This page breaks down the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and provides videos, handouts, and health management guidance.

ME/CFS Diagnostic Criteria 

National Academy of Medicine 2015 Diagnostic and Treatment Guidelines

A diagnosis of ME/CFS requires the patient to have three core symptoms: 

  • Impairment of normal function accompanied by fatigue >6 months
  • Post-exertional malaise (PEM)*
  • Unrefreshing Sleep* 

Plus at least one of the following manifestations: 

  • Cognitive Impairment*
  • Orthostatic Intolerance (OI)

*Must be moderate-to-severe and present >50% of the time


Plus at least one of the following manifestations: 

  • Cognitive Impairment*
  • Orthostatic Intolerance (OI)

*Must be moderate-to-severe and present >50% of the time


Additional Symptoms Supporting Diagnosis

Immune impairment: Acute infection-like onset, susceptibility to infection, perpetual flu-like symptoms, sore throat, tender lymph nodes, fever, new or worsened sensitivities to certain substances (e.g. foods, odors, medications, chemicals). Poor NK cell cytotoxicity (NK cell function, not number) correlates with illness severity in patients and could serve as a biomarker for the severity of the disease.

Neurological impairment: Impaired psychomotor function, muscle weakness, twitching, instability, spatial disorientation, ataxia, sensory changes (e.g. sensitivity or intolerance to light, noise and touch).

Other: Gastrointestinal impairments, genitourinary impairment, neuroendocrine manifestations (e.g. cold extremities, weight change, excessive sweating, high/low temperature, chills/shivers, loss of appetite, alcohol intolerance).

Pain: Headaches, arthralgia, myalgia, other pain symptoms (all highly variable in presence, nature and severity).

Other comoribid conditions may exisit in those with ME/CFS. For more about diagnosis and managment of these common comorbidities see our video series on Unraveling the Complexities of Pain & Fatigue as well as the Long COVID & Post-Viral Syndromes ECHO.

Diagnosing and Managing ME/CFS

U.S. ME/CFS Clinician Coalition 

Mayo Clinic Proceedings

Center for Disease Control (CDC)

Doctors with M.E.

Michigan State Medical Society (1.5 CME credits)

Long COVID & Fatiguing Illness Recovery Program

For CME specific to diagnosing and managing ME/CFS and related comorbid conditions, please refer here. 


Top Medical Professional Resources

Care Considerations 

Orthostatic Intolerance 

    Post-Exertional Malaise (PEM)

    Pre-visit Forms for Patients 

    University of Utah Health Project ECHO  (click for playlist pop-out!)

    Note:  Live ECHO sessions are reserved for healthcare professionals only. 1 CME credit, didactic, and case presentations.  


    Criteria Specific Assessment & Management

    Within each of the following syndrome criteria, you will find more information about the symptom with respective guidance on assessment and management.

    Substantial Reduction or Impairment

    There is sufficient evidence to suggest that fatigue in ME/CFS is profound, not the result of ongoing excessive exertion, and is not substantially alleviated by rest.

    Fatigue must be accompanied by a substantial reduction or impairment in one’s ability to engage in pre-illness levels of occupational, educational, social, or personal activities, and must persist > 6 months.

    Identification & Management

    Fatigue, and particularly the impact of illness on function, should be assessed in making a diagnosis of ME/CFS.

    Assessing Impaired Function (in association with fatigue)

    1. Questionnaires:
    2. Hours of Upright Activity (HUA)
      • An effective tool in estimating impaired function is to evaluate an individual’s hours of upright activity (HUA). This accounts for time with feet on the floor,  IE: Walking, standing, and sitting.
        • Consider asking your patient to fill out this simple Health Assessment Form which can provide you with a snapshot into what they are experiencing. This may also be used to help the patient describe their “good days” and “bad days.”
    3. 2 day CPET testing


    Address impaired function and provide support as needed. By definition, patients with ME/CFS have significant disability. Patients may need help in obtaining accommodations for school and work or when applying for disability. They may also need parking permits, assistive devices, and/or home health aides. Due to financial impact, some patients may need help with shelter and food.

