Chronic Fatigue Syndrome (ME/CFS)

Quick Reference

Critical Alerts

• Post-exertional malaise (PEM) is the hallmark feature: Delayed worsening of symptoms 12-72 hours after physical, cognitive, or emotional exertion is pathognomonic
• Diagnosis of exclusion: Must rule out thyroid disease, diabetes, anemia, coeliac disease, sleep apnea, malignancy, and primary psychiatric disorders before diagnosis
• NICE NG206 (2021) paradigm shift: Graded exercise therapy (GET) removed as treatment; energy management (pacing) is now central
• Do NOT recommend "pushing through": Overexertion worsens PEM and can cause permanent deterioration
• 25% of patients are housebound or bedbound: ME/CFS can be severely disabling; severity ranges from mild to very severe
• No diagnostic biomarker exists: Diagnosis is clinical based on symptom criteria (IOM 2015, NICE 2021)
• Long COVID overlap: Many post-COVID patients meet ME/CFS criteria; same management principles apply
• CBT is adjunctive only: CBT helps manage impact of illness but is NOT curative; do not present as treatment for ME/CFS itself

Classic Presentation

• difficulty concentrating, word-finding, short-term memory | | Orthostatic Intolerance | Dizziness, lightheadedness, palpitations on standing; may have POTS | | Duration | Symptoms present for at least 6 months (3 months for suspected) | | Pattern | Fluctuating; often worse after exertion ("boom-bust" cycles) |

Emergency Considerations

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Definition

Overview

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, multisystem disease characterized by profound fatigue not explained by ongoing exertion, not substantially relieved by rest, and accompanied by post-exertional malaise (PEM), unrefreshing sleep, and cognitive dysfunction. [1,2] The condition represents a significant clinical challenge due to its heterogeneous presentation, lack of validated biomarkers, and limited treatment options. [3]

The Institute of Medicine (IOM), now the National Academy of Medicine, published landmark diagnostic criteria in 2015 and proposed the alternative name "Systemic Exertion Intolerance Disease" (SEID) to better reflect the pathophysiology. [2] The NICE guideline NG206 (2021) represented a paradigm shift in UK clinical practice, removing graded exercise therapy (GET) as a treatment option and emphasizing patient-centered, pacing-based management. [1]

ME/CFS affects an estimated 0.2-0.4% of the population worldwide, with significant underdiagnosis. [4] The condition can range from mild (ambulatory with reduced activity) to very severe (bedbound, totally dependent for care). Approximately 25% of patients are housebound or bedbound at some point. [5] The economic burden is substantial, with estimated annual costs of $17-24 billion in the United States alone due to lost productivity and healthcare utilization. [6]

Diagnostic Criteria

IOM/National Academy of Medicine Criteria (2015) [2]:

Diagnosis requires all three of the following:

1. Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, persisting for more than 6 months, accompanied by fatigue that is:

   • Profound
   • Of new or definite onset (not lifelong)
   • Not the result of ongoing excessive exertion
   • Not substantially alleviated by rest

2. Post-exertional malaise (PEM): Worsening of symptoms following physical, mental, or emotional exertion that would not have caused a problem before illness onset

3. Unrefreshing sleep: Despite adequate duration, patients feel unrestored after sleep

Plus at least one of:

• Cognitive impairment (problems with memory, concentration, word-finding)
• Orthostatic intolerance (symptoms worsen upon assuming and maintaining upright posture)

NICE NG206 Criteria (2021) [1]:

All four symptoms must be present:

1. Debilitating fatigue that is worsened by activity, not caused by excessive physical or cognitive exertion, not significantly relieved by rest, and not explained by another condition
2. Post-exertional malaise after activity - delayed worsening of symptoms with prolonged recovery
3. Unrefreshing sleep or sleep disturbance (or both)
4. Cognitive difficulties ("brain fog")

Duration requirements:

• Suspected ME/CFS: Symptoms for at least 3 months
• Diagnosis confirmed: Symptoms for at least 6 months

Classification by Severity

Severity-Specific Features [1,5]:

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Epidemiology

Prevalence and Incidence

Demographics

Risk Factors and Triggers

Key Epidemiological Points:

