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Neurological Conditions

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome · G93.3

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem disorder characterized by debilitating fatigue lasting at least six months that does not improve with rest, accompanied by post-exertional malaise (PEM), sleep disturbance, cognitive impairment, and orthostatic intolerance.

2026-03-28

At a Glance

ME/CFS is a serious neurological, immunological, and autonomic nervous system disorder that differs from ordinary fatigue. The worldwide prevalence is approximately 0.2-0.4%, affecting an estimated 15-20 million people globally. Autonomic dysfunction (orthostatic intolerance, reduced HRV), immune hyperactivation, and energy metabolism disorders are recognized as key pathophysiological mechanisms. Although the etiology has not been fully elucidated and symptomatic treatment remains the mainstay, autonomic function assessment and intervention play an important role in symptom management.

Definition and Overview

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem disorder that causes significant functional impairment. The 1994 CDC (Centers for Disease Control and Prevention) criteria (Fukuda criteria) defined it as unexplained fatigue lasting six months or more accompanied by at least four of eight specified symptoms [1].

The 2015 Institute of Medicine (IOM) report proposed new diagnostic criteria (SEID criteria), emphasizing three core symptoms: substantial reduction in functioning with severe fatigue (six months or more), post-exertional malaise (PEM), and unrefreshing sleep. Additionally, at least one of cognitive impairment or orthostatic intolerance is required.

The worldwide prevalence is estimated at approximately 0.2-0.4% [2], with women affected approximately 2-3 times more frequently than men. The typical pattern involves previously high-functioning adults who experience abrupt functional decline following infection, surgery, or trauma.

Etiology

The pathophysiology of ME/CFS has not been fully elucidated, but multiple mechanisms are involved [2].

Post-infectious Onset

A substantial proportion of ME/CFS cases develop after infection. Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), enteroviruses, and SARS-CoV-2 have been reported as triggering agents [2]. Cases of Long COVID producing ME/CFS-like symptoms have increased dramatically following the COVID-19 pandemic.

Autonomic Dysfunction

Reduced heart rate variability (HRV) and orthostatic intolerance are consistently identified in ME/CFS patients [5]. Postural orthostatic tachycardia syndrome (POTS) has been reported to be comorbid in approximately 25-50% of patients [5]. Reduced cerebral blood flow upon standing, leading to worsening cognitive impairment and brain fog, is linked to autonomic dysfunction.

Energy Metabolism Dysfunction

Mitochondrial dysfunction affecting cellular energy production and alterations in energy metabolism pathways have been reported [4]. In particular, metabolomics analysis in ME/CFS patients has revealed metabolic patterns similar to the energy-conserving state of hibernating animals [4].

Immune Dysregulation

Immune regulatory abnormalities have been reported, including reduced natural killer (NK) cell function, cytokine imbalance, and neuroinflammation [2]. Neuroinflammation within the central nervous system contributes to neurological symptoms and cognitive impairment.

Symptoms

Core Symptoms

1. Post-exertional malaise (PEM)

PEM is the most characteristic symptom of ME/CFS. Fatigue, pain, and cognitive impairment markedly worsen 24-72 hours after physical or cognitive activity, and can persist for days to weeks. Unlike ordinary fatigue, it does not recover with rest, and exercise actually exacerbates symptoms [1].

2. Unrefreshing sleep

Despite sleeping for an adequate duration, patients persistently feel as though they have not slept at all. Polysomnography may reveal abnormal sleep architecture and reduced slow-wave sleep.

3. Cognitive impairment (brain fog)

Characteristic features include impaired concentration, short-term memory deficits, word-finding difficulty, and slowed information processing speed. It is described as "feeling like being in a fog" and is termed "brain fog."

4. Orthostatic intolerance

Dizziness, palpitations, headache, and cognitive impairment worsen when standing or sitting. POTS, orthostatic hypotension, and cerebral hypoperfusion are underlying causes [5].

Associated Symptoms

  • Myalgia, arthralgia
  • Headache (tension-type or migraine pattern)
  • Sore throat, cervical lymph node tenderness
  • Gastrointestinal symptoms such as irritable bowel syndrome
  • Sensitivity to light and noise
  • Sexual dysfunction, bladder hypersensitivity

Diagnosis

Diagnostic Criteria

There is no specific diagnostic test, so diagnosis is based on clinical criteria. Other organic causes (thyroid dysfunction, anemia, diabetes, sleep apnea, autoimmune diseases, cancer, depression, etc.) must first be excluded [1].