    Post-exertional malaise (PEM)

    PEM is worsening of a patient’s symptoms and function after exposure to physical, cognitive, orthostatic exertion and/or emotional stressors, which were previously tolerated before disease onset. Exceeding cellular energy capacity results in a “payback of symptoms” or “crash” which can occur up to 24-48 hours after peak exertion. A crash can last for hours, days, weeks, and even months in severely ill patients. True PEM is pathognomonic for ME/CFS and can help distinguish against other illnesses.

    Identification & Management

    The Institute of Medicine defines post-exertional malaise as an “inability to recover normally following physical, cognitive, or emotional exertion,” resulting in a “level of fatigue that is more profound, more devastating, and longer lasting than is observed in patients with other fatiguing disorders.”

    This fatigue is accompanied by a profound loss of stamina and overall reduction in functional capacity for the duration of the episode of PEM. This immense fatigue appears to be accompanied by augmented perturbations of physiological dysfunction, including aberrancies among both autonomic functioning and hypothalamic-pituitary-adrenal (HPA) axis functioning.

    Patients experiencing post-exertional malaise often describe an augmentation of “flu-like symptoms”  (including subjective fevers, sore throats, myalgia, and arthralgia) worsening cognitive symptoms (including brain fog, difficulty with maintaining concentration, and word-finding difficulties), worsening insomnia, headaches, increasing sensitivity to sensory stimuli such as light or sound, and/or exaggerations of their abnormal cardiovascular responses to upright positioning, also referred to as “orthostatic intolerance.”

    It is not uncommon for those experiencing the symptoms of PEM to remain confined to bed for much of the duration of their episode, often so functionally limited that they struggle to complete simple activities of daily living such as toileting or eating prepared food.

    Approaching PEM

    Bateman Horne Center has partnered with the University of Utah Health to conduct a Long COVID and Post-Viral Syndromes ECHO (Project ECHO). This series delivers information to healthcare professionals utilizing short didactics and case-based learning to enhance their ability to manage patients with long COVID, ME/CFS, FM, and related comorbid conditions. Watch the video recording or view Dr. Yellman’s presentation slides!

    In this presentation, Brayden Yellman, MD, reviews:

      • PEM presentation in post-acute sequelae of COVID-19 (PASC/long COVID), ME/CFS, and related post-viral syndromes (PVS)
      • Triggers and PEM onset
      • The science behind PEM: VAT reductions, decreased aerobic metabolism, altered cellular metabolism, neurobiological changes, dorsal midbrain activity post-exercise
      • Clinical implications of PEM
      • How to clinically manage PEM

    Assessing PEM

    PEM assessment often overlaps that of impaired function. Providers can discern a great deal of information from a patient simply by asking a few targeted questions, and utilizing these simple, yet individualized tools.

      1. Questionnaires:
      2. Hours of Upright Activity (HUA)
        • An effective tool in estimating impaired function is to evaluate an individual’s hours of upright activity (HUA). This accounts for time with feet on the floor. This includes: walking, standing, and sitting.
      3. Two-day CPET testing (use with caution, as this may induce severe PEM symptoms)
      4. Guided provider questions
          • “What happens when you engage in normal (previously tolerated) physical or mental exertion?”
          • “How much activity does it take to make you feel ill or to trigger illness worsening?”
          • “How long does it take to recover from physical or mental effort?”
          • “Do you avoid or change certain activities because of what happens after you do them?”
      5. Patients may describe:
          • A crash, relapse, collapse after physical activity
          • Being mentally tired after the slightest effort
          • Being physically drained or sick after mild activity
          • The more demanding, prolonged or repeated the activity, the more severe and prolonged the payback



    The key to managing ME/CFS lies in the ability to recognize and understand physical and cognitive limitations, and teaching patients how to “pace” all activity to prevent severe or prolonged PEM.

    An important role for the medical provider is to teach patients about PEM and how to manage through pacing. Pacing is an individualized approach to managing physical, cognitive, and emotional energy within a patient’s specific limits by carefully planning where and how to spend their available energy. It is a critical tool to prevent and/or reduce PEM.

