David Bell, Part Two: Low Blood Volume in Myalgic Encephalomeylitis--Shocking
In 1980 while at Life magazine, I reported on the nation’s first emergency room dedicated to treating trauma victims who were in danger of circulatory shock. Also called “hypovolemic shock” and “hemorrhagic shock,” it’s a potentially deadly condition caused by significant blood loss. In trauma victims, blood loss is usually caused by either external wounds or internal bleeding.
The Shock Trauma Center, as it was called, was housed in the University of Maryland hospital in Baltimore. Nurses and surgeons at this one-of-a-kind emergency center were trained to follow a multi-step protocol developed by the late R. Adams Cowley, a heart surgeon. "Shock," Cowley wrote, "is a momentary pause in the act of dying." The point was to stop the death by stopping the shock. Cowley believed trauma doctors had a “golden hour” before a patient in shock lost so much blood they would die of their trauma—not necessarily immediately, but nearly always within a few days or weeks—if they were not treated according to this protocol. Today, as then, Cowley’s “golden hour” is considered a guidepost, not a hard rule. Cowley’s basic shock protocol is followed at most ER trauma centers, which have proliferated since 1979.
Blood carries oxygen-rich red cells to all the tissues of the body. A lack of oxygenation by way of slowed blood circulation results in cell death. Depending on degree, blood loss can lead to a cascade of lethal effects, including a shutting down of major organs: kidneys, liver, lungs, heart and brain. When shock results in inadequate blood flow to the brain, it’s called "ischemic hypoxia." Patients suffering from traumatic shock are always in serious jeopardy, even when they receive treatment at trauma units in emergency rooms. Epidemiological research papers published in 1995 and 2003 found that death rates from hemorrhagic shock in civilian trauma units ranged from 21 to 39 percent of all trauma deaths.
The Baltimore hospital experts rushed to stabilize patients by supplying fluids and assessing their injuries. Everyone seemed to know their role in the grizzly ballet. Blood loss didn’t necessarily mean the blood was flowing out of the body. Invisible internal injuries resulting from blunt force trauma, particularly common in vehicular accidents, were of particular concern. Blood might be cascading into the interior of the body due to an injury directly to an organ or the body’s vasculature system—the blood vessels carrying blood throughout body—or both. If the source of the internal bleed went undetected, patients could bleed to death internally in short order.
By ten o’clock in the evening, a helipad on the hospital’s roof was in near-continual use as people with gunshot and stab wounds, victims of car accidents and with gruesome regularity, motorcycle accident victims, arrived. One evening I witnessed a teenager, who had collided with a car while traveling at 60 mph on his motorcycle, arrive on a stretcher with a portion of his brains lying next to his head. Without irony, the staff called motorcycles “murdercycles." Teams of doctors and nurses rushed up the stairs to await shock trauma patients on the roof, their scrubs flapping violently in the downdraft created by whirring helicopter blades.
"Shock is a momentary pause in the act of dying."
At the center of my story was a man without any visible injuries who had been in a freeway accident. A boat slid off a trailer onto the road ahead of him and his car skidded into it with tremendous velocity. When he arrived at the shock trauma unit, he was alert and talking. Within the hour, he was floating in and out of consciousness, ashen-faced and clammy. A senior surgeon, arms folded, paced nearby awaiting the results of imaging and blood tests. Upon evaluating the tests, the surgeon ordered staff to move the accident victim into surgery. There, the doctor removed the man’s spleen, the source of internal hemorrhaging. Two hours later, however, blood continued to drain from the man's body through a clear plastic tube. The surgeon reopened the man's abdomen and removed part of his pancreas. Finally, the blood stopped, but he remained "critical," with a 50-50 chance of survival, according to the surgeon.
The Life story was unavoidably gory. ER staff toiled on floors slick with blood and discarded Latex gloves. Their blood-drenched paper booties left tracks on the tiles outside the 12-bay emergency room. By the end of their shift, surgeons’ socks tended to be soaked by blood that had penetrated their shoes. When the story was published, the photographs themselves seemed drenched in blood.
Essentially a triage center akin to a field hospital in a war zone, the shock trauma unit made for riveting life and death drama, even if covering the story left me with month's worth of PTSD. Soon after, a documentary, then a feature movie and more recently a mini-series were made about the Baltimore center.