• 75-80% of patients report onset following acute infection [10]
• Significant "iceberg" of undiagnosed cases - estimated 84-91% undiagnosed [2]
• Higher rates in healthcare workers and other high-stress occupations [7]
• COVID-19 pandemic has significantly increased post-viral fatigue presentations [9]

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Pathophysiology

Current Understanding

The exact etiology of ME/CFS remains unknown. It is likely a heterogeneous condition with multiple contributing factors converging on common pathophysiological pathways. Current evidence supports a post-infectious, immune-mediated process with neurological involvement. [3,10,11]

Proposed Mechanisms

1. Immune Dysregulation [10,11,12]:

2. Autonomic Nervous System Dysfunction [13,14]:

3. Neuroinflammation and Central Sensitization [15]:

• PET studies show microglial activation in multiple brain regions
• Altered brain connectivity patterns on fMRI
• Elevated cerebrospinal fluid cytokines
• Intracranial hypertension in subset of patients
• Glial cell activation and neuroinflammatory markers

4. Energy Metabolism Dysfunction [16,17]:

Post-Exertional Malaise (PEM) - The Hallmark Feature

PEM is the pathognomonic feature of ME/CFS and distinguishes it from other causes of chronic fatigue. [1,2,18]

Characteristics of PEM:

PEM vs Normal Exercise Fatigue:

Two-Day Cardiopulmonary Exercise Testing [19]: Research shows that ME/CFS patients demonstrate:

• Normal or near-normal performance on day 1
• Significant decline in peak oxygen consumption on day 2 (10-25% reduction)
• This pattern is unique to ME/CFS and validates the PEM phenomenon
• Used in research; not routine clinical practice

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Clinical Presentation

Core Symptoms

1. Fatigue:

2. Post-Exertional Malaise (PEM):

• Delayed worsening 12-72 hours after exertion
• Can be triggered by minimal activities (showering, conversation)
• Patients describe as "crash," "payback," or "collapse"
• Duration proportional to degree of overexertion
• Key distinguishing feature from other fatigue conditions

3. Unrefreshing Sleep:

4. Cognitive Dysfunction ("Brain Fog"):

Additional Common Symptoms

Orthostatic Intolerance

A crucial symptom that should be actively screened for:

Types:

NASA Lean Test (Office screening for orthostatic intolerance):

1. Patient rests supine for 10 minutes
2. Record baseline HR and BP
3. Patient stands leaning against wall, feet 6 inches from wall
4. Record HR and BP at 2, 5, and 10 minutes
5. Positive findings: HR increase ≥30 bpm, BP drop ≥20/10 mmHg, or symptom reproduction

Red Flags Requiring Alternative Diagnosis Consideration

[!CAUTION] Red Flags - Investigate for Organic Causes Before Diagnosing ME/CFS:

• Unexplained weight loss (> 10% body weight)
• Fever of unknown origin
• Night sweats
• Focal neurological signs
• Significant lymphadenopathy (> 2 cm)
• Hepatosplenomegaly
• Persistently elevated inflammatory markers (ESR > 30, CRP elevated)
• Symptoms entirely explained by major psychiatric disorder
• Progressive neurological deterioration
• Age > 50 with new-onset symptoms (higher malignancy risk)

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Clinical Examination

Approach to Examination

Physical examination in ME/CFS is often unremarkable but is essential to:

1. Exclude alternative diagnoses
2. Identify orthostatic intolerance
3. Document baseline functional status
4. Identify comorbidities requiring treatment

Systematic Examination

General Inspection:

Vital Signs:

Cardiovascular:

• Orthostatic vital signs (critical)
• Heart sounds (usually normal)
• Signs of heart failure (exclude)

Respiratory:

• Usually normal
• Exclude respiratory causes of fatigue

Neurological:

Lymph Nodes:

• May have mild tenderness (cervical, axillary)
• Significant lymphadenopathy requires investigation

Abdomen:

• Usually normal
• Exclude hepatosplenomegaly
• May have IBS-type tenderness

Musculoskeletal:

• Tenderness without swelling common
• May have features overlapping with fibromyalgia
• Exclude inflammatory arthritis

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Investigations

Purpose of Investigations

Investigations in ME/CFS serve to exclude alternative diagnoses, not to confirm ME/CFS. There is no validated diagnostic biomarker. [1,2]

First-Line Investigations (All Patients)

Second-Line Investigations (As Indicated)

Investigations NOT Routinely Recommended

• Extensive "fishing" panels add cost without benefit
• No evidence for routine EBV serology (past infection is near-universal)
• Specialized immunological panels not validated for diagnosis
• "Chronic Lyme" panels not recommended without appropriate exposure history

Orthostatic Testing

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Differential Diagnosis

Conditions to Exclude

ME/CFS vs Depression

Important: Depression and ME/CFS can coexist. Depression as a comorbidity should be treated, but treating depression alone does not resolve ME/CFS.