    • Ideally, the patient should only engage in the amount of activity that doesn’t induce PEM in 24-48 hours. The goal is to get back to “baseline” the following morning. If PEM is induced, rest is required until it resolves.
    • Help the patient develop a heightened sense of awareness about the threshold of relapse and the consequences of moving beyond their envelope.
    • Activity logs, heart rate monitors, smart watches, and the Oura Ring are all helpful tools to give immediate/daily/weekly/monthly feedback on activity and pacing.

    Unrefreshing Sleep

    Sleep that remains non-restorative and unrefreshing regardless of sleep duration.

    Identification & Management

    Unrefreshing sleep is the most consistently reported symptom in those with ME/CFS. This may include insomnia, sleep disturbances, daytime sleepiness, and irregular sleep cycles. While polysomnography is not required to diagnose ME/CFS, it may reveal abnormal sleep architecture with delayed onset of sleep, fragmented sleep, increased alpha waves and decreased delta waves.

    Assessing Unrefreshing Sleep

    Polysomnography may be helpful in screening for treatable (primary) sleep disorders. Diagnosis of a primary sleep disorder does not rule out a diagnosis of ME/CFS.

    Test affordable wearable devices that can be used at home over long periods of time to get a more realistic picture of disturbed sleep patterns.

    • Fitbit, Apple Watch, etc. 
    • Oura Ring (


    1. Treat primary sleep disorders if indicated
    2. Identify central sensitivities which disturb sleep and target treatment
        • Pain amplification/hyperalgesia (fibromyalgia)
        • Sensory amplification (noise/bright light/temperature)
        • Central “overload” PEM disturbs and unravels normal sleep
    3. Addressing reversible sleep disturbances
        • Caffeine, alcohol, decongestants, stimulants
        • Avoid brain activating activities before bed
        • Treat restless leg syndrome (RLS0, myoclonus and periodic limb movement disorder (PLMD)
        • Treat Obstructive Sleep Apnea (OSA)
        • Address Central Sleep Apnea
          • Reduce medications that cause CNS depression


    1. Longer acting sleep “sustainer” examples used off-label for sleep:
      • *These longer acting drugs may cause “hangover” symptoms the next morning if dosed too high or taken too late in the evening. Choose a sleep medication based on comorbid conditions and the nature of the sleep disturbances.*
        • *TCA: amitriptyline, doxepin
        • Other antidepressants: trazodone, mirtazapine
        • *Anticonvulsants:  gabapentin, topiramate
        • Benzodiazepines:  clonazepam, lorazepam, temazepam
        • Neuroleptics: quetiapine, olanzapine
    2. Sleep “initiators” or hypnotics FDA approved for insomnia, not specifically for FM or ME/CFS. Chronic use is discouraged, and thus problematic for chronic insomnia. Tolerance or dependence typically develops. Better for sleep initiation than to sustain sleep all night. Consider PRN use.
        • Zolpidem
        • Zaleplon
        • Eszopiclone
        • Benzodiazepines (be mindful of habituation)
    3. Sleep Disturbances
        • Belsomra/suvorexant
        • An orexin recepor antagonist (suppresses wakefulness)
        • Note: may prove different than other sleep agents. There is not a generic form, so the cost to the patient is higher.

    Cognitive Impairment

    Cognitive impairment may include short-term memory problems, inability to concentrate, difficulty expressing thoughts, confusion, disorientation, and difficulty performing simple activities. Slowed information processing is common, and may play a role in overall neurocognitive impairment.

    Identification & Management

    Impairments of cognitive function, and particularly slowed information processing, are frequently reported in those with ME/CFS. Many patients will describe a “mental cloudiness” or “brain fog” resulting in difficulties concentrating, forming sentences, finding words, and memory recall.

    Cognitive performance often worsens as a consequence of continued physical, mental, emotional, or orthostatic exertion. Symptoms can wax and wane with energy expenditure.

