Differentials
Post-acute sequelae of coronavirus disease (COVID-19)
SIGNS / SYMPTOMS
Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, or COVID-19 "long haulers" develop symptoms of fatigue, cognition, worsened symptoms after physical or mental activities, chest pain, orthostatic symptoms of dizziness, palpitations, gastrointestinal symptoms, abnormal movements, chronic cough, changes in smell or taste, and hair loss, some of which are shared with ME/CFS.[165]
Anosmia, loss of taste, and chronic cough are SARS-CoV-2 symptoms that differentiate long COVID from ME/CFS. However, there are indications that airway symptoms may resolve over time leaving the residual core findings of ME/CFS.
Ongoing epidemiologic and clinical studies are needed to further differentiate long COVID and ME/CFS.
INVESTIGATIONS
Diagnosis of COVID-19 may be confirmed as probable or doubtful through polymerase chain reaction and antibody testing, COVID-19 symptom presentation, and community transmission.
Migraine
SIGNS / SYMPTOMS
Recurrent headaches lasting 4-72 hours.
Headache has at least 2 of the following characteristics: unilateral location; pulsating quality; moderate or severe pain intensity; or aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs).
Nausea and vomiting, and/or photophobia and phonophobia must also be present during headache episode.
Auras occur in approximately 33% of ME/CFS patients with migraine.[166]
Approximately 40% to 70% of patients with migraine meet the criteria for fibromyalgia and/or ME/CFS.
INVESTIGATIONS
Clinical diagnosis.
Anxiety
SIGNS / SYMPTOMS
Generalized anxiety disorder and other forms of anxiety can present with dizziness, dry mouth, dyspnea, sensation of choking, palpitations, tachycardia, nausea, stomach churning, excessive sweating, hot flushes, chills, trembling, or paresthesiae.
May co-occur with ME/CFS; around 40% people with ME/CFS have clinical depression and/or anxiety, which is similar to many other chronic medical illnesses.[160]
INVESTIGATIONS
Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) or International Classification of Diseases (ICD-11) criteria for an anxiety disorder.
Feelings that objects are unreal (derealization), that one's self is distant or not really here (depersonalization), fear of losing control or dying, and restlessness suggest an anxiety disorder. Difficulty falling asleep may be due to excessive worrying.
Major depressive disorder
SIGNS / SYMPTOMS
Feelings of sadness, hopelessness, helplessness, worthlessness, and/or guilt.
Loss of interest.
Psychomotor retardation or agitation.
Anhedonia.
Somatization.
Thoughts of suicide.
Standard ME/CFS criteria do not include diagnosis of depression, suggesting that major depression is not a typical feature of ME/CFS. However, depression may co-occur with ME/CFS; around 40% people with ME/CFS have clinical depression and/or anxiety, which is similar to many other chronic medical illnesses.[160]
INVESTIGATIONS
Meets DSM-5-TR or ICD-11 criteria for a depressive disorder.
The affective dysfunction does not follow an infection, and is not typically associated with new onset of pain, migraine, irritable bowel, or autonomic dysfunction. It is generally improved by exercise instead of exhibiting post-exertional malaise and exhaustion.
Sleep apnea
SIGNS / SYMPTOMS
Periodic breathing, transient dyspnea, or headaches upon arising may be observed.
INVESTIGATIONS
Overnight polysomnography is abnormal.
Sleep apnea may be a coexisting but independent finding that should be treated to see whether the fatigue and unrefreshing sleep improve.
Fibromyalgia
SIGNS / SYMPTOMS
Fibromyalgia is a syndrome characterized by widespread pain in the body present for at least 3 months, and is thought to be related to amplified pain signals in the spinal cord and brain.[153]
There is considerable overlap between fibromyalgia and ME/CFS, and it is often challenging to differentiate the two. In practice, a concomitant diagnosis of both conditions is often made.[10] A large portion of patients with fibromyalgia meet criteria for ME/CFS, including post-exertional malaise. In practice, diagnosis and treatment should consider the predominant phenotype: that is, if pain is the predominant issue and fatigue seems like a secondary symptom, it may be more appropriate to consider a preliminary diagnosis and offer initial treatment for fibromyalgia. If patients appear tender, but have significant fatigue, it may be more appropriate to consider a preliminary diagnosis and offer initial treatment for ME/CFS.
