From CFS-NEWS@LIST.NIH.GOV Thu Mar 9 20:46:16 1995 with BSMTP id 8369; Thu, 09 Mar 95 19:29:16 EST BSMTP id 8361; Thu, 09 Mar 95 19:28:29 EST HHHHHH HHHHHH HHHHHH H H HHHHHH H H HHHHHH H H H HH H H H H H H HHHHH HHHHHH HHHH H H H HHHH H H H HHHHHH H H H H HHH H H H H H HHHHHH H HHHHHH H HH HHHHHH HHHHH HHHHHH Chronic Fatigue Syndrome Electronic Newsletter -------------------------------------------------------------------- No. 45 March 9, 1995 Washington DC -------------------------------------------------------------------- SPECIAL EDITION: HOPKINS STUDY LINKS CFS TO BLOOD PRESSURE AILMENT CONTENTS >>>1. Overview of Hopkins study >>>2. Press release for Hopkins study >>>3. Interview with Hopkins researcher Dr. Peter Rowe [This special edition of CFS-NEWS is devoted to reporting on the newly published Johns Hopkins research which links CFS to neurally mediated hypotension. -- Editor] ------------------------------------------------------------------- >>>1. Overview of Hopkins study Researchers at Johns Hopkins University have discovered what appears to be a link between CFS and a well established cardiac condition called neurally mediated hypotension, according to a study being published in the _Lancet_ this week. The fact that this known cardiac condition has diagnostic tests and treatments that are alrready accepted by medical science has important implications for CFS research and medical care. The journal citation for this study is as follows: Rowe, P; Bou-Holaigah, I Kan, J; Calkins, H;. "Is Neurally Mediated Hypotension an Unrecognized Cause of Chronic Fatigue?". Lancet, March 11, 1995. 345:623-624 The Hopkins researchers are studying many CFS patients at this time, however this initial _Lancet_ study involves only seven patients, several of whom have CFS. The condition called neurally mediated hypotension, which is also known a vasodepressor syncope, involves mis-regulated blood flow and blood pressure which can lead to recurrent fainting. Recurrent fainting has traditionally been considered the primary, or often the sole, symptom of this condition. But the new Hopkins study seems to indicate that many more people who do not have recurrent fainting may nonetheless have this condition, *and* many in this wider group have chronic fatigue generally and CFS in particular. Those patients in the Hopkins study who have gotten benefit from the treatment, and some of whom have CFS, have been enthusiastic about the results. The Hopkins researchers themselves are much more conservative in their claims. They are holding off on discussing the implications of their work pending further research they are now doing which they intend to also submit to a peer-reviewed medical journal. Although the results from this treatment seem encouraging, not all patients in the study respond positively to the therapy. This is consistent with the general experience of treating those who have neurally mediated hypotension, for whom about one third typically do not give a strong positive response to current therapies. Nevertheless, the possible link of CFS to another condition whose mechanism and treatment are well understood relative to CFS is important. Reports about the diagnostic test are more uniformly positive than are those about the responses to treatment. The test involves measuring heart and blood pressure responses while tilting the patient at a steep angle on a special "tilt table". Many cardiologists require tilt testing before deciding whether to treat for neurally mediated hypotension. Tilt table tests are usually available at major medical centers, and typically cost in the range of hundreds of dollars. The Hopkins team is devoting its limited resources to ongoing research and they cannot accept patients for general treatment. In the interview with Dr. Rowe in this edition of CFS-NEWS there is some discussion about how patients might explore getting these treatments from local cardiologists. The interview with lead researcher Dr. Peter Rowe, M.D. appears as article number 3 in this edition. Readers who are familiar with CFS-related medical terms may need to become familiar with new terms as they read information coming from this new (to us) field. "Syncope" means "fainting". "Syncopal" means "in a state of fainting". "Pooling" refers to the gathering of blood in the legs when people stand up. CFS-NEWS will continue to follow developments in this field of research. [Thanks to Katie Lucas, CFIDS Chronicle editor Vicki Carpman, Michelle Fizzano, and Tom Hennessy for special assistance with the reports in this edition of CFS-NEWS.] -=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=- >>>2. Press release for Hopkins study [The following press release was issued by the public affairs office of the Johns Hopkins Children's Center on March 9, 1995.] HOPKINS RESEARCH LINKS CHRONIC FATIGUE AND BLOOD PRESSURE Intermittent bouts of extremely low blood pressure may cause debilitating, chronic fatigue, say Johns Hopkins researchers. In this week's issue of _Lancet_, they report that seven teen-agers with constant malaise had "neurally mediated hypotension," a blood pressure abnormality brought on by a nervous system reflex. "When their condition was treated, chronic fatigue also disappeared in four of the seven adolescents," said Peter Rowe, M.D., associate professor and general pediatrician at the Johns Hopkins Children's Center. During routine examinations of weary tenn-agers, the researchers noted that chronic fatigue symptoms mimicked those of neurally mediated hypotension, minus the fainting spells. According to Rowe, patients with neurally mediated hypotension (also known as neurocardiogenic syncope or vasodepressor syncope) have a tendency to faint while upright for an extended period, such as standing in a line, especially in warm environments. This