What are the diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Diagnostic Criteria for ME/CFS

ME/CFS is diagnosed when a patient experiences 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 Requirements

The diagnosis requires all of the following components to be present:

1. Duration and Functional Impairment

• Symptoms must persist for at least 6 months with a significant reduction in ability to engage in pre-illness occupational, educational, social, or personal activities 1, 2
• The fatigue must be of new or definite onset (not lifelong) 2

2. Profound Fatigue

• The fatigue is not substantially alleviated by rest, distinguishing it from simple deconditioning 2
• This represents a pathological level of exhaustion beyond normal tiredness 3

3. Postexertional Malaise (PEM)

• This is the cardinal symptom that distinguishes ME/CFS from other fatigue conditions 2
• Defined as worsening of symptoms following physical or cognitive exertion, often delayed by hours or days 2
• Overlooking PEM is the most common diagnostic pitfall 2

4. Unrefreshing Sleep

• Sleep that does not restore normal energy or function, regardless of duration 2
• Patients wake feeling as exhausted as when they went to bed 1

5. Either Cognitive Impairment OR Orthostatic Intolerance (at minimum one required)

• Cognitive impairment: Problems with memory, concentration, information processing, and mental clarity 2
• Orthostatic intolerance: Symptoms that worsen upon assuming and maintaining upright posture, including lightheadedness, dizziness, or worsening fatigue when standing 2

Clinical Evaluation Process

Exclusion of Alternative Diagnoses

Before diagnosing ME/CFS, you must systematically rule out treatable conditions that cause chronic fatigue 1:

• Anemia (complete blood count)
• Hypothyroidism (TSH, free T4)
• Depression and anxiety disorders (clinical assessment)
• Sleep disorders (sleep study if indicated)
• Electrolyte disturbances (comprehensive metabolic panel)
• Chronic infections (appropriate serologies based on clinical suspicion)

Severity Assessment

Recognize that 25% of patients have severe ME/CFS, meaning they are bed-bound with extreme sensory sensitivity and dependent on others for care 2. Up to 75% cannot work full-time 3.

Symptom Pattern Recognition

• Onset often follows a viral or bacterial infection 2
• About half of long COVID patients meet criteria for ME/CFS 3
• The condition can follow various pathogens including EBV, SARS-CoV-2, and others 3

Screening Approach

Use a 0-10 numeric rating scale for fatigue severity at every clinical encounter, with scores ≥4 requiring comprehensive evaluation including assessment of physical, cognitive, and emotional domains 1.

Critical Diagnostic Pitfalls to Avoid

1. Misattribution to Deconditioning

ME/CFS involves complex pathophysiology with immune dysfunction, mitochondrial abnormalities, and neurological changes—not simple deconditioning 2

2. Misdiagnosis as Psychiatric Disorder

ME/CFS is a biological illness with neurological and immunological components, not a psychiatric condition 2. While patients may develop secondary depression from disability, the primary illness is physiological 3

3. Overlooking Postexertional Malaise

This symptom is essential for diagnosis and distinguishes ME/CFS from other causes of chronic fatigue 2

Associated Biomedical Findings (Not Required for Diagnosis)

While not part of diagnostic criteria, these abnormalities are commonly found and support the diagnosis 3, 2:

• Diminished natural killer cell function and T cell exhaustion
• Mitochondrial dysfunction with impaired energy production
• Vascular and endothelial abnormalities including deformed red blood cells
• Neuroinflammation and reduced cerebral blood flow
• Hypothalamus-pituitary-adrenal axis dysfunction with low cortisol levels

Differential Diagnosis Considerations

Postural Orthostatic Tachycardia Syndrome (POTS) frequently co-occurs with ME/CFS and is characterized by heart rate increase ≥30 bpm within 10 minutes of standing without hypotension 2. Many ME/CFS patients have both conditions.

Long COVID shares similar pathophysiological mechanisms, with approximately half of long COVID patients meeting full criteria for ME/CFS 3, 2.