    Assessing Impairment

    Neuropsychological testing is not necessary for diagnosis, however, it can be used to observe slowed information processing, memory impairments, reduced attention, and impaired psychomotor function.

    Neurocognitive testing: Use brain testing software that can assess processing speed and reaction time in minutes to measure brain fog.

    Signs of cognitive impairment:

    • Difficulty remembering instructions from previous visits
    • Completely forgetting to do something suggested from a previous visit
    • Delayed verbal responses that worsens as fatigue progresses
    • Easily confused by long complex explanations or instructions
    • Looks to companion for help answering questions or remembering details
    • Trouble remembering medications and pill strength
    • Dull eyes
    • Brings notes to visit to remember items of discussion
    • Attempts to take notes during visit but may have trouble


    Cognitive slowing, cognitive fatigability and cognitive PEM may be the most limiting aspects of ME/CFS illness, and a primary reason people with ME/CFS are unable to sustain employment or succeed in school. Helping the patient to recognize this process, learn how to pace and manage their energy envelope is critical.

    General Principles of Supportive Management

    1) Address all other conditions (complete a good medical work-up).  Rule out: anemia, thyroid, diabetes, sleep apnea, low Vit B12, polypharmacy, etc. 

    2) “Pace.” Work with patient to recognize energy depletion to prevent symptom escalation. Focus on preventive activity management, and reduce overload.

    3) Address the major aspects of illness

    • Pain: reduce severe pain
    • Sleep: achieve restorative sleep
    • Mental health: provide insight and support
    • Fitness: engage in restorative exercise
    • Orthostatic Intolerance

    4) Address potential contributors to “brain fog” and cognitive slowing

    • Medications for sleep, pain, anxiety, migraine, etc.
    • Chronic sleep disturbances
    • Secondary mental health conditions, ie: depression, anxiety
    • Orthostatic intolerance and other causes of reduced cerebral blood flow and perfusion.
    • Cognitive fatigue and fatigability
    • Low cellular energy production
    • Capacity for “function” is reduced
    • PEM—the consequences of exceeding cell energy capacity

    5) Medications that might help brain fog and cognitive impairment

    • Wellbutrin/bupropion
    • Stimulants – caution: can lead to a crash or PEM
    • Methylphenidate (Ritalin)
    • Dexadrine (Adderall) – caution: can raise BP and HR
    • Newer drugs for daytime somnolence
    • Modafinil (Provigil) and armodafinil (Nuvigil) – caution: can disrupt sleep
    • Supplements (a few examples, not supported by strong evidence)
      • Fish oil, omega 3 fatty acids
      • Phosphatidyl serine
      • Curcumin (from turmeric)
      • B vitamins (B6, B9, B12) related to homocysteine metabolism
      • Vitamin E (tocopherol), Vitamin A, Vitamin C

    6) Behavioral strategies for managing cognitive impairment

    • Allow more time and minimize interruptions
    • Complete cognitive tasks when more rested or during the individual’s best time of day
    • Utilize day-timer, iPhone, other recording/signaling devices
    • Dampen or remove other sensory input to the brain
      • Quiet room, ear plugs or sound-reducing headphones
      • Lower lighting, minimize glare on screens and devices
      • Reduce the number of people or other chaotic signaling/disruption

    Orthostatic Intolerance (OI)

    Orthostatic intolerance, at its core, is a manifestation of a group of heterogenous clinical conditions in which a constellation of symptoms notably worsen as a result of the sole challenge of upright posture.  These symptoms can be prevented by, become ameliorated by, or be reduced by recumbent positioning.

    Identification & Management

    Among those with ME/CFS, exacerbation of overall fatigue and function has been reported with upright stressors such as physical exertion, prolonged standing, warm environments, hot showers, and after lightheaded episodes. Validated N-Back task testing has observed pronounced cognitive delays, increase in testing errors, and decrements in memory, concentration, and information processing that directly correlate with the degree of tilt upon formal tilt table testing. At its core, upright positioning appears to increase venous pooling in the setting of decreased compensatory vasoconstriction in those with dysautonomia related to ME/CFS, resulting in decreased cerebral blood flow and a compensatory increase sympathetic nervous system response.

