Evidence browser

BiomarkersPost-Exertional Malaise

Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology.

Nepotchatykh, Evguenia, Elremaly, Wesam, Caraus, Iurie et al.·Scientific reports·2020

This study looked at tiny molecules called microRNAs in the blood of severely ill ME/CFS patients before and after a stress challenge designed to trigger post-exertional malaise (the worsening of symptoms after activity). The researchers found that eleven different microRNAs changed in response to this challenge, with patterns that varied depending on symptom severity. These microRNA signatures could potentially be used one day as blood tests to help diagnose ME/CFS.

E3 PreliminaryCohortPEM not requiredCase-Control

Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants.

Kelley, Mary A, Oaklander, Anne Louise·Canadian journal of pain = Revue canadienne de la douleur·2020

This study describes two patients who developed small fiber nerve damage (affecting the smallest nerves in the body) and severe fatigue after infections. Both had immune system abnormalities and improved dramatically with immune-suppressing treatments. Genetic testing found rare changes in a gene called SCN9A that affects how nerve cells communicate. The findings suggest that genetic variations in this gene might play a role in some cases of small fiber nerve damage that respond to immune therapy.

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Washington, Stuart D, Rayhan, Rakib U, Garner, Richard et al.·Brain communications·2020

This study used brain imaging to compare how the brains of people with ME/CFS and Gulf War Illness respond to exercise during a memory task. Researchers found that exercise affected brain activity differently in the two conditions—specifically in areas related to pain awareness, attention, and threat detection. These differences suggest that ME/CFS and Gulf War Illness may involve distinct biological mechanisms, which could help doctors distinguish between them.

E3 PreliminaryGuidelinePEM requiredEditorial

Medically Documenting Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Cases.

Comerford, Barbara B, Podell, Richard·Frontiers in pediatrics·2019

This guideline addresses how doctors can properly document ME/CFS symptoms to support disability claims, especially for children and teens. Many ME/CFS patients see doctors unfamiliar with the condition, which can lead to misdiagnosis and rejected disability applications. The guideline emphasizes that ME/CFS is a real physical illness affecting multiple body systems, not a psychological condition.

E3 PreliminaryCommentaryPEM requiredEditorial

Suggested pathology of systemic exertion intolerance disease: Impairment of the E3 subunit or crossover of swinging arms of the E2 subunit of the pyruvate dehydrogenase complex decreases regeneration of cofactor dihydrolipoic acid of the E2 subunit.

Bohne, Victoria J Berdikova, Bohne, Øyvind·Medical hypotheses·2019

This paper proposes that ME/CFS might result from a problem in how the body converts fuel into energy, specifically involving a protein complex called the pyruvate dehydrogenase complex. The researchers suggest that when this complex isn't working properly, it causes lactate (a byproduct of metabolism) to build up suddenly in the body, which could explain the exhaustion and post-exertional malaise (worsening after activity) that patients experience. They propose that the body isn't efficiently recycling important molecules needed for energy production, leading to low energy and fatigue.

E3 PreliminaryReviewPEM not requiredReview-Narrative

Oxidative stress in exercise training: the involvement of inflammation and peripheral signals.

Magherini, Francesca, Fiaschi, Tania, Marzocchini, Riccardo et al.·Free radical research·2019

When we exercise, our bodies produce harmful molecules called free radicals that can damage cells. While some free radicals are normal and needed for muscle function, too many can cause problems. This review explains how intense exercise, stress, and not eating enough can create excessive free radicals and inflammation, which might lead to chronic fatigue and overtraining syndrome—conditions where the body cannot recover properly from exercise.

Immune SystemPost-Exertional Malaise

Exercise challenge alters Default Mode Network dynamics in Gulf War Illness.

