Symposium Addresses Neuroendocrine Aspects of CFS
By Dimitris A. Papanicolaou, M.D.
Emory University

A panel of experts convened in March 2001 for the second in a series of scientific symposia on chronic fatigue syndrome (CFS).

The symposium, which focused on abnormalities in the neuroendocrine system, was sponsored by The Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America and the U.S. Centers for Disease Control.

Several studies have suggested a neuroendocrine component to CFS, but the exact role abnormalities play is still unknown. The meeting was organized as a "scientific court," a format used by the National Institutes of Health to accelerate current research.

Following a day of presentations by experts, an independent panel composed of well-respected researchers and practitioners in the fields of biostatistics, endocrinology, epidemiology, immunology, internal medicine, neurology, psychiatry, and sleep disorders, as well as two CFS advocates, developed a consensus statement on the key issues surrounding the role of the neuroendocrine system in CFS.

Key findings of the panel are summarized as follows:

The nature of hypothalamic-pituitary-adrenal (HPA) axis function in CFS needs to be clarified. There is evidence of HPA axis dysfunction in CFS, but testing has yielded inconsistent results. This may be due in part to the relapsing-remitting nature of the illness and to differences in research study designs. The panel suggested that studies comparing CFS patients with and without HPA axis dysfunction be conducted.

Cytokine abnormalities, neuroendocrine abnormalities, orthostatic intolerance, and CFS may be interconnected. Cytokines are chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection. A number of cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), have been implicated in CFS. The panel noted these findings are intriguing in view of research connecting CFS and a family of blood pressure-related disorders called orthostatic intolerance (OI). There is evidence that excessive secretion of inflammatory cytokines such as TNF-alpha may induce OI, although more studies delineating the links between these abnormalities are needed.

CFS is not synonymous with depression. The panel agreed that CFS should be differentiated from major depression. Individuals with major depression have an activated HPA axis, but HPA axis studies in CFS patients have been contradictory. Studies have shown that corticotrophin-releasing hormone levels in the cerebrospinal fluid are normal or even low in CFS patients, while they are often increased in depressed individuals. And as a group, persons with CFS also demonstrate a diminished cortisol response compared to persons with depression.

The panel suggested that these data may point toward a potential biological marker for persons with CFS compared to persons with depression.

No link has been established between CFS and stress. Past research has suggested that stressors such as viral infections, traumatic life events, physical abuse, and automobile accidents may cause CFS symptoms. However, the panel agreed that there is not enough evidence to date to establish a link between specific stressors and neuroendocrine abnormalities in CFS and related disorders.

Sleep abnormalities may contribute to CFS symptoms. Sleep disturbances can cause increased production of IL-6 and TNF-alpha, and some researchers believe that they contribute significantly to excessive daytime sleepiness in CFS. However, the panel pointed out that studies of the association between HPA axis alteration, cytokine secretion patterns, and sleep abnormalities in CFS patients are needed.

More research is needed to define the neuroendocrine aspects of CFS. The panel outlined future research needs, including studies to evaluate stressors previously hypothesized to cause CFS; test treatment strategies, such as drugs to affect HPA axis activity; and identify neuroendocrine activity in larger populations of persons with CFS, including those that fit specific subgroups of the disease.

Panelists also suggested ways to overcome potential research barriers, such as conducting long-term studies to capture the fluctuations in symptom severity most CFS patients experience and developing human experimental models to identify potential biological markers for the illness.

The CFS assessment symposia series is designed to examine the role of the neurological, endocrine, circulatory, and immune systems in CFS. The symposia gather experts to evaluate research findings, identify the most promising next steps, define research and funding priorities, and create research collaboration teams.

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