Overlapping Conditions

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Management

Management Principles

Core Principles (NICE NG206) [1]:

1. Diagnosis is the first step in management - Validation of the patient's experience
2. No curative treatment exists - Focus on symptom management and quality of life
3. Energy management (pacing) is central - Help patients stay within their "energy envelope"
4. Avoid harm - Do NOT recommend GET, "pushing through," or fixed-increment activity programs
5. Personalized approach - Tailor to individual severity and preferences
6. Multidisciplinary care - Access to specialist services when available
7. Regular review - Monitor for deterioration, adjust management plan
8. Supportive, believing approach - Patients often face disbelief; validate their experience

Management Algorithm

                    ME/CFS MANAGEMENT PATHWAY
                              |
                              v
    +--------------------------------------------------+
    |              CONFIRM DIAGNOSIS                     |
    +--------------------------------------------------+
    | - Symptoms ≥6 months (suspected at 3 months)      |
    | - Meets IOM or NICE criteria                       |
    | - Investigations exclude organic disease           |
    | - Assess severity (mild/moderate/severe/very severe)|
    +--------------------------------------------------+
                              |
                              v
    +--------------------------------------------------+
    |           PROVIDE DIAGNOSIS AND EDUCATION          |
    +--------------------------------------------------+
    | - Explain ME/CFS as real, physical illness        |
    | - Discuss expected course and prognosis           |
    | - Provide written information and resources       |
    | - Address misconceptions                          |
    +--------------------------------------------------+
                              |
                              v
    +--------------------------------------------------+
    |     CORE: ENERGY MANAGEMENT (PACING)              |
    +--------------------------------------------------+
    | - Identify current "energy envelope"              |
    | - Plan activities to stay within limits           |
    | - Avoid "boom-bust" pattern                       |
    | - Include rest breaks before exhaustion           |
    | - Prioritize essential activities                 |
    | - Use activity diary to track patterns            |
    |                                                   |
    | DO NOT OFFER:                                     |
    | - Graded Exercise Therapy (GET)                   |
    | - Fixed incremental activity programs             |
    | - Lightning Process or similar                    |
    +--------------------------------------------------+
                              |
                              v
    +--------------------------------------------------+
    |           SYMPTOM MANAGEMENT                       |
    +--------------------------------------------------+
    |                                                   |
    |   SLEEP DISTURBANCE:                              |
    |   - Sleep hygiene advice                          |
    |   - Low-dose amitriptyline 10-25 mg nocte         |
    |   - Melatonin 2-5 mg if appropriate               |
    |                                                   |
    |   PAIN:                                           |
    |   - Paracetamol                                   |
    |   - Low-dose amitriptyline for neuropathic pain   |
    |   - Avoid opioids if possible                     |
    |                                                   |
    |   ORTHOSTATIC INTOLERANCE:                        |
    |   - Increase salt intake (8-10g/day)              |
    |   - Increase fluid intake (2-3L/day)              |
    |   - Compression stockings (waist-high)            |
    |   - Consider fludrocortisone, midodrine (specialist)|
    |                                                   |
    |   COGNITIVE DYSFUNCTION:                          |
    |   - Pace cognitive activity                       |
    |   - Use memory aids, lists, reminders             |
    |   - Reduce sensory overload                       |
    +--------------------------------------------------+
                              |
                              v
    +--------------------------------------------------+
    |      MULTIDISCIPLINARY SUPPORT                     |
    +--------------------------------------------------+
    | - Specialist ME/CFS service referral              |
    | - Occupational therapy (ADLs, pacing, aids)       |
    | - Physiotherapy (gentle movement within limits)   |
    | - Psychology (managing chronic illness, CBT*)     |
    | - Dietitian (nutrition, food sensitivities)       |
    | - Social worker (benefits, social support)        |
    |                                                   |
    | *CBT for managing impact, NOT as treatment        |
    +--------------------------------------------------+

Energy Management (Pacing) - The Core Strategy

The Energy Envelope Concept [1,20]:

The "energy envelope" represents the amount of physical, cognitive, and emotional energy available each day. Staying within this envelope prevents PEM. Exceeding it triggers crashes.

