Notice that the title says ‘Causes’. There’s little doubt that different pathway end up in the state we know as “chronic fatigue syndrome”. The definition is too broad and the responses to treatments are too variable for this disease not to demonstrate significant heterogeneity.

complex system

Multiple theories abound regarding the cause of chronic fatigue syndrome. A heterogeneous population suggests several could be correct.

That said, some common findings have emerged and most researchers appear to believe ME/CFS is a multi-systemic disorder involving the autonomic, immune and neuroendocrine systems.

Triggering Chronic Fatigue Syndrome (ME/CFS): Infection, injury, physical or psychological stress, toxin exposure, vaccination and other stressful events have been reported to trigger ME/CFS.

Study findings suggesting that high cytokine levels and severe symptoms predispose people with colds to come down with ME/CFS are the closest, however, researchers have come to disentangling this complex process.

The Central Nervous System: Abnormal patterns of brain activity, reduced brain blood flows and brain volume, small brain lesions,high brain lactate levels, and others suggest areas of the brain involved in the stress response, energy production, concentration, motivation, fatigue and pain are damaged in chronic fatigue syndrome (ME/CFS). Natelson’s research suggests ME/CFS patients without mood disorders have increased rates of central nervous system abnormalities. Areas of particular interest in the brain include the brainstem, the prefrontal cortex, insula, orbitofrontal cortex and anterior cingulate, and the connections between these regions. Recent studies suggest neuroinflammation could be a core problem.

Immune Defects: The flu-like symptoms chronic fatigue syndrome (ME/CFS) patients often experience at the diseases onset has made the immune system an important research emphasis. Several immune abnormalities could contribute to the problems patients face. Many immune studies, however, have produced inconsistent findings.

  • Natural Killer (NK) and T-cell Dysfunction – NK dysfunction is consistently found and recent reports suggest a similar dysfunction may occurs in the T-cells.
  • Th1/Th2 Imbalance – There are two general branches (Th1/Th2) of the immune system. Some patients appear to have an over activation of the anti-inflammatory (Th2) branch and an under activation of the pro-inflammatory (Th1) branch of the immune system. This could cause increased rates of allergy and sensitivity on the one hand and difficulty fighting off pathogens on the other.
  • Th17 – recent studies suggest the Th17 system regulating inflammation and autoimmune processes may be affected.
  • Autoimmune – Two successful Rituximab trials have sparked interest in B-cells and autoimmune processes in ME/CFS.

An Undiagnosed Chronic Infection: Several researchers propose ‘atypical’ herpesvirus  (HHV6, EBV, Enterovirus) infections are triggering an immune response that is causing the symptoms of ME/CFS.  Others believe a difficult to diagnose brain infection (HHV6A) may be present.


With infectious onset being common, interest in pathogens is high. We should know much more about pathogens and ME/CFS by 2014.

Increased Sympathetic and Decreased Parasympathetic Nervous System (SNS/PNS) Activation: Narrowed blood vessels and low blood volume associated with increased SNS activity could caused reduced brain and muscle blood flows, heart abnormalities under stress and other problems seen in chronic fatigue syndrome (ME/CFS). Reduced PNS activity could also contribute to unrefreshing sleep.Impaired Stress Response: Impaired hypothalamic-pituitary-adrenal (HPA) axis functioning (apparently at the hypothalamus) and reduced cortisol levels are present in some patients. Chronically impaired HPA axis functioning could set the stage for a Th2 imbalance but the  research into this area has tapered off in recent years.

Genetics: Recent studies suggest a strong genetic component is present in both ME/CFS and FM. Several gene mutation studies have found increased rates of neuro-endocrine and immune mutations. The Open Medicine Institute is currently examining HLA genes in ME/CFS.

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