A Primer on Chronic Fatigue Syndrome

This article was originally published on Monday, January 12th 2015 at 1:15 pm for GreenMedInfo

Chronic Fatigue Syndrome, or CFS, is a serious illness with a terrible name.

CFS has been described as the flu that never goes away. Throughout the rest of the world, CFS is more accurately named Myalgic Encephalomyelitis, or ME. Many patients and clinicians have now adopted the combined term ME/CFS, with the belief that the name Chronic Fatigue Syndrome has the potential to cause harm to patients (1). Labeled with this diagnosis, patients are frequently dismissed from doctor’s offices under a psychiatric cloud, or erroneously told to exercise back to health. However, the defining characteristic of ME/CFS that differentiates it from other conditions, depression included, is post-exertional malaise. A simple bout of mental or physical activity can trigger flu-like symptoms in patients with lasting effects.

Imagine a trip to the mailbox being enough to confine you to bed for the rest of the day…or longer.

Despite growing numbers stricken--1 million Americans--research funding for the disease has remained paltry for nearly 3 decades. Many in mainstream medicine still do not accept the illness as organic, and all too often malign it with psychosomatic or conversion disorders. Worse still, many patients are not accepted by family or loved ones.

Is it any wonder then that a leading cause of death in this group of patients is suicide (2)?

Fatigue alone does not even begin to describe what a patient with ME/CFS experiences on a daily basis. Lack of understanding leads to onlookers assuming laziness, deconditioning, or simply over-work. Yet, the fatigue felt has been compared to the level of fatigue experienced by end-stage cancer or HIV/AIDS patients. Severely debilitating symptoms afflict those with the illness: cognitive problems, pain, irritable bowel, autonomic dysfunction, sleep disturbance…the list goes on. The larger impact of this illness is that disability due to ME/CFS is estimated to cost $9.1 billion in lost productivity every year in the US (3).

Research has not been able to pinpoint the exact cause or trigger for ME/CFS. A diagnostic marker remains elusive. However, many unique physiological signatures have been determined. As an example, abnormal cytokine and immune cells are hallmark findings (3). Certain cytokine patterns are thought to drive sickness behaviors and contribute to hypersensitivity to pain. Most patients also have limited natural killer (NK) cell number and function. This finding may be associated with increased rates of certain cancers in patients as well as harboring of opportunistic infections. Finally, patients have limited cardiopulmonary capacity and blood flow irregularities. These findings may explain the intolerance to exercise and depressive symptoms due to poor cerebral profusion (4,5).

Is it autoimmune?

While not classically defined as an autoimmune disease, there are striking similarities between ME/CFS and conditions such as Multiple Sclerosis. In fact, as many as 60% of patients have a comorbid autoimmune diagnosis (6). The chronic or recurring viral infections common in many patients can induce autoimmunity by molecular mimicry and bystander activation (6).  Similar to autoimmune conditions, viruses can flip a switch on the immune system leading to loss of “self” recognition. Others note the onset of illness following a vaccination, suggesting an autoimmune (auto-inflammatory) syndrome induced by adjuvants (7).

Is it in the cells?

Many ME/CFS patients mind their mitochondria—the vitally important energy supply house of the cell. Numerous studies have demonstrated mitochondrial insufficiency in patients which is likely due to a vicious cycle of oxidative stress (8, 15). Inflammatory cytokines and other immune cells propagate reactive oxygen species that damage cellular membranes, myelin, and mitochondria. As a consequence, studies have noted severely depleted CoQ10 in patients suggesting mitochondrial dysfunction. This finding also supports the epidemiological evidence that ME/CFS patients are more prone to develop cardiovascular diseases, since CoQ10 is vital for heart health. Some reports have found congestive heart failure can occur 25 years earlier in ME/CFS patients than in the general population (8).

Is it in the brain?

Advanced imaging studies in ME/CFS found widespread neuroinflammation in several key brain regions including the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons. Inflammation in these areas was 45%-199% times higher in ME/CFS patients than in healthy controls. Interestingly, the degree of neuroinflammation directly correlated with symptom severity (9). Larger studies are underway to determine which inflammatory marker is driving the vicious cycle of inflammation. At the moment, all eyes are on leptin. Leptin measured daily in a small cohort of patients was found to correlate with the degree of neuroinflammation. This inflammatory molecule released from fat tissue, can activate microglia in the brain which promotes neuroinflammation (10). 

Read more about Leptin here.

Still other studies have shown that ME/CFS patients have reduced white matter and abnormalities in gray matter, potentially offering additional clues to explain the cognitive difficulties and brain fog patients endure. Lastly, a recent study showed reduced Brain-Derived Neurotrophic Factor (BDNF) in ME/CFS patients that was far greater than in MS patients suggesting an obstacle in neurogenesis and plasticity (11). 

Is it in the gut?

Acclaimed virus hunter Dr. Ian Lipkin has launched a crowd-funded project to study the microbiome in ME/CFS. Putting aside the idea of viral etiology, Lipkin and his team at Columbia hope to find a unique dysbiotic signature in these patients. An exciting 2013 study in Belgian and Norwegian patients, found altered intestinal microbiota that may be linked to the pathogenesis of the illness (13).

Other researchers are also thinking about the role of the gut in this illness. A seminal paper from 2014 proposed that the latent viral infections harbored by ME/CFS patients can have major effects on cognitive function due to translocation via the vagus nerve (12). Could it be that viruses or bacteria harbored in the digestive tract of ME/CFS patients can exert effects on the brain using this cranial nerve as passageway?