Practical Pacing Advice:

• Start at 50-70% of current sustainable activity level
• Keep activity diary to identify triggers
• Plan high-energy activities for best times of day
• Break activities into small chunks with rest between
• Learn to recognize early warning signs of overexertion
• Accept help and delegate when possible

Pharmacological Management

There is no disease-modifying pharmacotherapy for ME/CFS. All medications are for symptom control.

Sleep Disturbance:

Pain:

Orthostatic Intolerance/POTS (Specialist Initiation):

Therapies NOT Recommended

Specialist Referral Criteria

Refer to ME/CFS specialist service when:

• Diagnosis is uncertain
• Moderate, severe, or very severe ME/CFS
• Symptoms not responding to primary care management
• Complex comorbidities
• Severe orthostatic intolerance requiring specialist assessment
• Occupational or disability assessment needed
• Patient request

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Special Populations

Children and Adolescents

Severe and Very Severe ME/CFS

Long COVID and ME/CFS

Many patients with post-acute sequelae of SARS-CoV-2 (long COVID) meet ME/CFS diagnostic criteria. [9]

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Prognosis and Outcomes

Natural History

Prognostic Factors

Mortality

• ME/CFS is not directly fatal
• Studies suggest slightly increased mortality, mainly from:
  • Cardiovascular disease
  • Suicide (higher rates due to illness burden and lack of support)
  • Cancer (possibly due to immune dysfunction or coincidental)
• Appropriate support and management can reduce these risks

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Evidence and Guidelines

Key Guidelines

NICE NG206 (2021) - Key Changes from Previous Guidance

PACE Trial Controversy

The PACE trial (2011) initially claimed GET and CBT were effective for ME/CFS. [21]

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Clinical Pearls

High-Yield Exam Points

"PEM Is the Cardinal Feature": Post-exertional malaise - delayed worsening of symptoms 24-72 hours after even minor exertion - is pathognomonic. Always ask about it specifically.

"GET Is No Longer Recommended": The 2021 NICE guideline removed graded exercise therapy. This is a major exam point. Pushing through symptoms causes harm.

"Diagnosis of Exclusion": You must exclude organic causes before diagnosing ME/CFS. Key exclusions: hypothyroidism, diabetes, anemia, coeliac disease, sleep apnea, depression.

"The Energy Envelope": Patients should identify their energy limits and stay within them. Boom-bust cycles (overdoing on good days) worsen PEM.

"NICE NG206 = Paradigm Shift": Know this guideline number and its key message: energy management replaces exercise therapy.

"Long COVID Overlap": Many post-COVID patients meet ME/CFS criteria. Same management principles apply.

Common Exam Errors

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Viva Questions

Common Viva Questions

Q1: A 34-year-old woman presents with 8 months of profound fatigue, cognitive difficulties, and worsening symptoms after activity. How do you approach diagnosis?

Model Answer: This presentation is highly suggestive of ME/CFS given symptoms of fatigue, cognitive dysfunction, and the key feature of post-exertional malaise.

I would take a detailed history including:

• Onset (often post-viral), specific triggers
• Nature of fatigue (profound, not relieved by rest)
• Specifically ask about PEM: "Do your symptoms get worse 1-2 days after activity?"
• Sleep quality (unrefreshing despite adequate duration)
• Cognitive symptoms ("brain fog")
• Orthostatic intolerance (dizziness on standing)
• Impact on function and daily activities
• Screen for red flags: weight loss, fevers, night sweats, focal neurological symptoms

Examination to exclude alternative diagnoses and assess for orthostatic intolerance with active standing test.

Investigations to exclude organic causes: FBC, U&E, LFTs, TFTs, glucose, coeliac serology, CRP, ferritin, vitamin D.

