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Chronic Neuroimmune Diseases
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Last updated January 1, 2014

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.)

From pain to brain fog
Bell hypothesized at that time that the low blood volume could help account for the prevalence of "orthostatic intolerance" - worsened symptoms, from pain to "brain fog" - among PWCs, because the limited amount of blood would tend to pool in the legs and feet, that common feeling of unbearable gravity and of wearing lead boots, with a corresponding drop in the amount of blood available to the brain. Other researchers' work has added to the evidence that this is a core problem in CFIDS, including reduced cerebral blood flow on SPECT scans, while some, like the Johns Hopkins group, have demonstrated neurally mediated hypotension on tilt-table testing (changes in posture).

Dr. Bell's Definition of "Fatigue"
Bell defines CFIDS symptoms as falling into four major clusters: so-called fatigue; neurological problems (balance, cognition, paresthesias, etc.); pain ("which can be anywhere-a lot of patients have skin pain, for example, and their doctor already thinks they're a fruitcake, so it's one of those symptoms the patient won't even mention to the doctor"); and multiple sensitivities.

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.)

Who You Calling a Wimp?
Bell and other clinicians, including Dr. Nancy Klimas, have long commented on their patients' (reported and observed) intolerance to being in an upright position, while they may feel "pretty good" while lying down. "When they get up," Bell said, "suddenly they have a lot of symptoms, so I suspected that what we call "fatigue" in chronic fatigue syndrome is really orthostatic intolerance. A patient might lie down for three hours and feel pretty okay, then get up for just 10 or 15 minutes before they're forced to lie down again to restore some blood flow to the brain."

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. 

Hard Data
Consistent with Bell's long-held assumptions, virtually all of his patients (18 or 19 of 20) showed abnormalities when standing, hard data that could be helpful in diagnosis, that generally correlated with disease severity, and that could prove a powerful new tool in fighting for disability benefits. Quantifiable and reproducible, not subjective, not "of exclusion".

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.

Physical Anomalies
As an introduction to his most recent findings, Bell shared his observations about the wealth of already existing data on physical anomalies in CFIDS for those clinicians who have been willing to <look> and do more than a rote physical exam and standard blood test. "The abnormalities in this illness are numerous and striking," Dr. Bell observed. Even before the last few years' research began pinpointing increasingly more aberrations in virtually every body system, he says, "I was always quite annoyed when doctors would say you can't find anything wrong on laboratory evaluations or physical exam. <It's just not true.> Among other things, findings are very, very interesting." Findings include increased CD8+ activated T-cells (generally a sigh of active viral infection), low natural killer cell (NKC) function, and elevated circulating immune complexes. Unfortunately, few doctors other than researchers are inclined to order up such esoterica as immune system tests even when faced with a patient whose symptoms are as severe as those found in CFIDS.

"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."

Sleep dysfunction
Another near-universal symptom is sleep dysfunction. "Sleep-lab studies in fibromyalgia and chronic fatigue syndrome show an amazing array if abnormal findings. Virtually everyone with these conditions has significant deviations from normal stages although different laboratories interpret the sleep data differently. I had one patient who didn't sleep for three days, and the lab report came back reading 'NORMAL STUDY; patient did not sleep for three days."

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.

The Five Basic Working Theories
Dr Bell noted that five basic theories of the illness have been set forth over time and remain current subjects of research:

Persistent infection (by a single agent)
"This theory is beginning to slip because it's just not felt by most researchers to be the most promising candidate; the problem is that we haven't found a single agent in this illness but in fact many pathogens." Just the same, the search is still on, as the recent interest in HHV-6 demonstrates.

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."

Primary sleep disorder
While common in CFIDS, it doesn't account for enough of the symptomatology.

Mitochondrial abnormality
Like sleep disorders, this is probably also just one piece of the puzzle, despite ongoing research in this area.

Autonomic nervous system injury or dysfunction (e.g., orthostatic hypotension)
Consisting of the parasympathetic and sympathetic nervous systems, the autonomic nervous system (ANS) is responsible for controlling dozens of functions, such as the functioning of the adrenals and other glands, and involuntary bodily functions like breathing, pulse, and blood pressure. The ANS is the reason you keep breathing while asleep and your heart keeps pumping, as well as why your system goes into overdrive and why you sweat more when you're nervous.

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.

A Word About Depression
"There is one piece of good news in this list of five theories, and that's the fact that you don't see psychiatric disease there. That theory has largely fallen out of favor. Psychiatric illness is serious and devastating, but there'' very effective treatment for it; by contrast, there is still no good treatment for chronic fatigue syndrome.

"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."

Decrease In Circulating Blood Volume
Eighty percent, or the vast majority, of the patients in Bell and Streeten's first study (of 19 patients, versus the 20 in the more recent study), had a "marked, striking" decrease in circulating blood volume. "One nice thing about that finding," Bell said wryly, "is that it is a discrete physiological abnormality that cannot possibly be explained as psychosomatic."

