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Part 2: Understanding the Symptoms: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

In this post, I review the literature on the pathophysiology specific to CFS/ME to look at what’s going on at the cellular level – why do patients have particular symptom clusters? Even though FM has its own diagnostic criteria, recall from last week’s post that the pain experienced in CFS/ME patients can sometimes meet the criteria for FM. The conditions are often found together, so although I focus on CFS/ME, it may be relevant for FM patients too.

Etiology – How does it all start?

Short answer: it’s unknown. It’s been estimated that in 50-80% of ME/CFS patients there was a precipitating infection, whether it was viral, bacterial, or parasitic. Instead of recovering, they get progressively worse. For FM, onset of symptoms can be usually traced back to a physical or emotional trauma.

But – many people get infections and/or experience trauma and recover just fine. Why not them? It’s been proposed that it’s a combination of factors that lead to the development of disease: nutritional status, types of gut bugs living in the gut, stress levels, genetic predisposition, environmental factors, strength of initial infection, etc.


Review of Literature

Immune System in Disarray

To put simply, the immune system doesn’t function normally, being over-active in some areas or situations, and under-active in others. For specifics:

-Increase in T-Helper 2 immune cells – resulting in hyper-reactivity of the immune system making patients more likely to be sensitive to food, chemicals, medications, etc.

-Low Natural Killer cells – these are a part of our innate immune system that float around and protect us from infection – so patients are more vulnerable to infection.

-High levels of Cytokines – As an over-simplification, consider cytokines as things secreted by immune cells that cause inflammation.

-They’ve noticed a pattern with ME/CFS patients: those with a new diagnosis had more variation in the types of cytokines secreted, whereas those who’ve been ill longer had less variation.

Post-Exertional Malaise = worsening of symptoms or inability to function after physical or mental exertion that had previously never been an issue prior to diagnosis. It can take days, weeks, or even months to recover. Here are the different hypotheses/findings:

-Muscles have impaired oxygen uptake and increased lactic acid production

-Mitochondrial dysfunction - There’s an impairment in generating energy (ATP) which is necessary for the functioning of every cell in the body.

-Mutated ion-channels on nerve cells - Normally sodium, potassium and chloride ions pass back and forth across a cell channel and the ratio of this generates nerve firing. With mutations, there is abnormal nerve firing and neurotransmitter release. This also generates a lot of oxidative stress contributing to widespread inflammation in the body and brain.

-With high baseline cytokine levels causing persistent peripheral inflammation, engaging in an activity that totally uses up energy reserves (whether it’s a high intensity activity or chronic low-intensity), increases the inflammation, whereas controls experience anti-inflammatory effects from exercise.

- Altered gut microbiome – 72 hr after a maximal exercise challenge, ME/CFS patients had higher levels of bacteria in their blood compared to controls. Stool analysis revealed an increase in 6/9 major bacteria phyla vs. an increase in 2/9 in healthy controls.

Cognitive Dysfunction – described by many as “brain fog.” In studies comparing ME/CFS patients to controls, they’ve found:

-Reduction in brain perfusion and glucose metabolism

-Electroencephalogram (EEG) studies have found decreased alpha wave activity (required for memory and cognitive performance.)

-Positron Emission Tomography (PET) scan showed widespread neuro-inflammation. This creates oxidative stress, which has been thought to explain the finding that ME/CFS patients have reduced grey matter.

-Clinical demonstrations of: reduced processing speed, poor word retrieval, slow working memory, etc.

Sleep Dysfunction – described by many as unrefreshed sleep

-Polysomnographic (sleep) studies have revealed that patients with ME/FM have decreased sleep efficacy, decreased total sleep time, have more interruptions in the night (increased alpha wave activity), and spend less time in deep restorative sleep stages (delta waves).

-Disrupted REM sleep is another finding and has been correlated with increases in fatigue


-Central sensitization: Not unique to ME/CFS, this is where in response to painful stimulation (trauma, chronic inflammation, virus, etc.) the spinal cord becomes “hyper-excitable” and upregulates the pain response.


-Proposed to be due to all of the above: aberrant immune functioning, mitochondrial dysfunction, impaired sleep, cognitive dysfunction, increased pain – not to mention all of the psychological effects this has on someone.

This is just a brief summary of what’s out there. It doesn't answer whether these findings are a consequence of the condition or part of the etiology/susceptibility to developing the condition, it’s still unknown. I didn’t even get into the genetic findings – for example, that certain genes are associated with viral susceptibility or inability to dampen mitochondrial damage. It’s pretty heavy, but I’ve provided references below for those who want more.

Stay tuned for Part 3 where I discuss my approach to treatment.



Bested AC, Marshall LM. Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians. Reviews on environmental health. 2015 Dec 1;30(4):223-49.

A Jason L, L Zinn M, A Zinn M. Myalgic encephalomyelitis: symptoms and biomarkers. Current neuropharmacology. 2015 Sep 1;13(5):701-34.

Meeus M, Nijs J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clinical rheumatology. 2007 Apr 1;26(4):465-73.

Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, Frank DN. Changes in gut and plasma microbiome following exercise challenge in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PloS one. 2015 Dec 18;10(12):e0145453.

Nicolson GL. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Integrative Medicine: A Clinician's Journal. 2014 Aug;13(4):35.

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