    Defined Syndromes of Chronic Orthostatic Intolerance (OI)


    • Orthostatic Hypotension: A BP reduction of at least 20mm Hg systolic or 10mm Hg diastolic within the first 3 minutes of upright posture.
    • Postural Orthostatic Tachycardia Syndrome (POTS): the reproduction of orthostatic symptoms with a +30 bpm increase in HR, from supine to 10 min upright, or an increase in HR of greater than/equal to 120 bpm. Age 12-19 heart rate increase must be +40 bpm.
    • Neurally Mediated Hypotension/Syncope (NMH/S): synonymous with vasovagal syncope, neurocardiogenic syncope.
      (Freeman R et al., Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.  Clin Auton Res. 2011 Apr;21(2):69-72.)


    Nonpharmacological Interventions

    • Increasing intravascular volume, often by aggressively increasing intake of fluid and sodium, can have an enormous clinical impact.
    • Mixtures of electrolyte rehydration packets dissolved within fluids that can be sipped throughout the day and “chugged” in boluses prior to physical or cognitive exertional challenges.
    • IV normal saline boluses are quite effective for both initiation of treatment and for rescue therapy among highly symptomatic or dehydrated patients.
    • External compression with compression clothing may prevent dependent venous pooling and increase venous return to the right atrium.  The more surface area upon which compression can be applied, the more notable the clinical response.


    Pharmacological Interventions

    • Fludrocortisone is often prescribed to assist with renal water and sodium retention.
    • Desmopressin can drastically reduce water losses and increase peripheral vasoconstriction.
    • Pharmacological compression by alpha-1 agonists like Midodrine can increase peripheral vascular resistance through constriction of arteries and veins.
    • Off-label use of pyridostigmine can be life-changing for some with ME/CFS. This drug appears to increase systemic oxygen extraction in tissues, resulting in pre-ganglionic acetylcholine stimulation of sympathetic ganglions innervating tissue arterioles with post-ganglionic fibers that result in tissue vasoconstriction and measurable increases in cardiac preload. Pyridostigmine also appears to increase parasympathetic inputs upon heart rate.
    • Low doses of non-selective beta blockers like propranolol and bisoprolol may be used to reduce rapid heart rates responses and may also interfere with the binding of adrenergic autoantibodies now known to be present in those with ME/CFS.
    • Beta blockers must be used with caution, however, as excessive heart rate suppression may inhibit compensatory heart rate increases intended to augment cardiac output for the support of physical or cognitive activities.

    Unraveling the Complexities of Chronic Pain & Fatigue Series 

    Understanding Illness Overlap and Post-Viral Syndromes 

    ME/CFS- The Severely and Very Severely Affected

    “ME/CFS—The Severely and Very Severely Affected” is a proposed themed Special Issue of Healthcare concerning housebound and bedbound Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. Our intent is to redefine ME/CFS as the serious disease that it is. Up to this point in time, all literature and case definitions of ME/CFS have excluded severely and very severely affected patients, and diagnosis, patient management, and case definitions have been based on the ambulatory ME/CFS patient. Although never formally studied, it is estimated that twenty-five percent of ME/CFS patients are either severely or very severely affected. What other disease’s diagnosis, patient care, and case definition exclude the most severely ill twenty-five percent?

    We aim to document, describe, and promulgate what can and should be done for this hidden patient population. By focusing on the severely affected, it is our hope that the pathophysiological nature of the disease will be better accepted and understood, and effective methods of symptom reduction and patient improvement will be placed in the medical literature. Kenneth J. Friedman, Ph.D. is serving as Guest Editor of the issue, with Drs. Lucinda Bateman and Kenny DeMeirlier serving as co-guest editors. If you would like to consider submitting a manuscript or have questions concerning the submission of a manuscript, please contact the guest editors.

    Dr. Kenneth Friedman
    Dr. Lucinda Bateman
    Prof. Kenny Leo De Meirleir
    Guest Editors

    Journal Articles

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