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.

Straight Off The Presses: The Latest Findings
Bell and Streeten obtained their most recent and detailed findings about ANS dysfunction in Bell's patients through a "very simple test, one that can be performed anywhere, using only a blood pressure cuff" - much like the 'poor man's tilt-table test' - but I would argue it is more accurate because it reproduces exactly what happens to a patient waiting in the checkout line at the supermarket."

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."

The Context
To put the study's findings in context, here is a quick review of the normal pulse and blood pressure, drawn from Dr. Streeten's book on orthstatic hypotension.

Normal Systolic Blood Pressure (sBP; the higher number in a blood pressure measurement):
Recumbent: 100-142
Standing (after 4 minutes): 94-141
Orthostatic change, if any: -19 to +11

Normal Diastolic Blood Pressure (dBP; the lower number in a blood pressure measurement):
Recumbent: 55-90
Standing (after 4 minutes): 61-97
Orthostatic change, if any: -6 to +22

Normal Pulse Pressure (the difference between the systolic and diastolic pressures):
No known norms
Orthostatic change, if any: Difference narrows to 18 mmHg (millimeters of mercury) or lower

Normal Pulse
Recumbent: 54-96
Standing (after 4 minutes): 62-108
Orthostatic change, if any: -6 to +27

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.

Findings And Five Subgroups
The normal baselines just outlined proved to be significantly different from the five basic patterns or subgroups Bell found in his study, despite the fact that his patient's pulses and BPs were generally "pretty normal" while laying down.

Abnormalities in ANS function documented in virtually all of Bell's patients - some of whom had multiple severe abnormalities - were as follows:

1. Orthostatic systolic hypotension:
A fall in the sBP of 20 mmHg or more. As with the other abnormalities, this presumably reflects a desperate attempt by the body to boost blood circulation to the brain. This phenomenon, like all five of the abnormalities, is probably most obvious to the laymen with subgroup 4, Orthostatic postural tachycardia.

2. Orthostatic diastolic hypotension:
A fall in the dBP of 10 mmHg or more. "This seems to be the least common abnormality in the CFS patients I have tested. The body will put out adrenaline and other chemicals as a result of decreased blood circulation, which narrows the blood vessels still further."

3. Orthostatic diastolic hypertension:
A rise in dBP to 98 mmHg or more. "The diastolic BP often reflects systemic resistance, and while standing many CFS patients seem to 'raise' this lower number up in an attempt to push blood to the brain."

4. Orthostatic postural tachycardia:
An increase in heart rate of 28 beats per minute (bpm) OR a pulse of more than 110-120 bpm. "A healthy person's pulse will not change even if they stand up for an hour. You need a steady pulse to circulate the blood."

5. Orthostatic narrowing of pulse pressure:
A fall in the pulse pressure to 18 mmHg or lower. "Usually, when the pulse pressure falls much below 20, you can't even read the person's pulse. When it falls this low, the patient is in a state of circulatory shock.

Case Study
In his Mass. CFIDS lecture, Dr. Bell presented case examples, with details and supporting slides, for each of the five abnormalities listed above. In one of the examples, he presented a patient who actually had several of the five abnormalities, falling into more than one subgroup, and was one of Bell's patients with only 50 percent of normal circulating blood volume. Her resting BP was actually a little higher than normal, at 160/100. As soon as she stood up, however, it dropped to 90/0 (!), before flattening out at 70/60, the 10-point pulse pressure that signifies "it's basically impossible to read a pulse." Even without her other anomalies, at that pulse pressure and that BP, she was in a shock state and could no longer remain standing. In the meanwhile, her resting pulse had jumped from 80 to 120 as her ANS attempted to get blood to her brain.

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.

Another Drop To Zero
In the most recent edition of his publication, the Lyndonville News (CFS-DSB@juno.com) Bell wrote briefly about another woman with systolic hypertension. "One patient I follow had a normal BP while laying down (100/60) but it fell to 60/0 on standing. No wonder she was unable to stand up - a blood pressure that low is really unable to circulate blood. In any ICU they would panic seeing a patient like that, and yet she was turned down for disability because she was considered a "hypochondriac."

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.

Some Chemicals Behind BP, P, And OI: An Area For Future Research
Among the chemicals released by the ANS are cortisol, dopamine, epinephrine (adrenaline), and norepinephrine (chemically very similar to epinephrine but with somewhat less direct effect on the heart). Dr. Bell concluded his lecture by noting that these chemicals probably play a role in CFIDS, especially when released inappropriately, causing further vasoconstriction in those furnace pipes.

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.

The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome.
Streeten DH; Thomas D; Bell DS, Department of Medicine, State University of New York Health Science Center, Syracuse 13210, USA.
Am J Med Sci 2000 Jul;320(1):1-8
CITATION IDS: PMID: 10910366 UI: 20365736

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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