I felt an affinity with the man whose ordeal I had written about and I stayed in touch with him long after the story was published. Months passed before his full recovery and even then, although he was able to return to this job, he admitted to me that he felt something was “off.” By all outward signs, he was well, but he continued to believe the accident had changed his ability to think—his perceptions—in ways that were hard to describe. He felt he was not the same. His life had been saved, but I wondered if he had he experienced a degree of ischemic hypoxia in the ordeal.
What does this have to do with ME?
Some weeks ago, I reached out to retired doctor David Bell for an interview. He agreed, adding, “I know what I want to talk about—low blood volume.”
It wasn’t until Bell and I began to discuss the topic in some detail that I remembered the Life story. I had once understood shock very well, but only as it applied to victims of acute trauma. Nearly forty years later, I realized as I talked to Bell, the same physiological principles and indexes of harm may apply to ME sufferers because they, too, are in shock.
Bell and his colleague David Streeten, an orthostatic intolerance specialist at Syracuse University, conducted investigations in the late 1990s that demonstrated severe hypovolemia in ME. In some cases, the loss was greater than 50 percent, well past the level of blood loss considered the most severe, "Class IV" shock. Indeed, the loss of blood was akin to the patients I saw in the shock trauma unit in Baltimore. Yet, as David noted, ME patients weren't dying in a matter of hours from organ failure even if their blood loss was as severe as trauma patients who were likely to die in a trauma unit.
"We don't see that in ME," Bell told me. "Low blood volume happens very subtly. Somehow, there must be a compensation, because it's not recognized as shock. But it is shock."
Whatever the compensatory mechanism, it's powerful. Bell noted that a trauma victim with a blood volume shortage of two liters would die, but ME patients with the same shortage do not die, at least not immediately, though their physical suffering is unspeakable.
"In shock patients," Bell continued, "one sees all those things that we associate with ME. Cognitive difficulty, extreme fatigue, confusion, ashen complexion and their pulse leaping upward if they try to stand--the whole clinical picture. This also goes hand in hand with orthostatic hypotension."
Orthostatic hypotension is a sudden blood pressure drop when the patient sits up or stands up after sitting or lying prone. Also called "postural orthostatic hypotension," it's an autonomic disorder common, if not universal, to ME.
Bell likes to cite an anecdote about an astronaut who lost about 15 percent of her blood volume on a flight. Whisked to a podium to speak after landing, the astronaut collapsed, unable to stand upright as gravity pulled even more blood away from her brain to her legs. Imagine what might be happening to the hearts and brains of ME patients who may be missing forty or fifty percent of their blood as they pedal on stationary bikes in "post exertional malaise" studies.
Intriguingly, although Bell and Streeten discovered that a majority of patients they studied had blood volumes as low or lower than fifty percent of normal, there existed a dramatic demarcation between genders that has never been published. Blood loss in women greatly exceeded blood loss in men.
"Women's blood loss was twice as severe as men's," Bell said. "All patients had a loss of blood, but women were twice as bad. I have no idea why, but it's a very important point--that women have the blood loss much more than men."
Certainly, some clinicians have observed--including Bell and another longtime ME expert, Paul Cheney, who has evaluated thousands of patients--that women with ME tend to be more ill than men with the disease. According to Cheney, women are also significantly less likely to recover. More commonly understood is that the ratio of women to men with the disease appears to be somewhere between four or possibly five to one.
Another point of demarcation between genders and severity of illness is the fact that in those men he tested, Bell found that the most severely ill did not appear to suffer from low blood volume at all. The finding remains anecdotal but obviously worth exploring.
"The correlation between low blood volume and degree of illness is not clear, it's not linear," Bell said. "A perfect low blood volume study would compare men and women of varying severities of illness and would have a number of participants. You would need controls to see whether length of illness was a factor. Let's say you had one-hundred patients and ten were almost recovered, would their blood volume be back to normal or still really bad? Does the blood volume vary with the severity of the illness? And, is it a predictor of normality? Does blood volume predict recovery? If it went back to normal at some point in the disease, does the patient recover?"
A large study like the one Bell described, he added, might turn heads in the scientific community.
"If there were a correlation between blood volume and recovery," Bell said, "That would really jump-start the research on blood volume."
Unfortunately, Bell continued, people hear about low blood volume in ME and are nonplussed.
"They think, what's the big deal? But at a certain point of low blood volume, you're having a form of shock."
