Further Organic Abnormalities in CFIDS
Tests of orthostatic intolerance shed light on cause and severity of symptoms
Joan S. Livingston, The Update, Mass. CFIDS Association, Summer 2000, 13(2)
When Dr. David S. Bell last addressed members of the Mass. CFIDS Association, he reported on a fairly astonishing finding: his discovery, along with Syracuse endocrinologist Dr. David Streeten, that a majority of Bell's chronic fatigue syndrome patients had "extraordinarily" low circulating blood volume (a combination of plasma and the red blood cells via which the plasma delivers oxygen throughout the body). While his average patients ran about 70 percent of normal, several PWCs had only half the blood volume of a healthy person, an amount so low that it would ordinarily cause shock and prove fatal in a car accident. (See Winter 1997-98 Update for details on that study.)
pain to brain fog
Bell's Definition of "Fatigue"
In a disease whose formal name is (still) chronic fatigue syndrome, it's thought-provoking that Bell disdains the word "fatigue" as a "very inappropriate term for what patients experience. It's not really fatigue at all, which is defined as a normal recovery state from exertion, and that is precisely what does NOT happen in this illness. It's the limiting of activity that defines this illness. Anybody who works a 20-hour day will be fatigued, but they'll recover from it-it's not the same thing. A typical CFS patient might function on a minimal level (housework, minor errands) for a total of 3 or 4 hours a day. They may say they're fatigued, but what's really restricting their activity may be pain, like headache, tremulousness, or weakness-a sense that they are on the verge of collapse. That is not "fatigue" as we commonly think of it."
When the renowned Lyndonville, NY, clinician and researcher returned to the Boston area this May, he had further research results to disclose regarding the implications of low circulating blood volume (but no answers yet-sorry-on how to fix the problems identified). Streeten and he had conducted tests of orthostatic intolerance (hypotension, tachycardia, and other inappropriate physiological responses to standing) in 20 of Bell's patients, simply by tracking their blood pressure and pulse while lying and then standing. Like the test in which they measured blood volume, the protocol for this one was simple, requiring no special equipment like tilt tables (except time: at 40 minutes per patient, you may have trouble selling your doctor - especially HMOs - on doing this test. But, since it may document a disabling condition for Social Security, it's worth fighting for.)
You Calling a Wimp?
Considering their blood volume and orthostatic intolerance, Bell's patients would be expected to have trouble during the 30-minute standing portion of his most recent testing. ["Fortunately, the nurse in our office, Paula, is very good about predicting when someone's about to go down-and obviously it's better to terminate the test than have patients hit the floor."] In addition, Bell stated, patients with CFIDS are widely assumed "to be 'wimps' - they're lazy, they're malingerers, right? But they'd say, 'I will push myself through this test, I can do it.' They might be swaying in absolute agony, but they'd finish. The normal controls, by contrast, were the wimps! After 20 minutes or so they'd say, 'I'm exhausted. Can you bring me a chair?'" Bell noted that his patients were presumably so used to "pushing to get something done that they often pushed themselves close to the point of passing out", that the sensations they experienced during the test were nothing new to them.
The new findings are particularly meaningful in bucking conventional notions of CFIDS as a disease of self-reported, possibly overstated symptoms. And no one, physician or Social Security judge, can reasonably provide an "AIYH" (all in your head) explanation to a patient with some of the specific physiological abnormalities itemized below, like a "pulse pressure" so low that no doctor can even read your pulse or dub as "within normal limits" a standing blood pressure so low it indicates circulatory shock.
"It's always been said that this is an illness of exclusion, that everything must be ruled out before the diagnosis of chronic fatigue syndrome can be made," Bell noted. "<That> is not true. The pattern of symptoms is unique: <there is no other illness in general medical practice that looks like this one.>" At first, he observed, the fluctuating symptoms may be baffling to the patient and doctor alike: "Not only do they fluctuate over the course of a single day, but also over the longer term. One week your sore throat is so bad you're about to have your tonsils out, then the next week your worst symptom is irritable bowel and you're off to see the gastroenterologist. It's only over a period of time that the characteristic pattern emerges and the diagnosis becomes evident."