type of hypotension is often detected using a tilt table test. Patients lie flat on a special table and then are tilted upright to a 70-degree angle. After several minutes, lightheadedness, nausea and fainting occur in those with the condition. In the Hopkins study, all of the teens, aged 12 to 16, became lightheaded or fainted during the tilt table test. Their average blood pressure dropped from 105/64 to roughly 65/40, which established the diagnosis of neurally mediated hypotension. None had a previous history of fainting. "It is unlikely that such consistent responses in seven consecutive patients are due to chance," says Hugh Calkins, M.D., director of electrophysiology in Hopkins' division of cardiology and co-author of the study. After treatment direected at this condition, including increased salt uptake,, four of the teens' chronic fatigue and related symptoms disappeared within one week. The other three reported no change in their condition. "Neurally mediated hypotension occurs when the nervous system's communications are out of kilter," explains Rowe. In normal individuals, blood pools in the legs when standing and blood flow to the heart is dminished. To compensate, the body discharges a surge of adrenaline that makes the heart pump faster and more vigorously so an adequate amouint of blood can reach the brain and other organs, says Jean Kan, M.D., professor and director of the division of pediatric cardiology. In patients with neurally mediated hypotension, there is a "miscommuncation" between the heart and the brain, she says. Just when it needs to beat more rapidly, the heart slows down and even more blood collects in the arms and legs. Lightheadedness and fainting can result. Researchers do not yet know the extent to which genetic influences, infections or other factors trigger neurally mediated hypotension, but they know that increasing dietary salt can help treat it. "We normally encourage patients with this kind of hypotension to shake more salt on their food, eat saltier foods (like pickles, olives and tuna fish), take salt tablets and increase their intake of fluid to help salt do its job," says Issam Bou-Holaigah, M.D., a fellow in Hopkins' division of pediatric cardiology and a co-author. Drugs that allow the kidneys to retain sodium otherwise lost in urine are effective, as are drugs that block the response to adrenaline. Although the physicians point out that the research is preliminary, they say it is possible that neurally mediated hypotension is linked to chronic fatigue syndrome, a disease that is hallmarked by bouts of malaise lasting six months or more. Some patients in this study did have classic chronic fatigue syndrome. Others had many similar symptoms of the syndrome. Future studies will help determine the prevalence of neurally mediated hypotension in patients with chronic fatigue and will determine if drugs used to treat this form of hypotension can consistently improve their daily lives. -=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=- >>>3. Interview with Hopkins researcher Dr. Peter Rowe [Dr. Peter Rowe, M.D. is the lead author for the Hopkins study. The interview below was conducted on March 7 and 8, 1995 and has been edited for readability.] CFS-NEWS: How did your team come across this discovery? Were you researching CFS when you were following this line of inquiry? Not specifically. My clinic looks at a children with a variety of problems that others have not been able to sort out, and an advantage to that set-up is that I end up seeing children whose problems cross a variety of disciplines. When seeing children who are having recurrent spells of fainting, I learned from Dr. Kan, one of my colleagues, about the problem of neurally mediated hypotension. The other name for that is "vasodepressor syncope". This refers to recurrent fainting with no obvious cause. I was also being asked to see children with prolonged fatigue and chronic fatigue syndrome, since no one else in pediatrics at Hopkins was looking at that group of patients. I noticed a similarity in the symptoms between the two groups. The children with recurrent fainting were also tired. But because their fainting was a more prominent symptom to everyone and much more distressing, the fatigue tended not to receive a great deal of attention. The children with CFS occasionally had fainting, but more commonly they would be able to abort an episode of fainting by sitting down. Their main symptom was the light-headedness which in the other patients preceded the faint. So in recognizing that overlap, and realizing that the test for the patients with neurally mediated hypotension was the "tilt test", we reasoned that the patients with chronic fatigue would also have similar tilt abnormalities, which was in fact the case in this group of seven adolescents. Dr. Calkins, one of the other co-authors, had done some independent work on vasodepressor syncope patients with recurrent syncope, and he recognized that fatigue is a common feature following fainting in those patients. So these observations fit together nicely. CFS-NEWS: Is your specialty cardiology? DR. ROWE: I'm a general pediatrician. The other three authors on the paper are cardiologists. Dr. Kan is the chief of pediatric cardiology here, Dr. Calkins is an adult cardiologist who is the head of the electrophysiology service at Hopkins, and Dr. Bou-Holaigah is a fellow in pediatric cardiology with Dr. Kan. EFFECTIVENESS OF TREATMENT CFS-NEWS: Regarding the CFS patients you have treated, are there other symptoms that are relieved in addition to fatigue and faint-headedness? DR. ROWE: For the CFS patients CFS who were in this _Lancet_ study, those who got better had an improvement in all symptoms including exercise intolerance, aches and pains including joint and muscle