If investigations normal and symptoms meet criteria (≥6 months, all four core symptoms), the diagnosis is ME/CFS per NICE NG206 criteria. I would explain the diagnosis sensitively, emphasizing this is a real physical illness, and discuss energy management strategies.

Q2: What is post-exertional malaise and why is it important?

Model Answer: Post-exertional malaise (PEM) is the hallmark and pathognomonic feature of ME/CFS that distinguishes it from other causes of chronic fatigue.

PEM is defined as a worsening of symptoms following physical, cognitive, or emotional exertion that would not have caused a problem before illness onset.

Key characteristics:

• Delayed onset: Typically 12-72 hours after the triggering activity
• Prolonged recovery: Duration of days to weeks, not hours
• Global symptom worsening: All ME/CFS symptoms exacerbate, not just fatigue
• Low threshold: Can be triggered by minimal activities like showering or conversation
• Cumulative effect: Repeated overexertion can cause permanent deterioration

PEM is clinically important because:

1. It is essential for diagnosis - present in nearly all ME/CFS patients
2. It distinguishes ME/CFS from depression, deconditioning, and normal fatigue
3. It informs management - patients must stay within their "energy envelope" to avoid triggering PEM
4. It explains why graded exercise therapy is harmful - pushing beyond limits triggers PEM
5. The two-day CPET protocol objectively demonstrates PEM in research settings

Always specifically ask about PEM when taking a history for chronic fatigue.

Q3: What changed in the NICE 2021 guideline for ME/CFS?

Model Answer: The NICE guideline NG206 (2021) represented a paradigm shift in ME/CFS management with several significant changes:

1. Graded Exercise Therapy (GET) removed: GET is no longer recommended as it can cause harm by triggering post-exertional malaise. This was a major reversal from the 2007 guideline.

2. Energy management (pacing) is central: Helping patients identify and stay within their "energy envelope" is now the core management strategy.

3. CBT repositioned: CBT is only offered to help manage the psychological impact of living with chronic illness, NOT as a treatment for ME/CFS itself.

4. Lightning Process not recommended: Explicitly stated as not to be offered.

5. Severity classification introduced: Detailed classification from mild to very severe with specific considerations for each level.

6. Emphasis on avoiding harm: Strong statements about the risk of worsening from inappropriate activity recommendations.

7. Patient-centered approach: Shared decision-making and validating patient experience emphasized.

8. PACE trial rejected: The controversial PACE trial was not used as a basis for recommendations due to methodological concerns.

The key exam point is knowing that GET was removed and pacing (energy management) replaced it as the core strategy.

Q4: How do you differentiate ME/CFS from primary depression?

Model Answer: Differentiating ME/CFS from primary depression is clinically important as both can cause fatigue and cognitive symptoms, but they require different management approaches. They can also coexist.

Key approach:

• Specifically ask about PEM - this strongly favors ME/CFS
• Ask "Do you want to do activities but feel physically unable?" vs "Have you lost interest in things you used to enjoy?"
• Assess orthostatic intolerance
• Screen for red flags suggesting alternative diagnosis

If depression coexists, treat it appropriately while still managing ME/CFS with pacing.

Q5: What are the management options for orthostatic intolerance in ME/CFS?

Model Answer: Orthostatic intolerance affects 70-90% of ME/CFS patients and can significantly impair quality of life. Management is multimodal:

Non-pharmacological (First-line):

• Increase fluid intake: 2-3 liters daily
• Increase salt intake: 8-10 grams daily (if no contraindication)
• Compression garments: Waist-high stockings (30-40 mmHg) or abdominal binders
• Physical counter-maneuvers: Crossing legs, squatting when feeling faint
• Avoid triggers: Prolonged standing, hot environments, large meals
• Elevate head of bed: 10-15 degrees to reduce nocturnal diuresis
• Rise slowly: Sit on edge of bed before standing

Pharmacological (Specialist initiation):

Choice of medication depends on subtype of orthostatic intolerance (POTS vs orthostatic hypotension) and should be guided by specialist assessment.

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Patient Information

What is ME/CFS?

ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is a long-term illness that causes extreme tiredness, problems with thinking clearly ("brain fog"), unrefreshing sleep, and something called post-exertional malaise (PEM) - where symptoms get worse after even small amounts of activity.

What causes it?

The exact cause isn't known. It often starts after a viral infection like glandular fever or COVID-19. Researchers think it may involve the immune system and how the body produces energy.

