Chronic Fatigue Syndrome: Implications for Women and Their Health Care Providers During the Childbearing Years

Peggy Rosati Allen, CNM, WHNP, MS, LCCE

Disclosures

J Midwifery Womens Health. 2008;53(4):289-301. 

In This Article

Definition and Etiology of Chronic Fatigue Syndrome

 

"Recent research from scientists around the world demonstrates multiple abnormalities of the brain and autonomic nervous system, a state of chronic immune system activation, a strong hereditary component, characteristic gene and gene expression patterns, and various abnormalities of energy metabolism in people with chronic fatigue syndrome."

— Anthony Komaroff [11]

Historically, CFS has been misunderstood and trivialized to the extent that even health care providers have doubted whether it really exists. Although the causes of CFS remain elusive, scientific evidence from more than 3000 internationally based research studies have shown unequivocally that CFS is a real physiologic medical condition and not a manifestation of depression or some other somatoform disorder.[4,12,13] Studies also indicate that many persons afflicted with CFS do not have any diagnosable psychiatric disorder.[5] The majority of people with CFS have not experienced depression before the onset of CFS but may become depressed from the profound impact of a chronic disabling illness on their lives.[14] This impact may be compounded by the manner in which a person with CFS is regarded by the health care provider. In a meta-ethnographic analysis of 20 qualitative studies of the experience of persons with CFS and doctors caring for them, the investigators found that the skepticism with which CFS is regarded can negatively impact an affected individual's self-identity and increase social withdrawal and isolation.[3]

A model of CFS pathogenesis that is gaining acceptance by scientists and CFS experts is that when genetically vulnerable individuals are exposed to a triggering event, such as infection, traumatic injury, emotional trauma, hormonal changes, environmental conditions and/or chemical exposure, the usual hypothalamic-pituitary-adrenal (HPA) axis and sympathetic response to such physiologic stress is dysregulated. This abnormal stress response plus the cumulative wear and tear on the body from these triggering factors results in what is termed a high allostatic load. The clinical manifestation of the high allostatic load may be CFS with its multisystem effects.[4,15]

Although symptom severity varies between individuals, all people with CFS are functionally impaired. Studies by the CDC indicate that the level of disability experienced by persons with CFS can be equal to disability experienced by persons undergoing chemotherapy or with other disabling chronic conditions, such as multiple sclerosis, end-stage renal disease, and heart disease.[4]

Now that science has accepted that CFS is a legitimate medical disorder, research efforts are focusing on defining the physiologic mechanisms of the disorder and discovering causes and effective treatments. Ongoing genetic studies at the University of Utah from a large population database have identified "high-risk" CFS pedigrees.[16] Genomic CFS research is revealing the involvement of genes connected to HPA axis activity, the sympathetic nervous system, and immune function.[15] Other genomic studies have revealed that persons with CFS have a disordered expression of genes that are important in energy metabolism.[17]

A number of studies suggest that the severity of CFS symptoms is positively related to the degree of immune system activation, as is similarly found in autoimmune disorders like multiple sclerosis and lupus.[12,18] A recently published study investigated the role in CFS of nuclear factor-kappa beta (NF-κβ), the major intracellular mechanism in white blood cells that regulates inflammation and oxidative stress.[12] In a comparison of the production of NF-κβ in unstimulated, tumor necrosis factor-α (TNF-α) and phorbolmyristate acetate (PMA)-stimulated peripheral blood lymphocytes of 18 persons with CFS and 18 age-sex matched controls, the researchers found that the production of NF-κβ is significantly higher in persons with CFS. Higher levels of NF-κβ production correlated with the increased severity of chronic fatigue symptoms, such as fatigue, muscular aches and pains, sadness, and the subjective feeling of infection. The findings of this study suggest that the symptoms of CFS may be caused by inflammation and oxidative stress. In addition, factors that increase production of NF-κβ, such as viral and bacterial infections, physical exhaustion, and psychologic stress, may also be the causes of CFS.[12] Similarly, a blinded study of immune function in CFS showed that persons with CFS (n = 57) have abnormalities in the ribonuclease L (RNase L) pathway, an enzyme-mediated mechanism in the body that fights infection, when compared to controls (healthy subjects, n = 28; persons with depression or fibromyalgia, n = 25).[18] The results of this study indicated that the presence of a higher level of smaller molecular weight RNase L found in persons with CFS (88%) versus controls (28%) may help to ultimately identify a biomarker for CFS.[18]

Significant advances have been made in identifying a subset of persons with postinfective onset of CFS, with herpesviruses, enteroviruses, Ross River virus, and Q fever being among the suspected causative agents.[19,20,21] In a prospective cohort study of 253 individuals with Epstein-Barr virus (EBV), Ross River virus, and Q fever infection, investigators found that approximately 12% of all the study subjects later developed postinfection fatigue syndrome and CFS, regardless of the original infectious agent, supporting the idea that viruses may trigger CFS in at least a subset of affected individuals.[21] In another recent study using endoscopy and stomach biopsy of CFS individuals with prominent gastrointestinal symptoms, investigators found evidence of enteroviral infection in 80% of 165 subjects with CFS compared to only 20% of 34 controls (P < .001).[20] These findings provide further evidence that infections may trigger or perpetuate CFS in a subset of affected individuals.

Research is beginning to investigate the symptom of "brain fog," a term sometimes used by persons with CFS to describe memory and concentration problems. In a population-based study of 43 patients with CFS and 53 matched non-fatigued controls, the relationship between subjective report of mental fatigue and cognitive dysfunction in CFS was measured by a battery of computerized tests. The investigators found a strong correlation among persons with CFS in subjective reports of mental fatigue and objective measurement of cognitive impairment in sustained attention and spatial working memory, suggesting that mental fatigue is an important component of cognitive dysfunction in CFS.[22] Other studies have examined fatigue and cognitive problems with chronic fatigue on a biochemical level.[23] In an effort to elucidate the neurobiologic effects of CFS and identify potential biomarkers for the illness, Nestadt et al.[23] used magnetic resonance imaging technology called proton magnetic resonance spectroscopic imagining (H MRSI) in a cross-sectional study of 16 persons with CFS, 16 healthy controls, and 16 persons with generalized anxiety disorder (GAD). The investigators found that ventricular lactate levels were significantly elevated in patients with CFS compared to persons with GAD and healthy controls (297% and 348% higher, respectively; P < .001). Additional chemical variations could be found in the occipito-hippocampal and other regions of the brain in individuals with CFS. In all 3 groups, lactate levels positively correlated to level of fatigue (P < .001). Elevated ventricular lactate levels suggest mitochondrial dysfunction and/or anaerobic energy conversion in the brain of individuals with CFS as cells utilize glucose for energy in the absence of adequate oxygenation.[23]

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