aches, sleep disorder when it was present, and cognitive dysfunction. One of the adolescents in this study had been taking home tutoring, and she was unable to sit upright during the home telephone teaching. She had to lie down for that because of the fatigue that would occur when she was sitting upright. And she found that despite having previously been an A and B student with good reading ability and comprehension, she was having to read over paragraphs five and ten times and still couldn't recall what was in the paragraphs. When in treatment, as her fatigue improved she reported that her cognitive problems improved as well. And she described it as "as if a fog had lifted", which was intriguing to us because cognitive dysfunction in CFS is often described as like a mental fogginess. For those patients where we can find effective therapy for the blood pressure abnormalities and the light-headedness, usually there is a consistent improvement in all of the symptoms they've been reporting. CFS-NEWS: Have you treated more CFS patients with this new regimen than just those in this Lancet study? DR. ROWE: We have. I'll need to wait before commenting on that. We have been actively investigating the issue of neurally mediated hypotension as it relates to chronic fatigue and CFS since last summer, and we have tilt-tested over 75 patients. But we must not comment on the results of those studies yet because we are submitting them for publication. CFS-NEWS: How effective does your treatment appear to be with regard to CFS symptoms? DR. ROWE: Again, I think that's something we ought to wait on. With regard to the _Lancet_ paper, the four who had a substantial improvement in symptoms clearly benefited from therapy. The three children who did not improve despite having the same therapies have continued to have the same chronic fatigue and CFS symptoms in the last six months since we'd submitted this study for publication. Those who are improved have remained improved, but they have been maintained on the same treatments. It would be premature for me to comment on how effective this program may be for a general CFS population because we haven't done that study. CFS-NEWS: But you are undertaking something along those lines? DR. ROWE: Yes, we think that is the next logical step from the work that we've done thus far, to study the rates of response, and the different therapies that are used for neurally mediated hypotension. CFS-NEWS: There is speculation that has linked cognitive dysfunction in CFS to lessened blood flow in the brain. Does your treatment influence blood flow in the brain? DR. ROWE: What I can say about that is that there are some published papers which may shed light on that issue, in particular one by Dr. Blair Grubb from Ohio. Dr. Grubb looked at cerebral blood flow during tilt testing in patients with neurally mediated hypotension and he noted that at a time when one would expect the blood vessels to be dilated as blood pressure was dropping, there was instead a paradoxical *constriction* of those vessels, so that the implication would be that blood flow would actually be dropping at the time of fainting. Whether this is also going on in an attenuated manner whenever this reflex starts up -- which is essentially whenever people are upright for more than a few minutes -- is an interesting question. But at least in the patients who have *had* cognitive symptoms and have responded in other ways to therapy, the cognitive problems also improve. CFS-NEWS: Has any patient been able to cease treatment and have the good effects remain? That is, has anyone been "cured", so to speak? DR. ROWE: We have not seen that so far. And in the seven patients in this study, the four who improved on therapy have found that if they skip a dose or stop the medication for one reason or another, that the symptoms return. So the treatment really controls the symptoms but doesn't get rid of the underlying problem. In patients who have had recurring fainting that are described in the literature on neurally mediated hypotension, the situation is a bit more complicated. Some authorities believe that after a year of increased salt intake and medication, patients can be taken off the drugs and they do not have an increased frequency of syncope at that point. But whether they are simply ignoring the other symptoms of fatigue and light-headedness isn't clear. If they are just focusing on syncope, they may be missing a lot. CFS-NEWS: I want to step back for a moment and ask you -- since you're coming into this from the perspective of cardiology, I'm not clear on what is new in your treatment, since you are referring to cardiology literature that most of my readers and myself are not familiar with. DR. ROWE: Right. What we've done is take something from this literature on neurally mediated hypotension that has exploded in the cardiology literature in the last ten years, with the increased use of the tilt table for diagnosis of people with recurrent syncope. What *we* have done is to say that you don't have to be syncopal in order to have this physiologic abnormality. That's really the new observation here. More precisely, the physiologic abnormality which actually has been known for a long time is strongly linked to the symptom of chronic fatigue, and *that* had not been well appreciated in the past. Again, I think people would focus on the dramatic symptom of a faint, which would usually draw a crowd, draw a lot of people around, and the patient would get sent into the emergency room. No one pays particular attention if you happen to be just light-headed and tired. You're left to sit in your chair on your own, I think. CFS-NEWS: Yes. DR. ROWE: No news to you. CFS-NEWS: Yes! Nor to many others! DR. ROWE: Right. DISEASE MECHANISM CFS-NEWS: How does blood pressure