Severe hypovolemia, or shock, in ME provides compelling hypotheses not only about numerous pathological symptoms but about possible mechanisms of death. We have heard about patients relying on gastric feeding tubes or PIIC lines to sustain their lives or, when these routes of sustenance fail, starving to death, all because they have lost the ability to swallow. Inability to swallow is an autonomic nervous system sign, an involuntary response to brain damage. Could the source of that damage be ischemic hypovolemia?
“If you look at hypovolemia, death is considered as low blood flow to the brain,” Bell says, “If you have a diminished blood supply to the brain, I think it may have an effect on the ability to swallow.”
When feeding tubes fail or PIIC lines become infected, as was the case in the death of twenty-one-year-old Merryn Crofts in the UK last year, ME patients can die of starvation.
An inability to receive nutrition was the ultimate fate of sixteen-year-old Australian Alison Hunter, whose mother, Christine, established the largest foundation for ME in that country in 1997, one year after Alison’s death. Alison Hunter suffered from a number of extraordinarily severe problems near her life’s end. A standard autopsy revealed no abnormalities. The report stated, "...the negative organ and tissue profile was in sharp contrast to the severity of the symptomatic effects during life that included abnormal disabling fatigue, transient loss of consciousness ("blackouts"), loss of control over electrolyte balance and unexplained tissue edema." Ten years later, investigators identified Q fever pathogens in "various organs" and in astrocyte cells in Alison’s brain that had been fixed in paraffin on slides. (Frozen tissue was lost to freezer malfunction in 2000.) They concluded that attributing the disease to Q fever hardly did "...justice to the range of different effects [and] multiple host organ systems involved," including a range of cardiovascular and neurological symptoms.
Perhaps all ME deaths in which starvation is the endpoint should be investigated for brain damage due to shock. Blood volume may be an important measurement in cases where patients are having autonomic symptoms such as an inability to chew or swallow.
In addition, the end-stage of shock is coma, which has preceded some ME deaths, as well. Organ failure, another outcome of shock, is sometimes named as a cause of death in ME, as well.
Low blood volume also makes blood thicker, or more viscous, than normal. The many instances of cardiac and thrombotic or stroke-related maladies experienced by ME patients may be hypothesized as resulting from unusually thick blood due to hypovolemia.
“I’ve been very much—very much frustrated.”
Bell is the pediatric specialist on the Scientific Advisory Board of the Open Medicine Foundation at Stanford, the research consortium headed by geneticist Ron Davis. In this era’s current iteration of investigation, wherein scientists are using the latest technology to study cellular metabolism, the gut microbiome, genetics, the impact of exercise, cytokines, lymphoctyes and more in ME, I am not aware that any scientist is studying low blood volume exclusively, if at all. In Bell’s mind, however, the subject has remained Topic A, a critical piece of the ME puzzle that has fascinated him for twenty years.
“I’ve been very much—very much frustrated,” Bell said. “There is no question that the blood volume is decreased about fifty percent in many patients. I think it’s important. If you have a stroke and it cuts off a certain amount of blood to the brain, you have tremendous symptoms. But nobody has ever looked at [the impact on the brain of blood loss] in this disease. There so much that is unexplained in this illness that is related to the basics,” Bell adds. “We ought to start there.”
Significantly, Bell noted that infectious agents, too, can cause “infective shock,” which may follow on the heels of sepsis. In the latter, an infection spirals out of control, resulting in a massive inflammatory response. Infective shock is alternatively known as “septic shock.”
“Any severe infection can cause septic shock,” Bell said. “You get an overwhelming infection and the body shuts down and you go into septic shock.”
In such cases blood pressure plunges and vital organs may be damaged—most seriously, the brain. Organs are deprived of oxygenated blood just as they are in hemorrhagic shock.
In septic shock, an obvious question arises—where does the blood go? The mechanism of blood loss in septic shock is primarily due to a high rate of capillary leak, called a “tell-tale signal” by one expert. During capillary leak, a syndrome in its own right, proteins in the blood seep through weakened capillaries from the “intravascular” system into the “interstitial spaces” in the body. The latter are defined as the “small, narrow spaces between tissues or parts of an organ.”
Why might this happen in ME?
Bell postulates, “The capillaries may be infected.”
“[A causative pathogen] has never been shown in [ME], but it’s probable,” Bell added. “If [ME] is an infection, then it could be a form of septic shock. And if a person has low blood volume and fifty percent of your blood is not getting to your brain, you will have septic shock persistently—because the blood is not getting where it’s needed.”