Another notable irregularity to test for is "brain fog," though that can be problematic (because most doctors don't have pre- and post-illness IQ scores to compare): "If you give patients a basic cognitive test, they usually do pretty well," Dr. Bell said. "More sophisticated tests will identify the cognitive problems specific to this illness. But on a simpler level, you can also give one cognitive test while the patient is lying down [enjoying maximum blood flow to the brain], and one while the patient is standing. The difference between the two scores is often extraordinary.
"When doctors say that the physical exam is normal, that's also inaccurate," Bell continued. "Virtually all patients will have abnormalities on physical exam [such as lymph-node tenderness or swelling, flushing rash, abdominal pain, etc.], but on average the patient will look pretty healthy. What the doctor is thinking is that the physical exam is not abnormal enough to explain why someone says they can be up only two hours a day. The degree of reported activity restriction is so dramatic physicians frequently just don't believe it's possible."
But an understanding of low blood volume and severe orthostatic intolerance makes the degree of activity restriction more than "possible": it makes it hard to believe patients function as well as they do, because, as the data now suggest, many PWCs may function in a continuous state of hypotension, tachycardia, and/or other posture-related abnormalities.
Five Basic Working Theories
infection (by a single agent)
Agent-induced immune dysregulation (i.e., a pathogen creates an initial infection that causes the immune system to malfunction even after the infection may have cleared); "This has been the best candidate over the past five years because the disease so often begins with a sudden onset, theoretically leading to an upregulation of the immune system and other long-term immune abnormalities."
nervous system injury or dysfunction (e.g., orthostatic
The ANS is the root of orthostatic problems, and the inappropriate release of many chemicals; its dysfunction may explain a range of CFIDS symptoms. (For a full description of the parasympathetic and sympathetic nervous systems, see a good medical dictionary, like Taber's.)
Feigning irritation with this kaleidoscope of changing theories, Bell said, "As a clinician, you don't usually have to read much to keep up with what's going on." (His was a pediatric practice in a rural community before a CFIDS cluster epidemic struck young and old there in the 1980s.) "Sore throats haven't changed in 20 years. You give baby shots, that kind of thing."
With the Lyndonville outbreak, he suddenly had more on his mind than baby shots. "With the first two theories, I had to lean about all the intricacies of the immune system, about cytokines, about natural killer cells, the workings of one pathogen after the next. As soon as I had the immune system pretty well mastered, no one seemed to be talking about it anymore; people were talking about mitochondrial function [energy production at the cellular level]. So I read up on all that, and now we're not talking about mitochondria much anymore.
"Most recently the emphasis has been on the autonomic nervous system, which absolutely <nobody> understands." In this Bell is being a little disingenuous, as he has been one of the pioneers in researching the role of ANS dysfunction in this illness.
Word About Depression
"Having said that, I want to emphasize that, at some point in their disease, many CFIDS patients <will> become depressed. At least 60 percent of my patients have had periods of severe depression. This can take the form of despair that is truly life-threatening, and there may come a time for any individual patient when there is a role for counseling in their lives. I would hope everyone would be open to this when feelings of despair become overwhelming, and recognize that seeking help does not mean their disease is primarily psychological, but instead that counseling can play a valuable role in coping with any chronic physical illness."
In Circulating Blood Volume
How severe were the abnormalities? As mentioned before, the average was 70 percent of normal blood volume; still, "we have six people with only 50 percent of normal blood volume and yet they are still walking around. It seems to be a different mechanism than what happens to a healthy person [who loses that much blood] in a car accident."