Rayhan, Rakib U, Washington, Stuart D, Garner, Richard et al.·BMC neuroscience·2019

This study looked at brain activity in Gulf War Illness patients before and after exercise to understand post-exertional malaise (PEM)—a condition where symptoms get worse after physical or mental effort. Using brain scans, researchers found that after exercise, patients showed unusual patterns of brain deactivation (regions that should 'turn off' during focused tasks) compared to healthy people. This suggests PEM may involve how the brain manages activity, providing a potential biological marker for the illness.

Understanding neuromuscular disorders in chronic fatigue syndrome.

Jammes, Yves, Retornaz, Frédérique·F1000Research·2019

This study examined how muscles work differently in people with ME/CFS. Researchers found that both the brain's ability to signal muscles and the muscles' ability to respond are impaired in ME/CFS patients. The muscles also appear to have trouble managing harmful molecules called free radicals, especially after exercise, and they may not be producing enough protective proteins that normally shield cells from damage.

E3 PreliminaryReviewPEM requiredReview-Narrative

Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Emerging Osteopathic Approach: A Narrative Review.

Larrimore, Christopher, Ramnot, Amanda, Jaghab, Annmarie et al.·The Journal of the American Osteopathic Association·2019

This article reviews what scientists know about ME/CFS, including its symptoms, how it affects the body, and why it's hard to diagnose. The authors discuss both traditional medical approaches and osteopathic treatment (a type of hands-on therapy that focuses on the body's structure and function) as possible ways to help people with ME/CFS feel better. The review emphasizes that ME/CFS is a real, serious illness that deserves more awareness among doctors and better treatment options.

Immune SystemCognitive ImpairmentPost-Exertional Malaise

E3 PreliminaryMechanismPEM requiredObservational

Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - a secondary analysis of experimental comparative studies.

Polli, Andrea, Van Oosterwijck, Jessica, Meeus, Mira et al.·Scandinavian journal of pain·2019

This study explored whether exercise-triggered immune system changes in ME/CFS patients are connected to increased pain sensitivity. Researchers compared immune markers and pain thresholds in ME/CFS patients and healthy people before and after two different types of exercise. They found a link between changes in a immune protein called C4a and pain sensitivity in ME/CFS patients, but this connection was weak and only showed up in some measurements.

Immune SystemPost-Exertional Malaise

E3 PreliminaryDiagnosticPEM requiredMethods-Paper

The DePaul Symptom Questionnaire-2: A Validation Study.

Bedree, Helen, Sunnquist, Madison, Jason, Leonard A·Fatigue : biomedicine, health & behavior·2019

Researchers improved a questionnaire called the DSQ-2 that helps doctors identify and understand ME/CFS by asking patients about their specific symptoms. They tested this updated questionnaire with 399 people who have ME or CFS and found that it works well at measuring the main symptoms of these illnesses, including post-exertional malaise (feeling worse after activity), brain fog, pain, and sleep problems. The questionnaire is now a more reliable tool for both diagnosing ME/CFS and understanding how the illness affects different people.

[From neurasthenia to post-exertion disease: Evolution of the diagnostic criteria of chronic fatigue syndrome/myalgic encephalomyelitis].

Murga, Íñigo, Lafuente, José-Vicente·Atencion primaria·2019

This study traces how ME/CFS has been named and diagnosed over the past 150+ years, from 'neurasthenia' in the 1800s to today's 'post-exertional malaise.' The researchers reviewed medical literature to show how our understanding of this disease has evolved, and highlight that doctors still diagnose it mainly by symptoms and by ruling out other conditions, since no single biological marker has been found.

E3 PreliminaryDiagnosticPEM requiredMethods-Paper

Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey.

Holtzman, Carly S, Bhatia, Shaun, Cotler, Joseph et al.·Diagnostics (Basel, Switzerland)·2019

This study worked directly with ME/CFS patients to create a better way to measure post-exertional malaise (PEM)—the symptom where activity makes you feel significantly worse. Over 1,500 patients completed a survey to help researchers understand what aspects of PEM are most important to measure, including what triggers it, how quickly symptoms start, and how long they last. The study shows that involving patients in designing assessment tools leads to more thorough and meaningful measurements.

