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NIH CFS Workshop Report: David S. Goldstein, M.D., Ph.D., on Autonomic Nervous System & Orthostatic Intolerance

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By Rich Van Konynenburg, Ph.D.

David S. Goldstein, M.D., Ph.D., is Chief of the Clinical Neurocardiology Section of the NIH’s National Institute of Neurological Disorders and Stroke. His research and writing have focused on various topics including disorders involving the control of the heart by the nervous system, catecholamines, stress, and the autonomic nervous system in general.

Dr. Goldstein’s talk at the NIH Workshop on CFS on June 12, 2003 in Bethesda, MD, included a brief introduction to the autonomic nervous system (ANS) and the sympathetic arm of the ANS in particular, a discussion of his work on orthostatic intolerance, a new concept of stress different from that of Hans Selye, and an experimental technique for visualizing the sympathetic nerves in the heart. He covered a lot of ground in a relatively short time, and I have had to refer to some of his published papers to obtain a better understanding of what he said.

Before describing his talk, I would like to provide some background. The nervous system of the body can be divided arbitrarily into the central nervous system, composed of the brain and the spinal cord, and the peripheral nervous system, which includes those parts of the nervous system external to the central nervous system. The ANS is composed of selected parts of both the central and peripheral nervous systems. It is the part of the nervous system that takes care of regulating “housekeeping” activities inside the body (Dr. Goldstein referred to this as the “inner world” in his talk).

The ANS in turn is composed of two arms: the sympathetic and the parasympathetic nervous systems. The reason the ANS is of interest in connection with CFS is that many PWCs suffer from orthostatic intolerance (inability to stand upright for very long without developing unpleasant heart and circulatory symptoms). The response of the heart and circulatory system to standing upright is under the control of the sympathetic arm of the ANS. It thus appears that there is some malfunction that involves the sympathetic nervous system in CFS; hence, the interest in the sympathetic nervous system and in the ANS in general at the Workshop.

In regard to stress, Hans Selye developed the concept of stress as a nonspecific response of the body to any demand placed upon it, of whatever sort. In other words, his concept was that whatever the type of stressor involved, the body undergoes the same response. Researchers since Selye have questioned this idea, Dr. Goldstein among them. Since various kinds of stress have been shown to be triggering factors for CFS, it is of interest to understand the body’s response to different stressors.

The reason for wanting to visualize the sympathetic nerves in the heart is to see if they are damaged in disease states. For example, in Parkinson’s disease, some of the sympathetic nerves in the heart are lost. The interest in CFS is to see if the blood pressure and heart rate abnormalities observed in orthostatic intolerance in CFS can be attributed to damage to or loss of sympathetic nerves in the heart.

Moving now to the talk Dr. Goldstein presented, he first discussed the ANS in general and the sympathetic nervous system in particular. He talked about the relevant anatomy and the history of the understanding of these systems. He explained that the ANS regulates the smooth muscle, the glands and the cardiovascular system. He noted that there is a relationship between the sympathetic nervous system and the adrenal medulla. Sympathetic nerves from the spinal cord go directly to the adrenal medulla, without a ganglion between, while nearly all other sympathetic nerves have ganglia between the spinal cord and the nerves that go to the various organs they control. The main hormone secreted by the adrenal medulla in response to stimulation by the sympathetic nervous system is epinephrine (adrenalin), while the messenger produced by the sympathetic nerves is norepinephrine (noradrenalin).

Dr. Goldstein emphasized that while in the past it had been thought that the sympathetic nervous system and the adrenal medulla acted together as one unitary system, it has since been learned that this is not true. He stressed that these are separate components of the ANS, and when they are dysregulated, as occurs in neurocardiogenic syncope (fainting due to neurally mediated hypotension or NMH) they are separately dysregulated.