In fact, the blood vessels in CFIDS seem to be constricted dramatically, and yet attempts to restore normal blood volume (through use of Florinef, salt, saline injections, transfusions) have met with only limited success so far. "All of the body's normal mechanisms to restore blood [when it is lost in other ways] seem to be turned off." It is as if the CFIDS body <wants> to have low blood volume and that its blood vessels want to stay constricted. Bell likens the blood vessels to water pipes that are only half the proper diameter - you simply cannot make a metal pipe hold any more fluid than the pipe is built to carry.
"When you tell people about these findings, their immediate question is, 'What happened to the blood? Where did it go?' The answer is we don't know. It's not like the patients bled out or are dehydrated - although they do experience a lot of thirst." Turning to the audience, Dr. Bell noted that his patients carry "buckets of fluid" with them at all times - an observation made by other clinicians. "How many people here also have excessive thirst? Whoa - look at all those hands!" It's as though some rudimentary alert system is crying out for more fluid, but because of the vasoconstriction, it just gets flushed away.
Off The Presses: The Latest Findings
The patient lies down quietly for 10 minutes while a nurse takes his or her pulse and blood pressure (BP) several times. The patient is then asked to stand quietly for 30 minutes while the same measurements are taken.
The following <objective> abnormalities - and the number of patients who actually passed out while standing - are compelling evidence for a disability case, Bell noted. "Bank tellers will stand on their feet for 8 hours a day without much discomfort, and this test will show definitively why a CFS patient may not be able to do that for 30 minutes. You can hand this data to a disability judge and say, "Obviously, this person can't work as a bank teller."
Systolic Blood Pressure (sBP; the higher number
in a blood pressure measurement):
Diastolic Blood Pressure (dBP; the lower number
in a blood pressure measurement):
Pulse Pressure (the difference between the systolic
and diastolic pressures):
Bell noted that when a normal person stands up, the pulse may or may not rise slightly; the blood pressure usually remains stable (a graph of the systolic and diastolic numbers is notable for its constancy - a "band" that stays the same size); and the pulse pressure (the difference between the sBP and dBP) remains constant, not surprising since the systolic and diastolic remain steady.
And Five Subgroups
Abnormalities in ANS function documented in virtually all of Bell's patients - some of whom had multiple severe abnormalities - were as follows:
Orthostatic systolic hypotension:
Orthostatic diastolic hypotension:
Orthostatic diastolic hypertension:
Orthostatic postural tachycardia:
Orthostatic narrowing of pulse pressure:
Her physiological abnormalities included systolic hypotension (sBP=70), a drop to zero in her diastolic (dBP=0) immediately upon standing, and a narrowing of her pulse pressure to 10 (70/60) from her resting BP of 160/100 (pulse pressure=60). With her rise in pulse to the tachycardia figure of 120, she had a BP too low and a pulse too high to circulate her blood.
Drop To Zero
These two examples are certainly sensational. Of the five slides Dr. Bell showed as examples of the five disparate patterns he and Streeten identified, he mentioned that three of his patients whose data he used to illustrate three other disorders also had tachycardia, so clearly some patients suffered from more than one form of orthostatic intolerance (OI). Unfortunately, he did not enumerate precisely how many patients fit into each of the five subgroups or several, or whether the slides he showed were representative of the whole study sample or were chose because they illustrated the most severe abnormalities. Nonetheless, this was an initial study and we can probably expect more results and more details down the line.
Chemicals Behind BP, P, And OI: An Area For Future Research
He favorably cited a recent article regarding norepinephrine, released by the adrenal gland. Many PWCs have long felt that the adrenal gland plays some central role in their illness, whether from underactvity, from long-term overuse, or from releasing too much adrenaline, leaving them with that frazzled, running- on-empty feeling.
In the study Bell cited, researchers performed measurements of norepinephrine on a twin subjects who have orthostatic intolerance as the result of a rare genetic defect, both while the subjects were recumbent and while standing. The subjects, who suffered from symptoms like rapid pulse, difficulty breathing, cognitive difficulties, and fainting spells, had excessive blood levels of norepinephrine while standing-but their symptoms were suggestive both of too much norepinephrine and of too little.
