and decreases in blood pressure are common, and substantial cerebral blood flow reductions have been noted.

The prevalence rates in the US range from 0.007%-2.8% in the general population and range from 0.006-3% in primary care or general practices (Afari, N, Buchwald D).

As many as 40% of patients with chronic fatigue syndrome have orthostatic intolerance and about half of these patients have postural tachycardia syndrome.

The greater the fatigue severity, the worse the prognosis.

Significantly associated with both over and under diagnoses.

No known cause and most patients do not recover.

Etiology and pathophysiology remain poorly understood.

Associated with a substantial increase in mortality from suicide

Presently there are no tests, clinical signs, or physiologic markers that are diagnostic.

The illness is diagnosed clinically, based on self-reported symptoms and clinical evaluation for medical and psychiatric conditions that present in a similar fashion.

Graded exercise and cognitive behavioral therapy are the two most consistently beneficial approaches to management.

Associated with a reduced concentration of endogenous opioids in peripheral blood mononuclear cells.

Drug therapy has not proven to have long-term benefit.

Overall risk of death seems to be no different than that of general population, however suicide risk is significantly increased.


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