He then moved on to discuss orthostatic intolerance (OI) in more detail. He reviewed the initial work on OI in CFS by Peter Rowe and colleagues at Johns-Hopkins using the tilt-table test, noting that two forms of OI had been found. The first was characterized by a sudden drop in blood pressure and a slow heart rate, leading to fainting. Rowe et al. had called this neurally mediated hypotension (NMH). The other form of OI they found involved an increased heart rate, with or without fainting. This was called postural orthostatic tachycardia syndrome (POTS). Sometimes both occurred in the same patient. While subsequent work by others has not found the rate of incidence of these syndromes in CFS to be as high as Rowe et al. did, these two types of behavior nevertheless have been confirmed in PWCs by other researchers.

Dr. Goldstein noted that in syncope (fainting) there are two classic features. The first is failure of the sympathetic nervous system: there is an observed loss of sympathetic outflow (outbound nerve

impulses) to the skeletal muscles and the heart. But the second classic feature is that the person turns pale, which is due to constriction of the blood vessels serving the skin. This latter effect cannot be caused by a loss of sympathetic outflow, because that would cause dilation of these blood vessels. Instead, turning pale is caused by increased epinephrine output by the adrenal medullas. This shows that the part of the sympathetic nervous system that produce norepinephrine and the part that stimulates the adrenal medullas to produce epinephrine are not unitary, i.e., they do not act together in the same direction.

Dr. Goldstein then reported on his own research on patients with the two forms of OI. Most, but not all, of the patients he studied also had a complaint of chronic fatigue. (He did not say how many actually fulfilled the case definition criteria for CFS.) His group measured the forearm vascular resistance response and the response of the blood plasma levels of norepinephrine and epinephrine to being tilted upright. In normal people upon being tilted upright, the forearm vascular resistance approximately doubled, and the plasma norepinephrine and epinephrine both went up about threefold, compared to their baseline levels. By contrast, in the patients who suffered from syncope, the forearm vascular resistance rose initially, but then crept downward and dropped lower than its starting point; in other words, the forearm became vasodilated. Their norepinephrine and epinephrine both rose initially, but then the epinephrine went much higher, while the norepinephrine “petered along.” Within minutes, these people underwent syncope. Their observed neurochemical pattern represented what Dr. Goldstein called “sympathoadrenal imbalance.”

The average extent of the imbalance was more than tenfold. After the patients were restored to the supine position, the imbalance was still present for a while, and then recovery occurred, but the elevated epinephrine persisted for “quite a while” afterward. Dr. Goldstein suggested that this is probably what makes these patients feel so bad for hours to days after the tilt table test. Understandably, they aren’t very enthusiastic to repeat the test! In between episodes of OI, the patients report that they can’t tolerate heat or exercise, they can’t get up, they “don’t feel right,” they can’t eat large meals, and they feel fatigued and disabled.

Dr. Goldstein’s research has shown that OI is not caused by a failure of the sympathetic nervous system or by a loss of sympathetic nerves in the heart. Instead, it is caused by sympathoadrenal imbalance. (He did not suggest an explanation for the proximal cause of this imbalance.) In addition, he has found that POTS and syncope differ markedly in cardiac sympathetic function. He and his coworkers have done cardiac catheterization and have infused tritiated (radioactively labeled) norepinephrine. By measuring how much it is diluted, they were able to determine how much norepinephrine enters the venous blood of the heart. The results were that in patients who have POTS, the cardiac norepinephrine “spillover” is higher than in normal subjects, while in those with syncope, it is lower, independent of an actual “event.”

Moving on to a discussion of stress, Dr. Goldstein first described the work of Hans Selye. In rats exposed to several types of stressors, Selye observed the same response: adrenal enlargement, gastrointestinal bleeding, and shrinkage of organs associated with the immune system. Dr. Goldstein pointed out that Selye was only interested in this nonspecific response, but that there are also specific responses that differ, depending on the type of stressor.