"It could be," Bell said, "that a physiological mishandling of norepinephrine ('norepinephrine transport'), for different reasons in CFIDS than in this exceedingly rare genetic condition, plays a role in both conditions."
Testing for "hyperadrenergic" (norepinephrine-related) orthostatic problems is likely to prove a useful tool in the future, Bell predicted. "Norepinephrine is the best method the body has for getting blood to the brain, to get that mental clarity of the fight-or-flight response," he noted. "But in CFIDS it seems to get kicked in inappropriately. Half the patients I've tested have an abnormality on testing. I think we'll soon see testing of such things as plasma norepinephnne when patients are experiencing orthostatic symptoms. It's good for getting blood to the brain but it's counterproductive in CFIDS as it probably causes further vasoconstriction and raises the pulse. It causes panicky symptoms and makes you feel tremulous, it causes exhaustion and forgetfulness, and it can cause poor sleep later."
Speaking of chemicals, Bell added, in regard to CFIDS pain, that PWCs might suffer from an inadequate supply of endorphins, the body's natural opiates. "Though there's no good research on this, there's a fellow in our area who's a superb acupuncturist, and what he's been doing with my patients has been knocking my socks off," Bell related. "I think that somehow acupuncture may have a relationship to the autonomic nervous system and centrally mediated pain."
While Bell and Streeten appear to have provided further insights into many of the body's different responses to low circulating blood volume, especially blood to the brain, there are no answers yet about how best to treat the five subgroups (and members of multiple subgroups) they identified. Perhaps one will turn out to comprise the "Florinef responders." In the past Bell has seemed bedeviled by the fact that the drug works so well for some PWCs but not others (relatively few of his own patients have shown improvement on it).
While there is still nothing as simple as a swab strep-throat culture for diagnosing CFIDS, the subgrouping may be a step in that direction, as well as toward determining the optimum treatment for each subgroup. "The reason I'm excited about this [most recent] study is that it provides a method to subgroup patients and perhaps to find the different mechanisms behind each abnormality," Bell said. With these mechanisms more fully understood, there should be advances in which therapies to use and which really work over time. And the simple orthostatic testing should provide more reliable data on treatment and responses than patients' comments on how they feel, since symptoms remit and relapse over time.
roles of orthostatic hypotension, orthostatic tachycardia,
and subnormal erythrocyte volume in the pathogenesis of
the chronic fatigue syndrome.
BACKGROUND: Orthostatic hypotension during upright tilt is an important physical disorder in patients with chronic fatigue syndrome. We have tested its occurrence during prolonged standing, whether it is correctable, and whether reduced circulating erythrocyte volume is present.
METHODS: Fifteen patients were randomly selected from a large population of patients with chronic fatigue syndrome, studied, and observed for several years (by DSB). Blood pressure (BP) and heart rate (HR) measured with Dinamap every minute for 30 minutes supine and 60 minutes standing were compared with these findings in 15 healthy age- and gender-matched control subjects and later during lower body compression with military antishock trousers (MAST). Plasma catecholamines and circulating erythrocyte and plasma volumes were also measured by isotopic dilution methods.
RESULTS: Abnormal findings in the patients included excessive orthostatic reductions in systolic (P < 0.001) and diastolic BP (P < 0.001) and excessive orthostatic tachycardia (P < 0.01), together with presyncopal symptoms in 11 of the 15 patients and in none of the control subjects after standing for 60 min. Lower body compression with the MAST restored all orthostatic measurements to normal and overcame presyncopal symptoms within 10 min. Circulating erythrocyte but not plasma volumes were subnormal in the 12 women (P < 0.01) and plasma norepinephrine concentration rose excessively after standing for 10 min.
CONCLUSION: Delayed orthostatic hypotension and/or tachycardia caused by excessive gravitational venous pooling, which is correctable with external lower-body compression, together with subnormal circulating erythrocyte volume, are very frequent, although not invariably demonstrable, findings in moderate to severe chronic fatigue syndrome. When present, they may be involved in its pathogenesis.
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