IOM (2015)/SEID criteria:
1. Fatigue lasting six months or more that substantially impairs daily functioning
2. Post-exertional malaise (PEM)
3. Unrefreshing sleep
4. Cognitive impairment or orthostatic intolerance (at least one)

Autonomic Function Assessment

Heart rate variability (HRV) analysis, tilt table testing, and active standing tests are used to evaluate the type and severity of autonomic dysfunction. Heart rate and blood pressure responses upon standing, as well as changes in cerebral blood flow, are measured [5].

Treatment

There is currently no curative treatment for ME/CFS. The treatment goals are symptom relief and maintenance of function.

Energy Management (Pacing)

The energy envelope strategy for preventing PEM is central. Patients identify their energy limits and regulate activity levels by maintaining heart rate below the anaerobic threshold (AT). Heart rate-based pacing using a heart rate monitor is utilized.

Graded exercise therapy (GET) may exacerbate PEM and requires caution in ME/CFS. The 2021 UK NICE guidelines withdrew their active recommendation of GET.

Treatment of Autonomic Dysfunction

When POTS is present, increased fluid and salt intake, compression stockings, midodrine, and pyridostigmine are used [5]. Neuromodulation therapies such as stellate ganglion block and tDCS are used as adjuncts for restoring autonomic balance.

Sleep Improvement

Sleep hygiene education and, when necessary, short-term sleep aids are used to improve unrefreshing sleep.

Symptomatic Treatment

  • Pain: Low-dose naltrexone (LDN), low-dose antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Brain fog: Treating orthostatic intolerance to improve cerebral blood flow may also alleviate cognitive symptoms.
  • Comorbid anxiety/depression: Low-dose SSRIs or SNRIs

Lifestyle Guide

  • Identify your energy limits and stay within them. Do not overexert even on days when you feel better.
  • Stay adequately hydrated (at least 2 liters per day) and maintain appropriate salt intake.
  • Maintain a regular sleep-wake rhythm, but limit naps to no more than 30 minutes.
  • Incorporate stress management techniques (mindfulness, relaxation training) into daily routines.
  • Keep a symptom diary to identify activities and situations that worsen symptoms.
  • Regularly share your condition with your physician and adjust the treatment plan accordingly.

Frequently Asked Questions

Ordinary fatigue recovers with adequate rest, whereas the fatigue of chronic fatigue syndrome does not improve with rest and actually worsens after physical or cognitive activity -- a hallmark known as post-exertional malaise (PEM). It is accompanied by brain fog, sleep disturbance, and orthostatic intolerance.

No single definitive cause has been identified. It frequently develops after viral infections (EBV, HHV-6, etc.), and research suggests that immune dysregulation, autonomic dysfunction, and mitochondrial energy metabolism disorders are involved in a complex manner.

Chronic fatigue syndrome is diagnosed based on clinical criteria, as there is no specific blood test. Other organic causes (thyroid dysfunction, anemia, diabetes, sleep apnea, etc.) are first excluded. Heart rate variability analysis and tilt table testing are used to evaluate autonomic dysfunction.

Unlike ordinary fatigue, excessive exercise in chronic fatigue syndrome can trigger PEM (post-exertional malaise), significantly worsening symptoms. A pacing strategy using the "energy envelope" approach -- maintaining heart rate below the anaerobic threshold -- is recommended.

There is currently no curative treatment, but the goal is symptom management and functional maintenance. Treatment of autonomic dysfunction, sleep improvement, pain management, and cognitive support help improve quality of life. Spontaneous improvement has been reported in some patients, but many require long-term management.

A substantial proportion of Long COVID patients -- those with fatigue, brain fog, and orthostatic intolerance persisting for months after COVID-19 infection -- meet the criteria for ME/CFS. Post-infectious autonomic dysfunction and immune dysregulation have been proposed as shared mechanisms.

References

  1. [1] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994). "The chronic fatigue syndrome: a comprehensive approach to its definition and study." Annals of Internal Medicine, 121: 953-959. DOI PubMed
  2. [2] Komaroff AL (2021). "Advances in understanding the pathophysiology of chronic fatigue syndrome." JAMA, 326: 1000-1001. DOI PubMed
  3. [3] Carruthers BM, Kumar Jain A, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles AC, Sherkey JA, van de Sande MI (2003). "Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols." Journal of Chronic Fatigue Syndrome, 11: 7-115. DOI
  4. [4] Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E (2016). "Metabolic features of chronic fatigue syndrome." Proceedings of the National Academy of Sciences, 113: E5472-E5480. DOI PubMed
  5. [5] Raj SR, Guzman JC, Harvey P, Richer L, Schondorf R, Seifer C, Thibodeau-Jarry N, Sheldon RS (2020). "Canadian cardiovascular society position statement on postural orthostatic tachycardia syndrome (POTS) and related dysautonomias." Canadian Journal of Cardiology, 36: 369-372. DOI PubMed

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