“This disease could be a form of persistent septic shock—if it’s an infection."
In ME, as in septic shock, the blood may be leaking into “the third space” in the body, Bell suggests. The third space is the interstitial region, a non-functional space between cells, as opposed to the intravascular space—the blood vessels.
“The third space is essentially lost to the circulation,” Bell said.
There exists one other possible explanation for hypovolemia in ME, one proposed more than forty-five years ago by a researcher at the University of Adelaide in South Australia. Tapendra Mohan Mukherjee, who died in 2001, was head of electron microscopy at the University of Otago in Dunedin, New Zealand beginning in 1965, then moved to Adelaide in 1969, where he became “a pioneer researcher” in ultrasound pathology, according to his obituary. Using electron microscopy, Mukherjee reported that the red blood cells in ME patients were distorted by significant structural abnormalities, also known as morphological changes.
The red cells were misshapen—so badly misshapen, in fact, that Mukherjee postulated that these oxygen-carrying cells were unlikely to be able to pass through small blood vessels. A precendent for this hypothesis is sickle cell disease, in which an abnormality of the hemoglobin causes the body’s red blood cells to become misshapen, preventing them from passing through small vessels. By many accounts, Mukherjee’s observation was the first finding to demonstrate an organic pathology in ME. Mukherjee reportedly felt passionate about his finding and throughout his life lobbied, unsuccessfully, for equipment and funding for ME research in South Australia in order to pursue study of the disease.
Mukherjee’s tantalizing red blood cell discoveries were never replicated to my knowledge. Bell adds to this story the fact that he tried to repeat Mukherjee’s findings and failed. Bell did not use an electron microscope as Mukherjee did, but instead employed “light microscopy,” an illuminated form of microscopy.
“Those findings Mukherjee described were big enough so that you would see them under light microscopy,” Bell said. “So, that’s what I tried to do—to see if there were any abnormalities on red blood cells that were like those kind of structural abnormalities [described by Mukherjee.] But I couldn’t see anything that looked like that. Plus, I’m aware that some people tried to replicate his study under electron microscopy and they couldn’t."
Sheerly coincidentally, just as I was going to press, I noticed a new paper on the topic of red blood cell deformities in “Gulf War Illness.” The title: “Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study.” (Rheology is defined by Wikipedia as the study of “materials with both solid and fluid characteristics.”)
In their paper, the investigators described the red blood cells as “deformed” in all seventeen patients with Gulf War Illness. The ten healthy controls were negative for this finding.
They wrote that the disease was marked by “chronic symptoms that include fatigue, pain and cognitive impairment.” Their conclusion? “This symptom cluster may be the consequence of impaired tissue oxygen delivery due to red blood cell dysfunction.” (Italics added)
Orthostatic intolerance opened the door to Bell’s blood volume discoveries. In extreme cases, the blood pressure drop will cause the patient to pass out upon standing. According to Bell, fainting is a more common consequence in children and in fact is rare in adults, who Bell says are better able to compensate. Nevertheless, depending on how adults with ME are manipulated on tilt tables, they can almost always be made to faint.
When Bell met him, David Streeten was an Emeritus Professor of Medicine at the State University of New York (SUNY) Upstate Medical University in Syracuse, New York. Streeten’s authoritative monograph, Orthostatic Disorders of the Circulation: Mechanisms, Manifestations and Treatment (Plenum Medical, 1986) continues to be considered a classic work on the topic. Bell came to admire Streeten enormously. Unfortunately, Streeten died in 2000, just two years after the collaborators’ first paper on low blood volume in ME was published. He was seventy-nine. In an obituary about Streeten, published in the Journal of Clinical Endocrinology and & Metabolism on February 1, 2001, the authors wrote, “(Streeten was) a world authority on abnormal postural effects on blood pressure.”
Bell remembers that when Streeten began to evaluate ME patients, his unfamiliarity with the disease turned to fascination.
“He had never heard of chronic fatigue syndrome,” Bell remembers. “but he was really impressed.”
“[Streeten] called the symptom ‘delayed orthostatic hypotension’ in these patients,” Bell remembers. “He [did so] because in ME patients, it wasn’t a sudden thing—as if you stood up and immediately fell down. For Streeten, it was the chronicity of the symptom and the fact that it didn’t happen all at once.”
