Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome¶
Chapter 461 | Part 13: Neurologic Disorders | Section 4: Syndromes Associated with Fatigue · Part 13 – Neurologic Disorders · Chapter 461
Key Clinical Points¶
- Hallmark: Persistent, unexplained fatigue resulting in significant functional impairment.
- Postexertional Malaise (PEM): Worsening of symptoms after physical, mental, or emotional exertion; lasts >1 day to weeks.
- Epidemiology: 3-4 times more common in women; peak prevalence at ages 40-50; 836,000 to 3.3 million Americans affected.
- IOM 2015 Criteria: Requires fatigue (>6 months), PEM, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance.
- Management: No approved drugs; focus on individualized pacing to avoid 'push and crash' cycle.
- Pathophysiology: Complex multisystem disorder involving immune, autonomic, HPA axis, metabolism, and microbiome systems.
- Post-infectious: ~10% of infections (e.g., EBV, SARS-CoV-2) may lead to persistent illness resembling ME/CFS.
- Clinical Trap: Patients may appear well during an office visit but relapse after exertion surrounding the consultation.
- Early Evaluation: Consider for symptoms >1 month; support can begin as early as 4-6 weeks post-onset.
- Comorbidities: High overlap with fibromyalgia, POTS, Sjögren's, and other autoimmune/autonomic conditions.
DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): The hallmark of ME/CFS is persistent and unexplained fatigue resulting in significant impairment in daily functioning, along with worsening symptoms following physical or mental exertion that would have been tolerated before illness (postexertional malaise). • Clinical Nature: Chronic complex illness with multisystem manifestations and long-term impact on functional impairment comparable to multiple sclerosis, rheumatoid arthritis, and congestive heart failure. • Associated Symptoms: Pain, cognitive dysfunction, unrefreshing sleep, headache, sore throat, tender lymph nodes, muscle aches, joint aches, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. • Nomenclature History: ◦ ME: Historically implied absence of definitive inflammation in brain/spinal cord. ◦ CFS: Criticized for trivializing the illness by confusing it with general fatigue. ◦ ME/CFS: Composite name adopted by U.S. Dept. of Health and Human Services to address limitations of both terms. • Clinical Awareness:* Recognition as one diagnosable condition in Long COVID has increased awareness, though stigma remains.
EPIDEMIOLOGY¶
• Prevalence: 836,000 to 3.3 million Americans affected. • Demographics: ◦ Sex: 3-4 times more common in women than men. ◦ Age: Peak prevalence 40-50 years; broad range including children and adolescents. ◦ Race/Ethnicity: All races and ethnicities are affected. ◦ Socioeconomic Status: Some evidence that socioeconomically disadvantaged groups are at increased risk. • Economic Impact: Costs U.S. economy 18 to 51 billion annually (medical costs + lost income). • Diagnosis Gap: ≥80% of those meeting criteria for ME/CFS had not been diagnosed by a health care provider.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Infectious Triggers: ◦ Viral: Epstein-Barr virus, SARS-CoV-1, SARS-CoV-2. ◦ Nonviral: Ross River virus, Coxiella burnetti (Q fever), Ebola virus, Giardia. ◦ Persistence: ~10% of those infected remain ill for ≥6 months. • Non-infectious Stressors: Toxins, physical trauma, adverse events, and allostatic load ('wear and tear'). • Genetic/Environmental: Twin studies and family histories suggest roles for both shared environment and genetic factors. • Immune System Alterations (Inconsistent findings): ◦ Antinuclear antibodies: Modest elevations. ◦ Immunoglobulins: Reductions in subclasses. ◦ Lymphocyte proliferation: Deficiencies in mitogen-driven. ◦ Natural killer cells: Reductions in activity. ◦ Cytokines: Disturbances in production; hypothesis of excess IL-1 or interferon α lacks compelling data. • Systemic Dysfunctions: ◦ Autonomic nervous system dysfunction. ◦ Hypothalamic-pituitary-adrenal (HPA) axis abnormalities. ◦ Altered metabolism and intestinal microbiome dysbiosis. ◦ Brain imaging: Nonspecific changes in regional structures.
CLINICAL FEATURES¶
• Core Diagnostic Symptoms (IOM 2015): ◦ Fatigue: Profound, new/definite onset (not lifelong), not from excessive exertion, not substantially alleviated by rest. ◦ Duration: >6 months. ◦ Postexertional Malaise (PEM): Worsening of symptoms after physical, mental, or emotional exertion that would not have been problematic before illness; lasts >1 day and sometimes weeks. ◦ Sleep: Unrefreshing sleep. ◦ Cognitive: Impairment ('brain fog'). ◦ Orthostatic: Orthostatic intolerance. • Additional Symptoms (Table 461-2): ◦ Joint pain without swelling/redness; muscle aches; new headaches; tender lymph nodes. ◦ Sensitivity to sensory stimuli (light, noise, smells); sore throat; shortness of breath. ◦ Irregular heartbeat; alcohol intolerance; difficulty with temperature regulation (feeling feverish or chilled). ◦ Psychiatric problems; allergies; abdominal cramps. • Temporal Course & Presentation: ◦ Onset: Sudden (within day/week) or gradual. ◦ Clinical Trap: Patients may appear well during an office visit, only to relapse after exertion surrounding the consultation. ◦ PEM Recognition: Relation of relapse to activity level may not be apparent; PEM may not be recognized.