How is it diagnosed?

There is no specific blood test for ME/CFS. Doctors diagnose it based on your symptoms - mainly tiredness lasting at least 6 months, post-exertional malaise, unrefreshing sleep, and brain fog - and by ruling out other conditions with blood tests.

How is it managed?

There is no cure, but there are things that help:

• Energy management (pacing): Learning your limits and staying within them. This is the most important strategy.
• Rest: Allow yourself proper rest periods.
• Symptom treatment: Medicines can help with sleep, pain, and dizziness.
• Support: Occupational therapy, support groups, and specialist ME/CFS clinics when available.

Important: "Pushing through" or forcing yourself to exercise more does NOT help and can make things worse.

What to avoid

• Don't try to "fight through" the fatigue
• Avoid boom-bust cycles (overdoing it on good days)
• Graded exercise therapy (GET) is no longer recommended

Where to get support

• ME Association: meassociation.org.uk
• Action for ME: actionforme.org.uk
• NHS ME/CFS services (if available locally)
• Local support groups

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References

1. National Institute for Health and Care Excellence (NICE). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management (NG206). London: NICE; 2021. Available from: https://www.nice.org.uk/guidance/ng206

2. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015. doi:10.17226/19012

3. Komaroff AL, Lipkin WI. Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Postacute COVID-19 Syndrome. Trends Mol Med. 2021;27(9):895-906. doi:10.1016/j.molmed.2021.06.002

4. Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020;18(1):100. doi:10.1186/s12967-020-02269-0

5. Pendergrast T, Brown A, Sunnquist M, et al. Housebound versus nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome. Chronic Illn. 2016;12(4):292-307. doi:10.1177/1742395316644770

6. Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S. The economic impact of ME/CFS: individual and societal costs. Dyn Med. 2008;7:6. doi:10.1186/1476-5918-7-6

7. Jason LA, Jordan K, Miike T, et al. A pediatric case definition for myalgic encephalomyelitis and chronic fatigue syndrome. J Chronic Fatigue Syndr. 2006;13(2-3):1-44. doi:10.1300/J092v13n02_01

8. Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health. 2013;53(2):154-165. doi:10.1016/j.jadohealth.2013.03.009

9. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146. doi:10.1038/s41579-022-00846-2

10. Blomberg J, Gottfries CG, Elfaitouri A, Rizwan M, Rosén A. Infection elicited autoimmunity and myalgic encephalomyelitis/chronic fatigue syndrome: an explanatory model. Front Immunol. 2018;9:229. doi:10.3389/fimmu.2018.00229

11. Sotzny F, Blanco J, Capelli E, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmun Rev. 2018;17(6):601-609. doi:10.1016/j.autrev.2018.01.009

12. Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017;114(34):E7150-E7158. doi:10.1073/pnas.1710519114

13. Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2012;302(5):H1185-H1194. doi:10.1152/ajpheart.00994.2011

14. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. 2012;87(12):1214-1225. doi:10.1016/j.mayocp.2012.08.013

15. Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an 11C-(R)-PK11195 PET study. J Nucl Med. 2014;55(6):945-950. doi:10.2967/jnumed.113.131045

16. Tomas C, Newton J. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochem Soc Trans. 2018;46(3):547-553. doi:10.1042/BST20170503

17. Missailidis D, Annesley SJ, Fisher PR. Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2019;9(3):80. doi:10.3390/diagnostics9030080

18. Bateman L, Bested AC, Bonilla HF, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clin Proc. 2021;96(11):2861-2878. doi:10.1016/j.mayocp.2021.07.004

19. Stevens S, Snell C, Stevens J, Keller B, VanNess JM. Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Pediatr. 2018;6:242. doi:10.3389/fped.2018.00242

20. Jason LA, Brown M, Brown A, et al. Energy Conservation/Envelope Theory Interventions to Help Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fatigue. 2013;1(1-2):75-84. doi:10.1080/21641846.2012.733602

21. Geraghty K, Jason L, Sunnquist M, Tuller D, Blease C, Adeniji C. The 'cognitive behavioural model' of chronic fatigue syndrome: Critique of a flawed model. Health Psychol Open. 2019;6(1):2055102919838907. doi:10.1177/2055102919838907

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