Together, Bell and Streeten published a paper called “Circulating Blood Volume in Chronic Fatigue Syndrome” in the Journal of Chronic Fatigue Syndrome. By any standard, it’s fair to say the majority of patients in this study were suffering from blood loss that put them in the category of shock—or, to borrow Bell’s phrase, “persistent shock.”
Medicine has long staged hypovolemia into four classes. Class IV, “severe,” is reserved for a blood loss greater than 40 percent. One patient in Bell and Streeten’s study had a red cell mass that was just 46 percent of her predicted normal, less than half of normal. The majority of patients, sixteen of nineteen, had significantly reduced red blood cell volumes that were "quite striking," Bell and Streeten wrote.
They evaluated blood volume by measuring red blood cells, which typically comprise fifty-five percent of blood volume. They also measured plasma, the liquid portion of the blood that remains when red blood cells are removed. Immune system cell subsets, including B, T and NK cells, are in plasma.
Given the financial limitations that perennially beleaguer ME research, it was a pilot study, one with profound implications. Sixteen of the nineteen patients had a reduced red blood cell mass. Eleven of the nineteen had abnormally low plasma volumes. Twelve patients were found to have subnormal “total circulating blood volume,” which includes red blood cells and plasma.
They concluded, “The high prevalence and frequent severity of the low RBC (red blood cell) mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients.” (Italics added)
In another experiment, Bell and Streeten encased ME sufferers in military anti-shock trousers (MAST), inflatable pants that work by compressing the lower limbs and pushing blood toward the upper body and brain in an effort to prevent shock. MAST pants were invented during the Vietnam War and initially used to help wounded soldiers survive during transport to surgical units. Bell and Streeten’s hypothesis was that if blood could be pushed to the brain in ME sufferers by using MAST pants, the symptoms of orthostatic hypotension--tumbling blood pressure, dizziness, extreme fatigue--might be reversed. The doctors reported that improvement in all ME symptoms, including sudden-onset mental clarity, was immediate. Nevertheless, the MAST study was a proof of concept exercise. Wearing inflatable pants, which feel like a lower body blood-pressure cuff, for any reason other than transport to a trauma unit is hardly practical, of course. Let it not go unreported, however, that one of Bell's patients bought a pair so she could stand at her sink and wash dishes.
"Potentially, all the neurological symptoms of ME are all due to hypoxia."
A notion that ME patients might be in a persistent, if unrecognized, state of shock—meaning they do not have enough blood circulating to their tissues and vital organs because it is leaking through their capillaries into the interstitial space between cells—seems plausible. Certainly, Bell’s work in the late 1990's on low blood volume will resonate with any ME patient who has ever read the following on their brain scan radiology reports: “significant hypoperfusion” (low blood flow to the brain) and/or “diminished gray” and/or “white matter.”
"Loss of brain tissue could be a result of cell death due to hypoxia (lack of oxygen)," Bell said. "Potentially, all the neurological symptoms of ME are all due to hypoxia."
Patients whose radiologists note small lesions in the brain’s white matter tract during MRI brain studies (“WMLs” for “white matter lesions”), or who receive a diagnosis of “progressive white matter ischemic disease,” will be curious about blood volume issues, as well. The same goes for ME sufferers who have been diagnosed with encephalitis, sub-acute encephalitis, or who suffer from what is euphemistically called “brain fog” or—more accurately—ME-related dementia.
Administrators at the Centers for Disease Control have known about abnormal findings of white matter brain lesions in ME since 1985--or thirty-three years.
White matter lesions are seen predominantly in the elderly--people in their eighties and nineties--but have been identified in ME sufferers of all ages. The first doctor to perform an MRI scan on an ME patient, Paul Cheney, found white matter brain lesions in a twelve-year-old ballet prodigy in Incline Village, NV days after she fell ill and became unable to stand due to an inability to maintain her balance. The year was 1985. The colloquial name for these tiny lesions among mystified neurologists at the time was "unidentified bright objects," or UBOs.
After ordering several more MRI brain scans on adult patients with similar results, a deeply concerned Cheney reported these findings to the Centers for Disease Control. Gary Holmes, the agency’s epidemic intelligence service officer who had been assigned to investigate an outbreak in Incline Village, NV in 1985, told me in 1987 that he had wanted to return to Nevada in order to follow up on the MRI brain findings. He added that he was prevented from doing so by his superiors at the Atlanta agency. He also noted that he felt personally discouraged about returning to the region because patients and doctors alike in the region were “bad mouthing” the CDC in the press as a result of its 1985 investigation.