DIFFERENTIAL DIAGNOSIS¶
• Clinical Evaluation: Required to identify and treat other illnesses that could explain or contribute to symptoms. • Comorbid Conditions (Table 461-3): ◦ Chronic overlapping pain: Fibromyalgia (FM), chronic migraine, temporomandibular joint disease (TMJ), irritable bowel syndrome (IBS), endometriosis, vulvodynia, urologic chronic pelvic pain syndromes (UCPPS). ◦ Autonomic/Systemic: Postural orthostatic tachycardia syndrome (POTS), Sjögren's syndrome, Ehlers-Danlos syndrome, Mast cell activation syndrome (MCAS), Dysautonomia. ◦ Others: Allergies, multiple chemical sensitivities.
INVESTIGATIONS & DIAGNOSIS¶
- Clinical Assessment: Evaluation by an experienced clinician to identify cases based on patient-reported symptoms.
- Patient Interview: Ask specific questions regarding current activity levels vs. pre-illness, what triggers relapse, and how long it takes to recover after exertion.
- Laboratory Panel (Rule out other causes): ◦ CBC; ESR; Electrolytes; Fasting glucose. ◦ Renal function: BUN, GFR. ◦ Calcium, phosphate. ◦ Liver function: Bilirubin, ALT, ALP, AST, GGT, total protein, albumin/globulin ratio. ◦ C-reactive protein. ◦ Thyroid function: TSH, free thyroxine. ◦ Iron studies: Serum iron, transferrin saturation, ferritin. ◦ Celiac disease screening; Urinalysis.
- Early Identification: ◦ Consider ME/CFS for symptoms persisting >1 month. ◦ Evaluation and support can begin as early as 4-6 weeks after onset.
MANAGEMENT & TREATMENT¶
- General Principles: ◦ No approved drugs to treat or cure ME/CFS. ◦ Individualized plan based on most problematic symptoms. ◦ Medication Sensitivity: Patients are more sensitive to medications; start at lower doses and increase slowly. ◦ Avoidance: Narcotics should be avoided; avoid toxic, expensive, or unreasonable modalities.
- Pharmacologic Management: ◦ Acyclovir: No significant benefit. ◦ Fludrocortisone: No significant benefit. ◦ Galantamine: No significant benefit. ◦ Modafinil: No significant benefit. ◦ IVIG: No significant benefit. ◦ Rituximab: Large prospective double-blind study found no benefit.
- Nonpharmacologic Management: ◦ Sleep: Sleep hygiene. ◦ Pain: Massage, acupuncture, hot/cold packs. ◦ Activity Management (Pacing): → Identify limits → avoid 'push and crash' cycle → maintain tolerated activity levels → advance activity very gradually as tolerated.
PROGNOSIS & COMPLICATIONS¶
• Functional Impact: Long-term impact on functional impairment comparable to MS, RA, and CHF. • Economic Burden: 18-51 billion annual cost to U.S. economy.
KEY PEARLS & CLINICAL TRAPS¶
• PEM Definition: Worsening of symptoms after exertion not previously problematic; lasts >1 day, sometimes weeks. • Clinical Trap (Appearance): Patients may appear well during an office visit but relapse from exertion surrounding the consultation. • Clinical Trap (Recognition): Relation of relapse to activity level may not be apparent; PEM may not be recognized. • Management Strategy: Educate on 'push and crash' cycle; use pacing to maintain tolerated levels and minimize deconditioning.
Reference Tables¶
TABLE 461-1 2015 Institute of Medicine Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome…¶
Harrison's 22e, p.3650
- Substantial reduction or impairment in the ability to engage in pre-illness
levels of activity (occupational, educational, social, or personal life) that:
• lasts for >6 months
• is accompanied by fatigue that is often profound, of new or definite onset (not
lifelong), not the result of ongoing excessive exertion, and is not substantially
alleviated by rest - Postexertional malaise (PEM)a—worsening of symptoms after physical, mental,
or emotional exertion that would not have caused a problem before the illness - Unrefreshing sleepa
- Cognitive impairment or orthostatic intolerancea
TABLE 461-2 Additional Symptoms Experienced by Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Joint…¶
Harrison's 22e, p.3650
- Joint pain without swelling or redness
- Muscle aches
- New headaches
- Tender lymph nodes
- Sensitivity to sensory stimuli (e.g., light, noise, smells)
- Sore throat
- Shortness of breath
- Irregular heartbeat
- Alcohol intolerance
- Difficulties with temperature regulation (feeling feverish or chilled)
TABLE 461-3 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Comorbid Conditions Chronic overlapping pain conditions…¶
Harrison's 22e, p.3650
- Chronic overlapping pain conditions: fibromyalgia (FM), chronic migraine,
temporomandibular joint disease (TMJ), irritable bowel syndrome (IBS),
endometriosis, vulvodynia, urologic chronic pelvic pain syndromes (UCPPS) - Postural orthostatic tachycardia syndrome (POTS)
- Allergies
- Sjögren’s syndrome
- Ehlers-Danlos syndrome
- Mast cell activation syndrome (MCAS)
- Dysautonomia
- Multiple chemical sensitivities