get mis-regulated in this condition? Does it seem to be due solely to irregular levels of adrenaline, or other hormones? Do nerve signals play a role? DR. ROWE: That's a great question, and the information about that is imperfectly known. What we do know is as follows. When we stand, blood pools in the veins in the lower part of the body. As a result, less blood is available to flow back to the heart. One challenge when we are standing is to keep a satisfactory flow of úÿ úÿ(Continued from last message) blood moving to the brain. The way we accomplish this is that the heart is prompted by adrenaline to beat faster and more vigorously. However, if there is too little blood in the heart ventricle, the adrenaline leads to an abnormal, very vigorous heart beat. This in turn can falsely signal the brain that the blood pressure is high, when in fact it is low. So the brain sends a command via nerves to lower the blood pressure even more, based on the information it had received. This lowering of already low blood pressure naturally makes the situation worse and can lead to fainting or, as seen by the current research, chronic fatigue and other symptoms. While we do understand the sequence of events following the excessively pooled blood in the legs, it is unclear in all instances why the heart ventricle might have too little blood in the first place. In any case, some corrective treatments which address that portion of the mis-regulation which we do understand can be effective in alleviating symptoms. CFS-NEWS: Could you explain that process in more detail? DR. ROWE: Sure. When you stand up, everyone has *some* pooling of blood, just by the simple effect of gravity. And one of the main jobs of the heart when you're standing is to send a constant amount of blood flow to the brain. If you're getting less blood back to the heart and brain from the legs, because of the effects of gravity and the pooling of blood, then your body needs to make an adjustment. That adjustment is usually a secretion of adrenaline, which causes the heart to beat faster and more vigorously, thereby restoring the stnadard blood flow to the brain. On the other hand, if for some reason the blood pressure is too *high*, then one possible normal response might be for vigorous contractions of the heart to stimulate nerves that are inside the wall of the left ventricle, which in turn will send a message to the vaso-motor center in the brain to indicate that the blood pressure is too high. The brain will respond by sending a command to lessen the heart rate and thus lower the blood pressure. Now when there is an unusually low amount of blood returning to the heart -- a low amount in the *ventricle* of the heart -- then the heart will have especially vigorous contractions. These vigorous contractions are thought to erroneously trigger the heart's nerve signal to the brain which signify high blood pressure. The brain responds in accordance with this signal, and it sends out its own nervous system signal to tell the heart to lower the pressure even further by dropping the heart rate. This causes more pooling of blood in the peripheral circulation. In healthy people who have enough circulating blood volume and who don't have excessive pooling, the heart has a reasonable amount of blood in it, so that when it responds to adrenaline it contracts against a fair amount of blood and pushes that out. There is usually no overly vigorous contraction to change the shape of the ventricle enough to stimulate the nerves from firing off a message. Normally, that message is something the heart will send if the blood pressure is way too high. You *need* a protective mechanism if blood pressure is too high. The paradox for those with neurally mediated hypotension is that the signal is getting activated by a *low* blood pressure condition. And once it's activated, it makes the condition worse. It is believed that if you put any person through a tilt table test, healthy or ill, for a prolonged enough period of time and with enough fluid depletion, and in a warm enough environment, they will likely have a positive tilt test. What what will be different is how rapidly that reflex develops. We think that in these patients, the heart is generally normal and the brain is normal, but the reflex interaction *between* the two is what is out of kilter. And what seems to trigger that dysfunction is a state of a low amount of blood in the ventricle of the heart while standing. It is either low because you've started with a lesser volume of blood, for whatever reason, OR because the amount of *effective* blood volume that is potentially available is not getting delivered to the heart because of an excessive amount of pooling in the extremities. CFS-NEWS: The term "neurally" in the phrase "neurally mediated hypotension" refers to the "high-blood-pressure" nerve signal that's sent from the heart to the brain? DR. ROWE: Yes. CFS-NEWS: One of the key things I'd like to focus on in describing this process is to make clear at what point does the error occur, in those who are getting the recurrent fainting or the chronic fatigue. What is different from the normal person in how this whole blood regulation process works? DR. ROWE: The abnormal nerve reflex which falsely signals high blood prrssure can be triggered by at least two things. One is if there is too high a level of adrenaline. Another is that if the heart ventricle doesn't have a sufficient amount of blood in it because of too low a volume of circulating blood or because of too much pooling in the arms and legs. If either of those alone or in combination is occurring, there is a chance for this reflex to be activated in an abnormal way. CFS-NEWS: One of the broader theories about the cause of CFS focuses on possible HPA dysfunction. In particular, cortisol