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

What is ME/CFS?

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystem neuroimmune illness characterized by a substantial reduction in pre-illness functional capacity lasting at least 6 months, accompanied by profound fatigue unrelieved by rest, postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. 1, 2

Core Diagnostic Features

The diagnosis requires all of the following cardinal symptoms present for at least 6 months 1, 2:

• Substantial functional impairment: Significant reduction in ability to engage in occupational, educational, social, or personal activities compared to pre-illness levels 1, 2
• Profound fatigue: New or definite onset fatigue that is not substantially alleviated by rest 1, 2
• Postexertional malaise (PEM): Worsening of symptoms following physical or cognitive exertion, often delayed by hours or days—this is the cardinal distinguishing feature of ME/CFS 1, 2
• Unrefreshing sleep: Sleep that does not restore normal energy or function 1, 2
• Cognitive impairment: Problems with memory, concentration, and information processing 1, 2
• Orthostatic intolerance: Symptoms that worsen upon assuming and maintaining upright posture 1, 2

Disease Severity and Impact

ME/CFS causes severe disability with measurable functional consequences 1:

• Up to 75% of patients cannot work full-time 1
• 25% have severe ME/CFS, often bed-bound with extreme sensory sensitivity and dependence on others for care 1, 2
• Prevalence in the U.S. is estimated at 0.5-1.5%, with higher rates among females 3
• Economic burden ranges from $17-24 billion annually in the United States 4

Pathophysiological Mechanisms

ME/CFS involves multiple documented biological abnormalities 1:

Immune dysfunction:

• Diminished natural killer cell function 1, 2
• T cell exhaustion and other T cell abnormalities 1, 2
• Pro-inflammatory state with immune dysregulation 5

Metabolic and mitochondrial abnormalities:

• Mitochondrial dysfunction with impaired energy production 1, 2
• Altered fatty acid and amino acid metabolism 1
• Exercise intolerance with impaired oxygen consumption and reduced anaerobic threshold 1

Vascular and endothelial dysfunction:

• Deformed red blood cells 1, 2
• Reduced blood volume 1, 2
• Microclots and hyperactivated platelets 1

Neurological abnormalities:

• Neuroinflammation 1, 2
• Reduced cerebral blood flow 1, 2
• Brainstem abnormalities 1, 2
• Elevated ventricular lactate levels 1

Endocrine dysfunction:

• Hypothalamus-pituitary-adrenal axis dysfunction 1, 2
• Low cortisol levels without compensatory ACTH elevation 1, 2

Triggering Factors

ME/CFS onset commonly follows infectious triggers 1, 4:

• Viral infections including Epstein-Barr virus (EBV), SARS-CoV-2, Ross River virus, and West Nile virus 1
• Bacterial infections including Coxiella burnetii (Q fever) 1
• Reactivated herpesviruses (EBV, HHV-6, HHV-7, cytomegalovirus) are associated with ME/CFS 1
• 27.1% of SARS-CoV survivors met ME/CFS criteria 4 years after infection 1

Relationship to Long COVID

ME/CFS and long COVID share striking similarities 1:

• Approximately 50% of individuals with long COVID meet diagnostic criteria for ME/CFS 1
• When postexertional malaise is specifically measured, a majority of long COVID patients report this cardinal ME/CFS symptom 1
• Both conditions demonstrate similar hemodynamic, symptomatic, and cognitive abnormalities during orthostatic stress testing 1
• Shared pathophysiological findings include mitochondrial dysfunction, endothelial abnormalities, neuroinflammation, and immune dysregulation 1

Critical Diagnostic Pitfalls to Avoid

Do not misattribute ME/CFS to simple deconditioning—the disease involves complex pathophysiology with documented immune, metabolic, and neurological abnormalities far beyond physical deconditioning 2, 4.

Do not overlook postexertional malaise—this symptom is the key distinguishing feature that separates ME/CFS from other fatigue conditions and must be specifically assessed 1, 2.

Do not misdiagnose as a primary psychiatric disorder—ME/CFS is a biological illness with measurable neurological, immunological, and metabolic components 2, 4.

Do not recommend graded exercise therapy without extreme caution—many ME/CFS patients report symptom aggravation with exercise due to postexertional malaise 5. Pacing of activities with strategic rest periods is the most important management strategy 4.

Diagnostic Approach

Diagnosis is purely clinical, based on meeting symptom criteria and excluding other fatiguing illnesses 4, 6:

• Thorough evaluation to rule out alternative diagnoses that could explain symptoms 2, 4
• Minimum 6-month duration of symptoms required 1, 2
• Assessment for co-existing conditions including orthostatic intolerance (present in many patients) 2, 6
• No specific diagnostic laboratory test exists for ME/CFS 4, 6

Management Principles

Current treatment is supportive and symptom-focused 1, 4:

• Pacing is the cornerstone of management: Strategic balance of rest and activity to prevent post-exertional symptom worsening 4, 6
• Cognitive-behavioral therapy shows evidence for improving physical functioning, though it does not cure the underlying disease 1
• Mindfulness-based therapies demonstrate small to moderate improvements in quality of life 1
• Stimulants are not recommended for treatment of fatigue in ME/CFS 1
• Medications can address specific symptoms including pain, insomnia, and orthostatic intolerance 4, 6
• Multidisciplinary care involving specialists in relevant organ systems is appropriate 2