In addition to the nonspecific responses to stress, Dr. Goldstein and coworkers have noted that there are also “primitively specific responses.” For example, in hypoglycemia the adrenomedullary system (epinephrine production) responds much more than the HPA axis does. In water deprivation the main response involves vasopressin secretion. With salt deprivation, the rennin-angiotensin- aldosterone system is the primary responder. Fight, flight, fright and faint are all different in terms of the body’s responses to stress. For example, a person or animal who is being aggressive in response to a stressor can generate saliva. One who is in fear in response to a stressor cannot.

In attempting to test Selye’s concept, Dr. Goldstein and his coworkers found that if no assumptions are made about threshold behavior of stressors, the concept can be shown mathematically to be untestable experimentally, and hence would not qualify as a scientific hypothesis. On the other hand, if assumptions are made about threshold behavior, the concept is testable, and is shown to be “wrong.” Dr. Goldstein also pointed out that Selye and his students dealt only with the HPA axis, while Walter Cannon and his students dealt only with the adrenomedullary hormonal system. A complete treatment of stress response must take both into account, as well as interactions between them.

In place of Selye’s concept, Dr. Goldstein and his coworkers have proposed a homeostatic definition of stress. This is analogous to a home heating system that has a thermostat with a set point. Afferent signals (inbound nervous system signals) are compared with the set point, and the discrepancy between the afferent signals and the set point drives multiple effectors in accordance with negative feedback. Dr. Goldstein also discussed his and Bruce McEwen’s concept of “allostasis.” This involves an extension of the homeostasis idea to include changes in the set point over time.

The notion of allostasis recognizes that there is no single ideal set of steady-state conditions in life, and different stressors elicit different patterns of activation of the sympathetic nervous and adrenomedullary hormonal systems. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. Using the analogy of the home heating system, allostatic load and risks of system breakdown increase if the front door is left open in the winter. They suggest this as a model for understanding how acute and chronic stress can exert adverse health consequences via allostatic load.

Dr. Goldstein then turned to a discussion of a technique he has developed for imaging the sympathetic nerves in the heart using radioactive fluorodopamine, a positron emitter. With this method it is possible to see that the sympathetic nerves are normally distributed uniformly in the heart. It is also possible to distinguish differences in the condition of the sympathetic nerves of the heart between patients with Shy-Drager syndrome, and Parkinson’s disease, for example. He also described a ligand displacement technique for studying the function of these nerves.

The following comments represent my views on the significance and application of the work of Dr. Goldstein and his coworkers to the pathogenesis of CFS. In my opinion, they have made very important contributions to our developing understanding of this topic. I note that the late Dr. David Streeten wrote a paper before he died entitled “Role of Impaired Lower-Limb Venous Innervation in the Pathogenesis of Chronic Fatigue Syndrome” (American Journal of the Medical Sciences 2001; 321(3):163-167). In this paper he reported that “there was strikingly increased venous contractile sensitivity to infused norepinephrine” in the foot veins of six of the seven PWCs he studied.

He suggested that orthostatic hypotension in CFS may be caused by “impairment of the normal orthostatic increase in norepinephrine release at the terminals of the sympathetic nerves innervating leg veins, with consequent up-regulation of alpha- adrenoceptors in these veins and perhaps at other venous sites in the lower body of human subjects.”

I find it interesting that Dr. Goldstein and coworkers observed that the plasma norepinephrine level “petered along” in patients who suffered from syncope when they were tilted upright. Putting these observations together, it seems to me that there may be a shortage of norepinephrine production initially in the sympathetic nerves regulating the constriction of the veins in the lower body of these patients when they are tilted upright, making it impossible for them to prevent blood pooling there, and leading to orthostatic hypotension and syncope. As time proceeds, this shortage may also appear in corresponding nerves in the arms, as observed by Dr. Goldstein and coworkers. I suggest that the rise in epinephrine secretion by the adrenal medullas is the sympathetic nervous system’s response to the lack of sufficient norepinephrine production, thus producing the sympathoadrenal imbalance. I suggest that the adrenal medullas have a higher priority for the limited supply of tyrosine, which they use as the substrate for their synthesis of epinephrine.