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure.

Lacourt, Tamara E, Vichaya, Elisabeth G, Chiu, Gabriel S et al.·Frontiers in behavioral neuroscience·2018

This study explores why people with ME/CFS experience persistent fatigue by examining how inflammation in the body may damage cells' ability to produce energy. The researchers propose that chronic inflammation forces cells to switch to a less efficient energy-production method, while at the same time the body may be spending energy at rates it cannot sustain, creating an energy crisis. Sleep problems and disrupted body rhythms may also play a role in this imbalance.

E3 PreliminaryDiagnosticPEM requiredMethods-Paper

Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Stevens, Staci, Snell, Chris, Stevens, Jared et al.·Frontiers in pediatrics·2018

This study explains how doctors can properly test ME/CFS patients using a special exercise test called CPET (cardiopulmonary exercise test) done on two consecutive days. The first test measures how much exercise a patient can do, while the second test 24 hours later shows how much the patient's performance has dropped due to post-exertional malaise (PEM)—the symptom flare that happens after exertion. This two-day approach objectively demonstrates one of the key features of ME/CFS: the inability to recover normal function after exercise.

E3 PreliminaryDiagnosticPEM not requiredMethods-Paper

Myalgic Encephalomyelitis (ME) or What? An Operational Definition.

Twisk, Frank·Diagnostics (Basel, Switzerland)·2018

This paper proposes a clear, practical definition of ME (myalgic encephalomyelitis) to help doctors reliably identify and study the condition. The authors argue that ME is a distinct multi-system illness characterized by severe muscle exhaustion after minimal activity, neurological symptoms (like brain fog and autonomic problems), and a pattern of symptom fluctuation and relapse over months or years. Having a precise definition is essential so researchers can study the right patients and develop effective treatments.

E3 PreliminaryCohortPEM unclearCross-Sectional

Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome.

de Vega, Wilfred C, Erdman, Lauren, Vernon, Suzanne D et al.·Epigenomics·2018

Researchers studied 70 women with ME/CFS and found that their DNA showed different chemical patterns in immune cells. These chemical differences matched up with specific symptoms and health problems that patients reported. The study identified four distinct subtypes of ME/CFS, each with its own pattern of DNA changes and symptom profile, suggesting that ME/CFS may not be one uniform condition but rather several related conditions with different underlying biology.

Immune SystemPost-Exertional Malaise

Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome.

Pietrangelo, Tiziana, Fulle, Stefania, Coscia, Francesco et al.·European journal of translational myology·2018

This study found that muscles in people with ME/CFS show patterns similar to muscles in elderly people, even though the patients are young. The researchers discovered problems with how muscles use energy, handle calcium, and produce new muscle protein. Importantly, the findings suggest that appropriate physical activity may actually help rather than harm, though the right type and intensity still need to be determined.

Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS.

Brown, Audrey E, Dibnah, Beth, Fisher, Emily et al.·Bioscience reports·2018

This study looked at muscle cells from ME/CFS patients to understand why their muscles struggle to use energy properly. Researchers tested two drugs (metformin and compound 991) that can activate AMPK, a protein that helps cells use glucose for energy. Both drugs successfully improved how the muscle cells used glucose, suggesting that the problem in ME/CFS muscles is not AMPK itself, but something that happens before AMPK gets activated.

E3 PreliminaryMechanismPEM unclearCase-Control

[Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise].

Chi, Ai-Ping, Wang, Zi-Nan, Shi, Bing et al.·Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology·2018

This study looked at chemicals in the urine of teenagers with ME/CFS before and after exercise to understand how their bodies process energy differently. Researchers found that people with ME/CFS had abnormal levels of several metabolites (chemical byproducts), and these changes got worse after exercise, suggesting their bodies struggle to recover from physical activity.