Today, white matter lesions have been closely associated with dementia and cognitive impairment in the aged. At least one paper has looked at cerebral blood flow in relation to white matter lesions in an elderly population and concluded the lesions were due to low blood volume: the paper, “Effect of white matter hyperintensities on cortical cerebral blood volume using perfusion MRI,” published in 2004, concluded that, “[White matter lesions] are associated with reduced regional cerebral blood volume in the cerebral cortex, particularly in individuals with extensive [WMLs].” (Italics added)
In sum, a tangle of common ME symptoms, including short and long-term memory deficits, executive function interference, encephalitis-like dementia, confusion, anxiousness and lethargy, inability to stand or walk, pathologically low blood pressure, shortness of breath and orthostatic intolerance, all may be intimately tied up in the overarching phenomenon of low blood volume.
DAXOR: Since Bell and Streeten undertook their collaboration, a New York-based company, DAXOR, has developed a new and faster technology for measuring blood volume that is akin to a blood draw and can be administered at beside in hospitals. In addition, private practice clinicians can order the test for patients via prescription; Medicare and Medicaid cover the cost. The company has approximately sixty sites around the country where the test can be performed on an outpatient basis. Interestingly, on their website, DAXOR lists “chronic fatigue syndrome” as one of the “indications”— along with septic shock, congestive heart failure, fainting (“syncope”) and orthostatic hypotension—for use of their blood volume measuring technology.
“It seems to us that [DAXOR technology] can be helpful to screen [ME] patients to see if blood volume is a contributing factor,” said Soren Thompon, a DAXOR executive.
When I mentioned the two-to-four million figure that has been postulated as an estimate of the ME population in the U.S. alone, Thompson added, “We’re aware of those numbers, too. We think the potential [for DAXOR] is great.”
Both the Cleveland Clinic and Vanderbilt University are using DAXOR technology to measure blood volume in patients who specifically are prone to fainting or who suffer from orthostatic hypotension, respectively. A subset of these groups are likely to be ME sufferers, Thompson noted. He added that another practitioner who relies on DAXOR technology to measure blood volume in patients with ME is Julian Stewart, a pediatric cardiologist at New York Medical College in Westchester County, NY.
A few important ME studies have included low blood volume as a variable in their hypotheses. Julia Newton is a clinician-researcher at the Institute of Cellular Medicine at Newcastle on Tyne in the UK who specializes in the autonomic symptoms of postural orthostatic intolerance and syncope (fainting). In 2015, she published on “small heart syndrome” and its possible relationship to hypovolemia in ME. Her paper was titled, “Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study.” Newton found significant reductions in red blood cell mass, total blood volume and plasma levels along with cardiac abnormalities. She wrote that there were “strong correlations” between the two. Disarming arguments by doubters, she added that her data indicated the small hearts of ME sufferers had nothing to do with being “deconditioned,” as other investigators have proposed. Instead, “small hearts” in ME were associated with hypovolemia, a condition that was present in patients no matter what the duration of their illness.
Julian Stewart, cardiologist and researcher in Westchester County, NY, has long been interested in hemodynamics and circulatory matters in child and adolescent sufferers of orthostatic hypotension, including ME sufferers. Stewart created a Center for Hypotension-Related Disease at his institution for children and adolescents suffering from “neurally mediated syncope, chronic orthostatic intolerance, chronic fatigue syndrome, orthostatic intolerance of other etiologies such as occur in the postural tachycardia syndrome (POTS).” Writing in a 2003 paper called “The Postural Tachycardia Syndrome,” Stewart noted that “The possibility exists that all forms of [orthostatic intolerance], including [postural orthostatic intolerance], result from central hypovolemia.” (italics added)
Years ago, Stephen Straus, the government's leading non-expert in ME, publicly suggested that ME was impervious to the science of the day. He proposed that comprehension of the disorder awaited more sophisticated technology and a new generation of scientists.
Anyone who has been paying attention over the last few years knows there have been several new lines of investigation in ME research. That new generation of scientists Straus envisioned has arrived. But is the fashionable technology of the day driving the direction of ME research or are the time-honored values of clinical observation and logic driving it? Will worthwhile investigatory efforts that were denied funding in decades past be relegated to the waste bin in coming years? Will they be sacrificed to the gods of an era where technology drives hypotheses rather than the other way around?