levels seem to be mis-regulated. How do your findings relate to the theory of HPA dysfunction generally, and do you perceive a relation between the mechanism you have found and the cortisol dysfunction observed in other research? DR. ROWE: We have not focused our inquiry on that area, although at some point the two areas need to be reconciled. So we haven't gotten any formal studies going about that. I should not speculate on that at this point. CFS-NEWS: As a general matter, what do you think causes the condition of neurally mediated hypotension? DR. ROWE: We think it's likely to have a very strong genetic component, in that many of the families we see with neurally mediated hypotension have more than one member affected. As just one example, one of the children in this study in the _Lancet_ had two siblings, her mother, two of her aunts, and a grandmother -- all affected by this problem. None were diagnosed until this girl was diagnosed. The entire family went through life believing that *everyone* has this abnormality, and that everyone needs to lie down for half an hour after taking a shower. That was one of the striking features of the history, which was that these individuals were often very fatigued by a shower. We think there is a strong genetic predisposition, and studies will need to focus on that more in the future. It's also clear that many of the patients had an abrupt onset of symptoms, even when they had a genetic predisposition, after what seemed to be a viral infection. And so that is consistent with what people have reported with CFS. Another feature that is common among these patients is that their salt intake has been very low. They have in effect listened to the medical advice that's really intended for those with *high* blood population of individuals, that advice would lower blood volume further to the point where symptoms would emerge. Overall, though, the answer to the question of what causes this is not well understood. And how viruses might make it worse is not known either. We suspect that they may do something to the nervous system's control over how much blood pooling there might be, or other things. But that's just speculation at this point. CFS-NEWS: I'll mention that some CFS researchers are looking into distinctions between sudden-onset and gradual-onset sub-groups within CFS, and that some preliminary data reported at the Florida conference last October seemed to indicate substantial percentages for both. Is this consistent with what you've seen among the people you've studied who also meet the CFS criteria? DR. ROWE: On question I'd rather hold off for now. In this group of seven, there were four who had had their symptoms triggered by an episode of pharyngitis which was thought to be viral. But beyond that I'd rather not comment because the research is pending. NEW DIAGNOSTIC TOOL: THE "TILT TABLE TEST" CFS-NEWS: You describe in your press release the "tilt table test" which formally identifies this condition of neurally mediated hypotension. Do you make objective lab measurements during this test, in addition to noting the patient's reports of light-headedness and nausea? DR. ROWE: Yes. They get monitoring of blood pressure about every five minutes, and continuous measurements of heart rate on an ECG monitor, as well as on a continuous holter monitor, so that the objective portion measures: whether or not heart rate drops as blood pressure is falling; the degree to which the blood pressure drops; variability of the heart rate when people are in the standing position; and whether or not the heart rhythm moves from a sinus rhythm to a junctional rhythm, which is a very common thing to occur at the point of syncope during the test. So there are a variety of objective measurements which no one can feign. They are reproducible and valid measurements. CFS-NEWS: And is this whole tilt table procedure a standard measurement that has long been established in the field of cardiology? DR. ROWE: Yes, this test has been around for a long period of time, but has been used much more in the last decade. Everybody has a slightly different way of doing it at each center. We ourselves have picked from among the various protocols that are in existence and have been published, and in our subsequent studies we've modified the protocol from that we used in our _Lancet_ paper. But in general, each protocol involves some period of time with patients tilted upright without any medication, followed by a couple of shorter periods during which they get isoproterenol, which is a drug in the adrenaline family which is intended to simulate what's going on on a day-to-day basis, and to thereby trigger the symptoms. CFS-NEWS: Among the different tests on the heart that you mentioned was a "holter" monitor? What is that? DR. ROWE: That is a continuous electrocardiogram reading that's stored on a tape. It's used in cardiology circles to evaluate patients who are complaining of palpitations and abnormalities in their heart rhythm. And many people are familiar with wearing it for 24 hours on a belt. CFS-NEWS: What symptoms are noted during the tilt table test? And what objective findings are observed? DR. ROWE: The symptoms usually include a provocation of the symptoms the patients came in complaining of. If they came in complaining of fatigue and light-headedness, often those will be provoked by the upright posture. But other things that can be provoked include muscle discomfort, sore throat, headache, nausea, warmth, and a general sense of profound fatigue. The objective findings that we look for are a drop in blood pressure accompanied by no increase in heart rate. Normally, when blood pressure drops your heart rate should increase to compensate. We look for the *absence* of that increase in heart rate, OR an actual *drop* in