How to Intervene

Just because ME/CFS remains a medical mystery should not suggest patients have no options for symptom relief. Without a FDA-approved medication for the illness, many patients look to integrative and functional medicine doctors to manage their most severe symptoms. With the information currently available, evidenced-based interventions can be applied.

It starts with food.

Undoing the cycle of inflammation can be best addressed by starting with an anti-inflammatory diet. This may provide modest relief of pain or fatigue in many patients. A nutrient-dense diet also provides abundant cofactors to promote energy production at the cellular level. Gut healing dietary strategies can also be utilized to ensure intestinal integrity and immune function. Many patients eliminate known gut irritants such as gluten, dairy, alcohol, and refined sugars (14).

Read more about dietary strategies here.

Smart Supplementation

Seldom is diet alone sufficient to make a substantial impact on severe ME/CFS. Most patients rely on a suitcase of supplements with the hope of finding the right combination. While research is slim in this arena, evidence grows for the need for mitochondrial nutrients as well as basic vitamin and mineral cofactors (15). One study showed significant improvement with just 2 months of supplementation with a multivitamin/multimineral (16).

Immune boosting nutrients are commonly utilized to support a healthy immune response, prevent viral reactivation, and improve NK cell function. These include such nutrients as transfer factors, medicinal mushrooms, and curcumin (17). Anti-inflammatory nutrients are also indicated including omega 3 oils, vitamin D, and antioxidants like resveratrol and EGCG.

Did you see the Smart Supplementation Webinar?

Mind and Body

Few can relate to the hopelessness that comes from living with a chronic illness for decades. Patients wrestle with the bleak reality that they may never completely recover. Finding hope through healthy attitudes and habits is of vital importance for these patients. Learning to say no, allowing adequate time for rest, and carefully pacing throughout the day are the norm for a patient with ME/CFS (4). Cultivating acceptance and practicing mindfulness provide other tools patients can use to cope. Mindfulness meditation is now accepted as a practice that can impact brain health and reduce the physiological stress response. Mind-body practices help many patients achieve better sleep and promote a deeper level of healing.


1  Tucker, ME. Does Chronic Fatigue Syndrome Need A New Name? NPR.org. 30 Jan 2014. Retrieved from http://www.npr.org/blogs/health/2014/01/29/268219979/does-chronic-fatigue-syndrome-need-a-new-name

2 Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S. (2006) Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 27(7):615-26. http://www.ncbi.nlm.nih.gov/pubmed/16844674

3  Lattie EG, et al. (2012) Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Brain Behav Immun. 26(6):849-58. http://www.ncbi.nlm.nih.gov/pubmed/22417946

4 Klimas NG, Broderick G, Fletcher MA. (2012) Biomarkers for chronic fatigue. Brain Behav Immun. 2012 Nov;26(8):1202-10. http://www.ncbi.nlm.nih.gov/pubmed/22732129

Fletcher MA, et al. (2010) Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 5(5):e10817. http://www.ncbi.nlm.nih.gov/pubmed/20520837

6  Morris G, Berk M, Galecki P, Maes M. (2014) The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol. 49(2):741-56. Epub 2013 Sep 26. http://www.ncbi.nlm.nih.gov/pubmed/24068616

Agmon-Levin N, et al. (2014) Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunol Res. 60(2-3):376-83. http://www.ncbi.nlm.nih.gov/pubmed/25427994

8  Maes M, Twisk FN.  (2009) Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 30(6):677-93. http://www.ncbi.nlm.nih.gov/pubmed/20038921

9  Nakatomi Y, et al. (2014) Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. J Nucl Med. 55(6):945-950. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24665088

10  Stringer EA, et al. (2013) Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 11:93. http://www.ncbi.nlm.nih.gov/pubmed/23570606

11  Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12:S2-013. http://omicsonline.org/open-access/brain-derived-neurotrophic-factor-is-decreased-in-chronic-fatigue-syndrome-and-multiple-sclerosis-2155-9562-S12-013.pdf

12  VanElzakker MB. (2013) Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 81(3):414-23. Epub 2013 Jun 19. http://www.ncbi.nlm.nih.gov/pubmed/23790471

13  Frémont M, Coomans D, Massart S, De Meirleir K. (2013) High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 22:50-6. Epub 2013 Jun 19. http://www.ncbi.nlm.nih.gov/pubmed/23791918

14  Trabal J., et al. (2012) Patterns of food avoidance in chronic fatigue syndrome: is there a case for dietary recommendations? Nutr Hosp. 27(2):659-62. http://www.ncbi.nlm.nih.gov/pubmed/22732998

15  Myhill S, Booth NE, McLaren-Howard J. (2013) Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int J Clin Exp Med. 6(1):1-15. Epub 2012 Nov 20. http://www.ncbi.nlm.nih.gov/pubmed/23236553

16  Maric, D. et al. (2014) Multivitamin mineral supplementation in patients with chronic fatigue syndrome. Med Sci Monit. 20:47-53. http://www.ncbi.nlm.nih.gov/pubmed/24419360

17  Ellithorpe, RR., et al. (2014) Nutrient supplement enhances natural killer cell function in women with chronic fatigue syndrome and fibromyalgia: Preliminary Report. CLINICAL REPORT FROM THE INSTITUTE FOR MOLECULAR MEDICINE. http://bit.ly/1uy9e6S