What is myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS)?

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

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating neurological disease characterized by profound fatigue lasting at least 6 months with substantial reduction in pre-illness activities, accompanied by postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. 1, 2

Core Clinical Features

ME/CFS is defined by five essential diagnostic criteria that must all be present:

• Profound fatigue of new or definite onset that is not substantially alleviated by rest and results in significant reduction in occupational, educational, social, or personal activities 1, 2
• Postexertional malaise (PEM), which is the hallmark distinguishing feature—a worsening of symptoms following physical or cognitive exertion, often delayed by hours or days 1, 2
• Unrefreshing sleep that does not restore normal energy or function 1, 2
• Cognitive impairment, including problems with memory, concentration, and information processing 1, 2
• Orthostatic intolerance, characterized by symptoms that worsen upon assuming and maintaining upright posture 1, 2

All symptoms must persist for at least 6 months to meet diagnostic criteria. 1, 2

Epidemiology and Impact

ME/CFS affects between 0.5-1.5% of the U.S. population, with estimates ranging from 836,000 to 2.5 million Americans. 3, 4 The disease predominantly affects adults with peak onset between ages 20-45 years, with a female to male ratio of 3:1. 5 The economic burden is substantial, costing between $17-24 billion annually in the United States. 4

Approximately 25% of patients have severe ME/CFS, meaning they are bed-bound with extreme sensory sensitivity. 1 The symptom pattern typically follows a viral or bacterial infection in many cases, and the ongoing COVID-19 pandemic has raised concerns about increased ME/CFS prevalence, as viral infection is an established trigger. 3

Pathophysiological Understanding

ME/CFS is recognized by the World Health Organization and the U.S. Centers for Disease Control and Prevention as a disorder of the brain, not a psychiatric condition. 5 The disease involves complex biological abnormalities across multiple systems:

• Immune dysregulation, including diminished natural killer cell function, T cell exhaustion, and a pro-inflammatory state 1, 6, 3
• Mitochondrial dysfunction with impaired energy production, reduced oxidative metabolism, and dysregulated bioenergetics 1, 6, 3
• Neurological abnormalities, including neuroinflammation, reduced cerebral blood flow, and brainstem abnormalities 1, 7
• Vascular and endothelial abnormalities, including deformed red blood cells and reduced blood volume 1
• Endocrine abnormalities, including hypothalamus-pituitary-adrenal axis dysfunction and low cortisol levels 1, 7

The severity of symptoms appears directly correlated to the degree of metabolic reduction, which may be unique to each individual patient. 7

Relationship to Other Conditions

ME/CFS overlaps significantly with other symptom-based conditions, including fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), and chronic multisymptom illness (CMI). 8 The case definitions for these conditions share common features of multiple chronic symptoms from different body systems including fatigue, mood/cognition, sleep, gastrointestinal symptoms, and pain. 8

About half of long COVID patients meet criteria for ME/CFS, as both conditions share similar pathophysiological mechanisms. 1 ME/CFS must be differentiated from Postural Orthostatic Tachycardia Syndrome (POTS), which is characterized by a heart rate increase ≥30 bpm within 10 minutes of standing without hypotension. 1

Critical Diagnostic Pitfalls

Three major diagnostic errors must be avoided:

• Misattribution to deconditioning: ME/CFS involves complex pathophysiology beyond simple deconditioning and cannot be explained by lack of physical fitness 1
• Overlooking postexertional malaise: This symptom is the key distinguishing feature that separates ME/CFS from other fatigue conditions and must not be missed 1
• Misdiagnosis as a psychiatric disorder: ME/CFS is a biological illness with demonstrable neurological and immunological components, not a psychological condition 1

Diagnostic Challenges

There is no unique ICD-10 code for ME/CFS, no universally accepted clinical case definition, and no reliable objective biomarkers. 8, 7 The diagnosis remains one of exclusion, requiring thorough evaluation to rule out other conditions that could explain symptoms, including anemia, hypothyroidism, depression and anxiety disorders, sleep disorders, electrolyte disturbances, and chronic infections. 2

Most patients (80%) struggle to obtain a diagnosis because physicians have not been taught how to diagnose or treat ME/CFS in medical schools or post-graduate training. 4 The 2010 Canadian Community Health Survey found that 29% of patients with ME/CFS had unmet healthcare needs and 20% had food insecurity. 4