heart rate, which would be very counter-productive for remaining upright. Whenever the blood pressure falls, you should have a compensatory increase in heart rate. And this test shows that those changes are not occurring as they should. CFS-NEWS: Can this test be easily reproduced by clinicians? DR. ROWE: It's a test that up until now has been supervised by cardiology specialists. It has not been adopted by general pediatricians or family physicians or internists. Part of the reason for that is that you need to have a nurse in attendance all during the test. We don't know what would happen if someone were to have a drop in blood pressure while they were unattended, but we don't want to think about that possibility. Whenever the blood pressure falls to a certain point and people become syncopal during the test, we immediately put the table back in a horizontal position. The subject's blood pressure then rises spontaneously. It could be disastrous if somebody were left unattended, so the test needs to be supervised by a nurse and usually by a physician, although it is not usually necessary for a physician to be continuously in attendance in the room. The people who typically have the training on how to supervise that test have been cardiologists and electrophysiologists. If further research shows that this an extremely common problem, the medical profession will obviously need to work on finding a cheaper and less cumbersome method for making the diagnosis. For now, this is what is available. CFS-NEWS: Since there are clinicians who may be reading this interview, would you say that it is inadvisable to administer this test without the special cardiologic training? DR. ROWE: They won't have a tilt table. No one will be able to do it without this tilt table. The only people doing this currently are the cardiologists, and the electrophysiologists in particular. We are now working on developing a less-involved test that would be a screening maneuver that would be used in an office setting. CFS-NEWS: We'll look forward to hearing further news about that. My next question: fainting is not usually noticed among CFS patients, but that is one of the usual criteria in cardiology for recommending this tilt table test for neurally mediated hypotension. Does this suggest that most CFS patients will not respond positively to the test? DR. ROWE: One of the important things that our _Lancet_ paper points out is that up until now one of the main criteria for having a tilt table test done is that you had fainted on a recurrent basis in the past. Our paper shows that you can have an abnormal response to tilt table testing without ever having fainted. So we would argue that at present, the indications for tilt testing need to be expanded to include those with recurrent severe light-headedness. And further work will tell whether all patients with chronic fatigue would be candidates for the test. The fact that CFS patients don't have frequent fainting may simply mean that if they get light-headed, they find a chair before they actually become syncopal. One of the hypotheses this generates for us is whether or not the main difference between recurrent syncope and chronic fatigue is simply the rapidity of onset in the drop in blood pressure, how quickly it comes, and do you have enough warning to sit down and perhaps abort the faint. CFS-NEWS: The alternate term for neurally mediated hypotension, "vasodepressor syncope", is associated by many with the more common term "orthostatic hypotension" ... DR. ROWE: Those two conditions are actually different. CFS-NEWS: Some clinicians might want to know -- would not the usual tests for orthostatic hypotension, such as measuring blood pressure while standing, sitting, lying down, adequately test for this condition? DR. ROWE: The term "vasodepressor syncope", which really is the same thing as neurally mediated hypotension, refers to the fact that blood pressure will drop after *prolonged* standing. "Orthostatic hypotension" usually refers to the fact that there is a drop in blood pressure within the first five minutes of standing and often almost *immediately* upon standing. The tests that are described in medical schools for bedside evaluation for orthostatic hypotension are the ones which you have described in your question -- measuring blood pressure when you're sitting, then standing, and then when you're lying down. But those examinations will uniformly *miss* patients who have the *delayed* drops in blood pressure that are seen in our patient population. So those two conditions need to be separated. But the standard clinical tests will not pick up those who have a very *profound* abnormality in blood pressure regulation that occurs some number of minutes into the actual standing. Patients who are tested in the office setting rarely stand for more than two to three minutes before their blood pressure is taken. SPECIFICS OF TREATMENT CFS-NEWS: Since CFS is often accompanied by high blood pressure and/or overweight, many people may find it illogical that you would recommend an increased salt intake, since that would seem to worsen these symptoms. How does salt intake play a role in this condition? DR. ROWE: Patients with neurally mediated hypotension usually have a reduced effective blood volume. Either their blood is pooling excessively in the limbs, or their total blood volume is actually diminished. And so increasing their salt intake will actually increase their blood volume, and should reduce the risk of the abnormal reflex from being activated. But those who have high blood pressure obviously need to be careful with salt intake, and that needs to be done in conjunction with a physician. Many of the children we evaluated in this paper had low-normal blood pressures -- they had blood pressures in the normal