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While medicine usually progresses by identifying
biomedical markers and indices of pathology, a large number of illnesses, ranging from autism and
schizophrenia to migraine and chronic fatigue
syndrome (CFS), do not fall within this model. CFS is characterized by extreme fatigue, producing a substantial decrease in activity accompanied by infectious, rheumatological and neuropsychiatric symptoms.
In 1991, the National Institute for Allergy and Infectious Diseases established a program of Chronic Fatigue Syndrome Cooperative Research Centers. I was fortunate enough to be awarded one of those Centers that
continued receiving funding until the cessation of this program in 2004. That program allowed me to assemble a cadre of researchers with different backgrounds, but common interests in medically unexplained fatigue and pain. This multi-disciplinary group was comprised of healthcare providers, including physiologists and psychologists.
The fact that medically unexplained fatigue is a component of major depressive disorder was recognized by the medical community. Consequently, it was believed that CFS was a forme fruste of depression. However, we and other groups have assembled a reasonable amount of data against this hypothesis. First, rates of major depressive disorder do not differ between CFS and multiple sclerosis, a neurological disease in which fatigue is prominent. Second, physiological measures, such as plasma cortisol and prolactin response to tryptophan, are reduced in CFS while increased in depression. Third, treatment with antidepressant drugs has little effect in CFS in contradistinction to its effect on depression. Finally, CFS patients have a symptom which is not seen in depression: namely, that even mild exertion — as simple as prolonged standing — produces a dramatic worsening of the patient’s fatigue and malaise.
We have done a number of studies that document and support this complaint. CFS patients show a decrease in activity and in neuropsychological performance following a standardized exercise challenge. The physiological concomitant appears to be a reduced capacity to respond to the stimulus. In other experiments, we have found that some CFS patients at rest have reduced stroke volumes and reduced global cerebral blood flow. This has led to the hypothesis that orthostatic challenge can further compromise cerebral blood flow to produce symptom exacerbation.
To test this hypothesis, we began assessing physiological parameters during orthostatic challenge. Prior reports had indicated that a substantial number of CFS patients had postural orthostatic tachycardia syndrome (POTS). We have found this in relatively few patients. However, substantially more patients show drops in end tidal CO2 during orthostatic challenge. While mild hypocapnia is known to occur during postural challenge, the levels that developed in some patients were frankly abnormal. We hypothesized that perhaps posturally induced hypocapnia could further reduce cerebral blood flow in patients who already were on the low side of normal with symptom worsening as the outcome.
Bharat Biswal, PhD, of the NJMS Department of Radiology, and I are collaborating on studies based on this hypothesis. Dr. Biswal’s major area of research looks at control of cerebral blood flow as assessed by non-invasive neuroimaging methods. Thus, he can determine cerebral blood flow by using a form of functional magnetic resonance imaging. Studying orthostatic challenge in the 3-T magnet environment, where it is impossible to stand, was an obvious challenge. To deal with this challenge, predoctoral student Pratap Kunwar developed an apparatus that mimics a postural challenge by drawing blood from the head and thorax into the lower extremities. We are currently embarked on a major study of the effects of postural challenge on cerebral blood flow as modulated by changes in blood CO2.
Another major project has to do with the hypothesis that CFS is an illness of immune dysregulation. That hypothesis stems from the fact that approximately 40% of CFS patients report a sudden onset. Because our own work has shown that the temporal pattern of these illness onsets is non-random, we believe they probably represent an infectious trigger. The high rate of infectious-type illness onset led patient advocates to label the illness “chronic fatigue and immune dysfunction syndrome” or CFIDS. The idea is that infection produces immune activation, leading to a chronic illness state. The fact that fatigue and diffuse achiness are common side effects of cytokine administration supports this hypothesis.
Unfortunately, studies failed to provide evidence to support the immune dysfunction hypothesis, possibly due to their design. Specifically, samples were usually collected at one time of day and we used only one method to quantify cytokines. My colleague, Neil Cherniack, MD, and I reasoned that perhaps the research tactics used to date could be improved. We focused on sleep in CFS since a very common symptom of patients is unrefreshing sleep. Reduced total sleep time with frequent arousals has been reported in laboratory assessed sleep. A major regulator of normal sleep is a balance between Type 1 (sleep producing) and Type 2 (sleep disrupting) cytokines. We hypothesized that CFS might result from an imbalance in the cytokine sleep network in favor of sleep disrupting cytokines. Collaborating with Stephan Schwander, MD, PhD, assistant professor, NJMS Department of Medicine, we decided to assess cytokines broadly — in plasma using ELISA technology, in white blood cells using rT-PCR to capture cytokine message, and in living white cells using ELIspot technology stimulated both by herpes viruses and phytoagglutinin.
We applied to the National Institute of Allergy and Immunological Disorders and were awarded funding last October. Our experimental design requires blood sampling before, during and after sleep in CFS patients and in healthy controls whose total sleep time was matched to that of a CFS patient studied earlier. We are only recruiting women and excluding those with depression, which can affect both sleep and cytokines. A second experiment uses the same approach following a cardiac stress test. Since exertion is known to exacerbate fatigue and produce additional sleep problems, the purpose of this experiment is to determine if syndromic exacerbation is due to further unbalancing of the cytokine sleep network. Finally, we reasoned that if CFS patients had an underlying immunological disorder relative to healthy controls, a night of total sleep deprivation would magnify the differences because healthy subjects would show a cytokine shift in favor of sleep production whereas CFS patients would still show a predominance toward cytokines that disturb sleep.
We have assembled a research team consisting of Mayka Benitez, study coordinator, Jennifer FitzGibbons, research nurse practitioner, and Carmen Garcon, research sleep nurse. We have begun these studies in the medical school’s prototype General Clinical Research Center. The study is really just getting started. Fifteen women have volunteered to date and we plan to study approximately another 65 research volunteers. Additional information about our work can be found at www.umdnj.edu/cfs.
Benjamin Natelson, MD, received his BA from the University of Pennsylvania and his MD from the University of Pennsylvania School of Medicine. He completed his neurology residency at Albert Einstein College of Medicine in the Bronx and his post doctoral research fellowship in behavioral neurosciences at Cornell Medical Center. Dr. Natelson is currently a professor in the Department of Neurosciences at NJMS. He was the previous director of the War-Related Illness and Injury Study Center at VA New Jersey Health Care System in East Orange. Dr. Natelson has been on the editorial board of many journals, with his most recent appointments on the journals Psychosomatic Medicine and Current Psychosomatic Medicine. He has also authored two books: Tomorrow’s Doctors: The Path to Successful Practice in the 1990s and Facing and Fighting Fatigue: A Practical Approach.§
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