What could lead to such a shortage of norepinephrine? As I have suggested in an earlier communication, this problem may arise because of a depletion of tyrosine, which is the substrate for synthesizing norepinephrine. Tyrosine depletion may in turn result from the constant demand for it to make norepinephrine by the sympathetic nerves that constrict the arterioles in the skin. PWCs tend to have a lower than normal metabolic rate, which causes them to operate at lower than normal peripheral body temperatures.

In order to conserve scarce heat and thus maintain the core body temperature at the normal level, which I suspect would have a higher priority than maintaining orthostatic tolerance, the sympathetic nervous system constantly constricts the arterioles serving the skin, which happens to be the largest organ of the body. I suggest that the resulting high demand on tyrosine leaves the sympathetic nerves that are supposed to regulate the constriction of veins in the lower body with a shortage of the raw material needed to do their job, and this in turn leads to the observed orthostatic intolerance.

As I have suggested in the past, I suspect that the low metabolic rate in CFS results from the observed glutathione depletion (which results from a history involving some combination of a variety of

stressors) and a consequent rise in concentrations of oxidizing free radicals in the cells, i.e. the observed oxidative stress. Peroxynitrite is one of these free radicals, and it is known to be able to put blockades into the Krebs cycles and the respiratory chains in the mitochondria of cells, thus limiting their capacity to generate ATP, leading to a decrease in the metabolic rate. I suspect that there are a number of vicious circles that hold down the glutathione levels. One of them may be the oxidation of norepinephrine to form noradrenochrome, which is detoxed from the body in Phase 2 detox by glutathione conjugation.

It might be objected that there have not been many reports of low plasma tyrosine from PWCs who have had amino acids tests run. I would suggest that this may be a very dynamic variable. In order to observe a low value, it may be necessary to take the blood sample during upright tilt, when tyrosine depletion would be expected to be the most severe.

If this pathogenesis model is valid, there are several possible interventions that could be attempted. One is to replenish glutathione, either with undenatured whey protein or with the amino acid precursors for glutathione. While this has been found to be helpful by many PWCs, it does not seem to be the whole answer. Another approach might be to supplement tyrosine or its precursor, phenylalanine. But a more effective complementary approach may to be to raise the metabolic rate, thus relieving the demands for tyrosine and glutathione.

Correcting the problem of the low metabolic rate by the usual methods of applying heat to the body, all of which involve heating the skin, has not been feasible for most PWCs, because the resulting vasodilation of the skin further depletes the flow of blood to the brain, tending to further encourage the onset of syncope. As I suggested in an earlier communication, it may be that the benefits that some PWCs have reported from far infrared (FIR) heating are due to the deeper penetration of this type of heating, allowing the tissue temperature to be raised without raising the skin temperature as much as with other methods of heating, thus preventing significant shunting of blood flow away from the brain.

Perhaps the increase in the average metabolic rate over time as a result of the heating of deeper tissues more gradually relieves the constriction of skin arterioles, lowering the demand for tyrosine to make norepinephrine there, thus lowering the production of noradrenochrome and relieving the high demand for glutathione to detox it. This would then allow the glutathione to be replenished so that it could counter the peroxynitrite formation. This would remove the mitochondrial partial blockades, and the steadystate metabolic rate would then be allowed to rise. Thus the vicious cycle might be broken. There would then be more tyrosine available to the sympathetic nerves serving the lower body veins, and orthostatic tolerance would be restored.

I want to caution readers that while I have attempted to report accurately what Dr. David Goldstein presented in his talk, my comments on the application of this work to the pathogenesis of CFS represent my own currently unproven hypotheses.

(c) 2003 Rich Van Konynenburg, Ph.D.

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