range but on the low side. Salt will draw fluid into the vascular system and thereby increase blood volume. CFS-NEWS: So you would say that those who have high blood pressure would be more difficult cases for this kind of treatment? DR. ROWE: Not necessarily, but their treatment might have to be modified. CFS-NEWS: One thing I'd like to clarify is that it is possible to have hy-PER-tension and this special hy-PO-tension both at the same time. Could you discuss that? DR. ROWE: Regardless of your resting blood pressure, be it regularly high or low, there is still the normal tendency for blood pressure to drop with standing. There are some studies suggesting that neurally mediated hypotension is more common among those with low-normal resting blood pressures, but it is true that this abnormality has been seen in people at all ranges of blood pressure. CFS-NEWS: Okay, so the phrase "neurally mediated hypotension" really refers to ... DR. ROWE: ... what happens *during* the *test*. CFS-NEWS: ... or in similar experiences in life, such as standing up. DR. ROWE: Right. People are not usually hypotensive when they start the test. CFS-NEWS: Are the specifics of your recommended treatment uniform for all CFS patients? That is, do you prescribe the same drugs at the same dosage levels for all patients? DR. ROWE: We don't have enough experience with the CFS patients generally. That will be the subject of our next paper. So it's a bit early to say. CFS-NEWS: Then, did the treatment regimen for those in your published _Lancet_ study, among whom were some CFS patients, require a lot of "fine tuning" for each case? DR. ROWE: Yes. While there are a number of drugs that have been recommended for the treatment of neurally mediated hypotension, there is a striking paucity of controlled clinical trials for children and adults who also have recurrent fainting, and so what we are left with is a number of case series for the most part in which one or another drug is thought to be effective in this condition. And in this setting of uncertainty, physicians have to pick from among these drugs those that they think are most likely to be effective or that have the least number of side effects. Dosages for the patients in our study varied somewhat. CFS-NEWS: So while for this first study you found that you needed to do a lot of fine tuning, you wouldn't want to conclude that that's necessarily the case in general because you don't have enough data yet to come to a general conclusion? DR. ROWE: Right. CFS-NEWS: Can you describe the specifics of your treatment program, since clinicians who read this interview may wish to try this out with their patients? DR. ROWE: I'd rather not go into the specifics of that. I think úÿ úÿ(Continued from last message) we'll end up doing more harm than good if we claim that one drug or another works without having a randomized trial to back that up. We are in the process of applying for funding of a randomized trial to look at different ways of treating CFS, and we hope that will lead to some useful results in the next couple of years. CFS-NEWS: Does your research shed new light on the role of current standard treatments for CFS? In particular, are there drugs now commonly prescribed for CFS that would now seem to be contra-indicated because of your findings? DR. ROWE: What we can say at this point is that if the abnormality we've seen in these seven adolescents is also seen in a large proportion of those with CFS, then certain drugs would also be contra-indicated in treatment, but we ought to wait for the next research to be completed before making those comments. In patients with neurally mediated hypotension with recurrent syncope, it has been recommend that they avoid drugs that would lower blood pressure, such as diuretics, including Diamox, and certain of the anti-depressants which will lower blood pressure predictably, such as some of the tricyclic anti-depressants. These drugs will often do that in adolescents. I can't speak about their response in adults with regard to the blood pressure effect, but in general drugs that are known to lower blood pressure would be expected to make the symptoms of neurally mediated hypotension worse. CFS-NEWS: After how long do the beneficial effects of treatment first become noticeable? After how long does the treatment reach its maximum effectiveness? DR. ROWE: In the patients treated in this study, the treatment was usually obviously beneficial to the children within one to two weeks of starting on an effective medication. In each of those four, though, we didn't always come up with the right drug in the initial treatment, so there was a lot of switching around throughout the study. For the three patients who were not improved with initial therapies, we've now tried a number of treatments for neurally mediated hypotension, and without much success. Some of those non-responsive patients have had repeat tilt testing which again defined severe abnormalities in blood pressure regulation. One of the girls recently had the same symptoms develop in her sister, and the sister had the same tilt-test abnormalities. So once we have the diagnosis, it is not a simple process to make people better. It provides us with some logical structure for picking among available treatments, but it's no guarantee that we'll be successful. Now, if we take our lead from the literature on neurally mediated hypotension as it relates to patients with recurrent syncope, about 60 percent of those patients respond to one of the available therapies, usually Florinef, Atenolol or another beta blocker, or Disopyramide. But in most people's experience, in the cardiology literature, there's somewhere between 20 and 40 percent of patients whose conditions are definable -- we're understanding *why* they are having these symptoms -- but response has been difficult. And they remain a challenge to the cardiologists treating patients with recurrent syncope. And that may be something that also applies if CFS is characterized uniformly by neurally mediated hypotension. In the literature on neurally mediated hypotension, medications which are used in varying doses are: Florinef -- the generic is fludrocortisone; Atenolol; and Disopyramide. When we talk about fludrocortisone to people with CFIDS, we've learned to say "this is not the same as cortisone -- it has none of the anti-inflammatory effects of cortisone, nor the effects on glucose control". CFS-NEWS: So patients who have participated in your study have needed to have some perseverance while you are exploring which treatment might be effective for them. DR. ROWE: Patients in this study who embarked on the treatment obviously need a fair bit of patience and faith that the symptoms were related to the abnormalities we demonstrated on the tilt testing, and that treatment *might* be effective. And I think it was clear that if a couple of them had not persevered, we would not have had the opportunity to find the drug that was ultimately beneficial and which worked. CFS-NEWS: Most clinicians who treat CFS find that lower-than-usual dosages of medications are required for treatment, due to an apparent hypersensitivity by CFS patients to drugs. Do you have any similar experience with regard to CFS patients who receive your treatment? Should cardiologists who may try to treat CFS patients for neurally mediated hypotension keep this in mind as they administer treatment? DR. ROWE: Among the patients in our current _Lancet_ study who had CFS and who responded positively to treatment, I did notice that they responded at lower dosages than would be expected from usual treatments for neurally mediated hypotension. At the same time, I would not want to make a premature generalization as to what that observation means. Nonetheless, it would seem that this is something that physicians who attempt this treatment should keep in mind. CAN THIS TREATMENT BE OBTAINED NOW? CFS-NEWS: Now that your paper is being published, there will be an immense interest by many CFS patients to try out this treatment program you've discussed. Can CFS patients obtain treatment at your facility? DR. ROWE: Not at this time. We only have the resources to conduct some limited research studies for now, and we are finding that we are stretched to our absolute limits in time and energy in trying to cope with those who are now enrolled in these studies. It would not be helpful if people were to come here and undergo the expense of a tilt table test, but then find that no treatment could be made available to them here, which is our situation. We will have to ask people to wait until better information is available from the research studies, or to contact their own physicians or their own local electrophysiology experts to evaluate whether or not they are candidates for the test and the treatment regimen. Our team's role must be to develop the tests that help guide other practitioners in their management of this problem. CFS-NEWS: Some health professionals who have fallen ill with CFS have written essays about how to obtain good medical care, about how to cultivate interest from a physician who may not initially have a background specifically regarding CFS. So something along this line might be written with respect to approaching cardiologists, including the advice to ask the cardiologist to consider the _Lancet_ article just published. And such recommendations should include a strong caveat that if you don't already have a working relationship with a cardiologist who is familiar with CFS, an attempt to educate them about both CFS and this very new link to neurally mediated hypotension will likely be an uphill struggle. DR. ROWE: That's good advice. And it will be important for the primary care physicians to help with making this decision. Our sense from looking at these seven patients is that this is a physiologic and organic problem that would be easy to miss, given the ways that we have evaluated patients with fatigue up until now. As with any innovation with treatment or testing, there is always a range of responses with regard to how rapidly people adopt those innovations, and some professionals will wait for better evidence, while others may say "this sounds reasonable, it won't be harmful -- let's try it". CFS-NEWS: Are electrophysiologists "the" specialists needed for administering the tilt table test? And are they the specialists needed to give treatment? What is an "electrophysiologist" ? DR. ROWE: They are cardiologists who have a special training in the abnormalities of heart rhythms. CFS-NEWS: And so that's the kind of expert needed to give these tests and treatments? DR. ROWE: Yes, or cardiologists who have familiarity with tilt-table testing. They don't have to be electrophysiologists. But electrophysiologists will have the needed background. Most of the major academic centers will have an electrophysiologist on staff. And I would expect that they would have a tilt table available. It's not the kind of thing that a community hospital would be likely to have. CFS-NEWS: That's all of my questions for today. Dr. Rowe, thank you very much for your time and for the very valuable work that you are doing with your colleagues. =================================================================== CFS-NEWS (ISSN 1066-8152) is an international newsletter published and edited by Roger Burns in Washington D.C. It is distributed: through the "CFS echo" (discussion group) on the Fidonet volunteer network of BBSs; via the NIHLIST Listserv on Internet; and as USENET Newsgroup bit.listserv.cfs.newsletter. 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