A multidisciplinary team may be required for diagnosis, with referral to appropriate specialists as part of the diagnostic exclusionary process.
INVESTIGATIONS
Clinical diagnosis.
Ehlers-Danlos syndrome
SIGNS / SYMPTOMS
Ehlers-Danlos syndromes (EDS) are a group of heritable disorders of connective tissue characterized by joint hypermobility, skin hyperextensibility, and tissue fragility that are associated with orthostatic intolerance.[167][168]
Classical EDS is determined by joint laxity and skin that is extremely hyperextensible and fragile, bruises easily, and has thin atrophic scars.
Hypermobile EDS is classified by history of dislocations, generalized joint laxity, and velvety texture of skin with an absence of extreme skin extensibility and profoundly abnormal scars.[168]
Vascular EDS is due to genetic variants of COL3A1, the gene encoding type III collagen.[169]
May co-occur with ME/CFS.[10] Joint hypermobility is more common in people with ME/CFS than in healthy controls (odds ratio 3.5).[170]
INVESTIGATIONS
Clinical diagnosis. Present from birth, and often diagnosed in childhood, although patients may be asymptomatic or have only mild symptoms.
Dehydration or volume depletion (e.g., due to diuretics)
SIGNS / SYMPTOMS
Postural hypotension, postural tachycardia.
INVESTIGATIONS
Recumbent and standing vital signs.
Infectious mononucleosis
SIGNS / SYMPTOMS
Fever, and enlarged spleen and/or liver. Waxing and waning symptoms. Periods of symptom remission suggestive of dormant Epstein-Barr virus.
More likely to be seen in adolescents.
INVESTIGATIONS
Positive for Paul-Bunnell heterophile antibody testing.
Positive for Epstein-Barr virus-specific antibodies. IgM indicates acute infection. IgG indicates prolonged humoral immune response.
Atypical lymphocytes; increased WBC count.
Positive reaction to the monospot test.
Irritable bowel syndrome (IBS)
SIGNS / SYMPTOMS
Manning criteria for IBS: abdominal pain or discomfort relieved by defecation; mild tenderness in lower quadrants (without a mass); alteration of bowel habits; abdominal bloating or distention; passage of mucus with stool.
Rome III criteria for IBS: recurrent abdominal pain or discomfort with improvement with defecation; onset associated with a change in frequency of stool; onset associated with a change in form of stool.[171]
INVESTIGATIONS
Clinical diagnosis.
Bristol stool scale is a visual scale for assessing the appearance (form) of stool that can be used for IBS subtyping.[172]
Chronic pelvic pain, vulvodynia
SIGNS / SYMPTOMS
Complex pain syndrome characterized by constant or intermittent generalized vulva pain (generalized vulvodynia), or localized burning sensations in the vestibule area when pressure is applied (vestibulodynia, or vulvar vestibulitis syndrome), in the absence of infectious, inflammatory, or neoplastic findings, or a specific clinically identifiable disorder of any kind (i.e., idiopathic).
Vulvar pain of at least 3 months' duration without an identifiable cause.[173]
INVESTIGATIONS
Physical exam of introitus.
Typically, vulvar tissue with vulvodynia appears normal, without infection or skin disease.
Orthostatic intolerance
SIGNS / SYMPTOMS
Orthostatic intolerance is defined by the dizziness, lightheadedness, nausea, spatial disorientation, visual changes, or malaise that are specifically linked to assuming or maintaining an upright posture. Symptoms abate once supine.[6][107][121]
History may include a cause of autonomic neuropathy (e.g., diabetes), neurologic disorder (e.g., Parkinson disease), volume depletion (e.g., due to diuretics or blood loss), causative medication, or other defined etiology.
INVESTIGATIONS
Focused testing when indicated may provide etiology.
Postural orthostatic tachycardia syndrome
SIGNS / SYMPTOMS
Sustained heart rate increment of >30 beats per minute (bpm; >40 for adolescents) within 5 minutes of standing or head-up tilt in the absence of orthostatic hypotension; standing heart rate >120 bpm. Other differentiating symptoms include visual blurring/tunnel vision, palpitations, tremulousness, weakness (especially in the legs), hyperventilation, shortness of breath, chest pain, and acral coldness or pain.[6][121][174]
May co-occur with ME/CFS.