Low blood volume in ME is by now an old finding. In 2018, a new generation of scientists are seeking to investigate ME using technology barely imagined in the 1980s. At the moment, few are looking at this profoundly abnormal finding, easily and cheaply measured, even though understanding the origins of low blood volume might explain aspects of the pathology of the disease and causes or death, or lead to a central hypothesis about the cause.
For sheer drama, one notable avenue of contemporary exploration includes the observation by UC San Diego’s Robert Naviaux of abnormal cellular metabolism. Psychiatrists and police in Britain have compared ME sufferers to animal rights terrorists, but to my knowledge no one has ever compared them to nematodes--until now.
Naviaux’s research was heavily influenced by his conversations with Paul Cheney, although Cheney’s name does not appear on Naviaux’s study. Cheney’s insights into ME have deep roots and long tendrils that reach in many directions, underpinning some of the most important ideas about the disease even if those contributions have gone unacknowledged. One of those ideas has been the notion of compensatory mechanisms in ME--what keeps patients alive in spite of their disease? The answer, overly simplified, has always been incapacitation.
Cheney preferred to compare ME sufferers to hibernating bears that enter a period of deep-sleep and slowed metabolism in their earth dens in winter. Naviaux compared the metabolic disorder in ME to the “dauer” state achieved by species of nematode worms that enter a near-deathlike stasis during periods of harsh environmental stress. When in this state, nematodes may survive up to four months, although their typical lifespan is about three weeks. Dauer is a German word, equivalent in English to “enduring.” A German scientist first described the phenomenon in 1937.
“Metabolomics showed that chronic fatigue syndrome (sic) is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer,” Naviaux wrote in the abstract to his paper in the Proceedings of the National Academy of Sciences (PNAS) in May 2016. He also stressed, after delineating the many metabolic abnormalities he and his colleagues found, that in no way should metabolic issues in ME be confused with the well-known “metabolic syndrome,” a common disorder associated with high blood pressure, diabetes, belly fat, etc.
He wrote, “A prediction based on [our] findings is that patients with CFS would be more resistant (italics added) to the constellation of hypertension, dyslipidemia, central obesity, and insulin resistance that increase all-cause mortality associated with metabolic syndrome, but at the cost of significant long-term disability, pain, and suffering.” (italics added)
These are interesting, hypothesis-generating findings and equally interesting interpretations. They resonated powerfully because if there is any mystery about ME it’s that ME patients do not seem to die quickly in spite of all that’s gone wrong. Nevertheless, unlike hibernating bears their suffering is extreme; they feel like they are dying. I’ve witnessed cancer deaths that are less excruciating than life with ME.
What's most interesting is that as distant as they may seem from each other, Naviaux's data may in fact lend support to the shock data collected in the 1990's.
"These people have low blood volume in the range of traumatic shock," Bell noted at one juncture during our conversation. "But this has just not been considered as being important to the hypometabolic state of ME. Shock is a metabolic state."
Is Naviaux's souped-up high-tech research just another fascinating/horrifying, look-see into how ME mucks up human biology? Or will it lead us back to one of the most shocking aspects of the disease: a loss of blood that would kill healthy people but one which ME sufferers are able to survive in the manner of nematodes? A question for another day, perhaps, and beyond the scope of this article.
Abstract from Bell's and Streeten's 1998 "Circulating Blood Volume in Chronic Fatigue Syndrome": Chronic fatigue syndrome (CFS) is an illness associated with severe activity limitation and a characteristic pattern of symptoms despite a relatively normal physical examination and routine laboratory evaluation. The recent description of delayed orthostatic hypotension in patients with CFS, and previous findings of reduced red blood cell (RBC) mass in other patients with orthostatic hypotension not known to have CFS, led us to measure RBC mass and plasma volume in 19 individuals (15 female, four male) with well characterized, severe CFS. RBC mass was found to be significantly reduced (p < 0.001) below the published normal range in the 16 women, being subnormal in 15 (93.8%) of them as well as in two of the four men. Plasma volume was subnormal in 10 (52.6%) patients and total blood volume was below normal in 12 (63.2%), The high prevalence and frequent severity of the low RBC mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients.