What is Myalgic Encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS)?

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS)

Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), is a serious, complex, multisystem disease characterized by profound fatigue lasting ≥6 months with substantial reduction in pre-illness activities, accompanied by postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. 1

Core Diagnostic Features

The diagnosis requires all of the following criteria to be met:

• Profound fatigue of new or definite onset that is not substantially alleviated by rest, lasting at least 6 months with significant reduction in occupational, educational, social, or personal activities 1, 2
• Postexertional malaise (PEM), defined as worsening of symptoms following physical or cognitive exertion, often delayed by hours or days—this symptom distinguishes ME/CFS from other fatigue conditions 2
• Unrefreshing sleep that does not restore normal energy or function 2
• Either cognitive impairment (problems with memory, concentration, and information processing) or orthostatic intolerance (symptoms that worsen upon assuming and maintaining upright posture) 1, 2

Terminology and Classification

The Institute of Medicine proposed renaming this condition "Systemic Exertion Intolerance Disease" (SEID) in 2015, though this terminology has not been universally adopted 3, 4. The condition overlaps with other symptom-based diagnoses including fibromyalgia syndrome and irritable bowel syndrome 3. ME/CFS affects an estimated 0.5-1.5% of the U.S. population, with higher prevalence among females (3:1 female to male ratio), and peak onset between ages 20-45 years 5.

Pathophysiology

While the precise etiology remains unknown, ME/CFS involves multiple biological abnormalities:

• Immune dysregulation including diminished natural killer cell function and T cell exhaustion 2, 6
• Mitochondrial dysfunction with impaired energy production and metabolic abnormalities 2, 7
• Neurological abnormalities such as neuroinflammation, reduced cerebral blood flow, and brainstem abnormalities 2
• Endocrine dysfunction including hypothalamus-pituitary-adrenal axis abnormalities and low cortisol levels 2
• Vascular and endothelial abnormalities including deformed red blood cells and reduced blood volume 2

Viral or bacterial infection often precedes symptom onset, and ME/CFS is recognized by the World Health Organization as a disorder of the brain 5. Approximately half of long COVID patients meet criteria for ME/CFS, suggesting shared pathophysiological mechanisms 2.

Clinical Severity and Impact

ME/CFS can be severely disabling, with 25% of patients bed-bound and experiencing extreme sensory sensitivity 2. The condition costs between $17-24 billion annually in the United States 4. Despite this burden, 80% of patients struggle to obtain a diagnosis because most physicians have not received training in recognizing or managing ME/CFS 4.

Critical Diagnostic Pitfalls to Avoid

• Do not misattribute symptoms to simple deconditioning—ME/CFS involves complex pathophysiology beyond physical deconditioning 2
• Do not overlook postexertional malaise—this is the hallmark distinguishing feature of ME/CFS 2
• Do not misdiagnose as a primary psychiatric disorder—ME/CFS is a biological illness with neurological and immunological components, though psychiatric comorbidities may coexist 2

Differential Diagnosis Considerations

Rule out treatable conditions that cause chronic fatigue including anemia, hypothyroidism, depression and anxiety disorders, sleep disorders, electrolyte disturbances, and chronic infections 1. Consider postural orthostatic tachycardia syndrome (POTS), which is characterized by heart rate increase ≥30 bpm within 10 minutes of standing without hypotension and may coexist with ME/CFS 3, 2.