INVESTIGATIONS
Exacerbated by exercise.
Tilt-table testing may be required for autonomic nervous system evaluation.
Idiopathic sinus tachycardia
SIGNS / SYMPTOMS
Elevated heart rate at rest and when recumbent. Sinus tachycardia when standing. The syndrome of inappropriate sinus tachycardia is defined as a sinus heart rate >100 bpm at rest (with a mean 24-hour heart rate >90 bpm not due to primary causes) and is associated with distressing symptoms of palpitations.[121]
INVESTIGATIONS
Exacerbated by physiologic and emotional stress. A 12-lead ECG is helpful for documenting tachycardia and determining sinus rhythm. A 24-hour Holter monitor may also be required.
Cardiovascular dysfunction
SIGNS / SYMPTOMS
Cardiovascular risk factors or symptoms/signs of cardiac ischemia or failure may be present.[175]
INVESTIGATIONS
Echocardiography.
Cardiology evaluation.
Lyme disease (and other endemic illnesses in different areas)
SIGNS / SYMPTOMS
Acute presentation of "bull's eye" rash.
INVESTIGATIONS
Clinical observation of rash; exposure to endemic Lyme areas.
Positive enzyme-linked immunosorbent assay and Western blot test.
Hypothyroidism
SIGNS / SYMPTOMS
Cold sensitivity, brittle fingernails/hair.
New-onset urticaria.
INVESTIGATIONS
Thyroid stimulating hormone is elevated in primary hypothyroidism.
Mild traumatic brain injury (mTBI)
SIGNS / SYMPTOMS
Many symptoms after mTBI are similar to chronic fatigue syndrome.[176]
History of trauma.
INVESTIGATIONS
Clinical diagnosis; brain magnetic resonance imaging may be considered, but has an approximately 10% rate of asymptomatic incidental findings that may confuse the diagnosis of ME/CFS.[177]
Gulf War illness (GWI)
SIGNS / SYMPTOMS
Military exposures in the 1990-1991 cohort of the first Persian Gulf War.[178][179]
The symptoms are similar to chronic fatigue syndrome, but there may be more severe irritable bowel syndrome with diarrhea, irritability, or PTSD.
INVESTIGATIONS
None in clinical practice.
Despite the similarity in symptoms, ME/CFS and GWI have different plasma metabolomic profiles.[180] Different responses to exercise measured by fMRI in the periaqueductal gray matter and reticular activating system of the midbrain have also been noted, suggesting differences in disease pathophysiology.[181]
Cancer and post-chemotherapy fatigue
SIGNS / SYMPTOMS
Fatigue is a common occurrence during and after cancer, and following treatment with chemotherapeutic drugs.[182]
INVESTIGATIONS
History of current/recent cancer.
Multiple sclerosis
SIGNS / SYMPTOMS
Diagnosed following at least 2 episodes of neurologic dysfunction (brain, spinal cord, or optic nerves) that are separated in space and time.
Classically presents with temporary sensory or visual loss, but patients may have subtle changes in vision, ambulation, or reflexes. Fatigue is common.
INVESTIGATIONS
If multiple sclerosis is suspected, brain MRI is a sensitive diagnostic test. Prudence in ordering MRI scans is warranted given that incidental findings of asymptomatic infarcts (7.2%), cerebral aneurysms (1.8%), and benign primary tumors (1.6%, mainly meningiomas) may lead to unwarranted investigations.[177]
Chronic idiopathic fatigue
SIGNS / SYMPTOMS
Diagnosis of exclusion when fatigue exists without sufficient other findings to designate ME/CFS or other illnesses.
Patients with chronic idiopathic fatigue do not have post-exertional malaise, and the physical and cognitive exhaustion can be overcome by cessation of physical, cognitive, emotional, or other activities combined with restful sleep, which is not the case in ME/CFS, where sleep is unrefreshing.
INVESTIGATIONS
Diagnosis is clinical.
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