Postcards from the Edge (Of Florida)

Hillary Johnson

The 12th Biennial IACFS conference was held in Ft. Lauderdale October 27-30. Florida betrayed its rep as the Sunshine State for the duration. Hurricane season had passed yet mid-coast Florida seemed to be throwing a tantrum anyway.  An unbroken gale from the Atlantic threatened to knock over anyone who failed to lean into it. For at least five days a deluge seemed imminent even if not a drop of rain fell.

Separated from the ocean by a coastal road, the Westin hotel had its own micro-climate, less tempestuous than the wind-pummeled beaches, but a pressurized environment nonetheless in which for some, at least, a tormented history hovered over an uncertain present. 

I cannot speak for scientists and other interested parties who attend these affairs, each of whom arrives with their own portfolio of experience and varying degrees of enthusiasm, realism and acquaintanceship with the long history of M.E.  I bring my own intimate acquaintanceship with that history and it never fails to imprison me in a bubble of frustration. No matter what happens next, the lives of millions already have been ruined or lost.

Another problem--for one who has been attending scientific conferences on M.E. since 1987--is the vaguely repetitive feel of so much of the science.  Are we there yet? For me, the "there" amounts to the identification of the cause of the disease and the answer from Ft. Lauderdale is No, we are not there. The majority of scientific presentations, the best of which demonstrated increasing technological sophistication equal to the standards of the day, continue to describe aberrant signs in the disease. The question is, to what degree will these sophisticated inquiries bring science closer to discovering the actual cause of the abnormalities?  

Replication is the essence of the scientific method, of course.  To that end, Maureen Hanson reported her Cornell lab's pilot metabolomics study of 17 patients, which supported and replicated in important ways Robert Naviaux's study of 45 patients that appeared in the Proceedings of the National Academy of Science (PNAS) last September.  (We are all nematodes, but that metaphor is for another day.)  She observed that "a notable number of metabolites that differ between patients and controls are involved in energy metabolism."  Hanson also looked at metabolites before and after exercise in a pair of identical twins, only one of whom suffers from M.E., and found that metabolites changed in both twins after exertion. Not unlike Naviaux, she proposed that a blood test using blood metabolite measures might be developed as an M.E. diagnostic test if the findings could be reproduced in a larger cohort.

Which raises another question: how much replication is required before a test is accepted as diagnostic? Naviaux claimed in PNAS last fall that his work has created a chemical marker that identifies M.E. with 90 percent accuracy. There have been numerous other studies that have provided a multitude of ways to identify M.E. with a high degree of certainty, starting with Natural Killer cell abnormalities first identified and published in 1987 by Caliguri et. al.  Instead of embracing a test and applying it, M.E. researchers seem locked in a perpetual cycle of looking for "biomarkers" (a.k.a., abnormalities common to the disease) even when myriad biomarkers have already been found, often many times over.

Colleagues:  Alexandra H. Mandarano, a Ph.D. student in the Hanson Lab at Cornell, and Ludovic Giloteaux, Ph.D., Postdoctoral Research Associate,  Department of Molecular Biology and Genetics, Cornell University.  Giloteaux presented more microbiome data from the Hanson Lab.  The study found markers of inflammation as well as microbial translocation--the passage of gut microbes into the blood.  The latter is a common finding in AIDS.   A 2013 journal article on microbial translocation in AIDS notes that the phenomenon has been proposed as "a major driver of the chronic immune activation that is associated with disease progression."  (From "Microbial Translocation in the Pathogenesis of AIDS and HIV Infection," in Clinical Microbiology Reviews, the journal of the American Society for Microbiology, 2013.)

Long-time M.E. investigator and medical doctor Kenny DeMerlier of Belgium, currently serving as Medical Director at the Nevada Center for Biomedical Research, reported a panel of biomarkers that he and his colleagues, among them Vincent Lombardi, scientific director at the Nevada Center, believe are able to "broadly diagnose" M.E. with high sensitivity and specificity in both men and women. The panel consists of four markers for either immune or inflammatory abnormalities, each of which "relate strongly to the disorder" and, significantly, were selected based on "...observations made in clinical practice."  The team also concluded that taken together, the biomarkers suggest that lipopolysaccharide (a.k.a., endotoxins), "likely from gut bacteria" are playing an "important" role in the symptoms of the disease. 

So, a third question is, who decides which test is diagnostic? Does the above study just sit on the shelves in a scientific journal, or is it put to use?  Maybe the IACFS should be making these decisions? Should the association's mandate be limited to hosting a conference every two years? And another: when will a test be standardized to the degree that it can be ordered from Quest or Lab Corp?  We know there are a handful of Quest/Lab Corp tests already in use that in combination provide experienced doctors with confirmation of a suspected M.E. diagnosis.  

Additionally, a belief, unsupported by scientific data, that M.E. is "heterogenous" and is actually a collection of multiple diseases with multiple causes, continues to hold sway with many who assembled in Ft. Lauderdale. Breaking the disease into subsets that are essentially clusters of symptoms that in reality may change or reassemble over time, as well as suggesting the disease has multiple causes, seems to me to be the refuge of the least informed, a newbie theory. Listen to the patient, as Sir William Osler would say; the patient is telling you what's wrong.  

Ron Davis of the Open Medicine Foundation at Stanford University (left) and physician David Bell, who has an advisory position with the OMF.

Syphilis is wildly heterogeneous if allowed to progress untreated over the human lifespan. Multiple sclerosis was long ago broken into four categories sheerly for diagnostic purposes or "staging" the disease (progressive, relapsing-remitting, etc).  But no one claims either disease has multiple causes, or is multiple diseases instead of one.  The "multi-multi" M.E. hypothesis certainly feels like an effective way to drive resolution of the disease toward infinity and beyond, however, by relentlessly over-complicating rather than simplifying.  It's also a means to hide an epidemic in plain sight, too, thus a useful tool for federal health agencies who need a lot of time--apparently, years, given their three-decade-late start--to get up to speed.  To me, it's a theory I might expect to hear from Professor Irwin Corey.  For the more cerebral among you, consider that Dr. Lewis Thomas ("Lives of a Cell" author), as quoted by Robert Gallo, called multi-factorial "multi-ignorance."

I can see the wisdom of stratifying patients by gender for purposes of research, as the veteran scientist Maryanne Fletcher is doing in her study of men with M.E. at Nova Southeastern University in Ft. Lauderdale. After all, there must be a reason 80 percent of M.E. sufferers are women. "Systems biologist" Gordon Broderick at Nova reported he is exploring the impact of hormones on severity, another kind of stratification, which might be a useful key to causation or therapies. Stratifying by duration of illness makes good sense to me, too, though a strangely neglected avenue of inquiry.  Anyone who has suffered from M.E. for years knows how this disease changes over time and rarely in a good way.  Ron Davis and his colleagues at Stanford's Open Medicine Institute are focused on severe M.E.  Might "geriatric" M.E. be an equally important field of inquiry for another group?

Given the inaccessibility of effective treatment for the vast majority of patients, the natural history of the disease is being played out in real time in the bodies of people who have been ill for 20 and 30 or more years. Why not find out what M.E. does to people over periods of decades rather than taking a snapshot? The snapshot may tell you about the disease on a particular day or month, but maybe the disease is best viewed as a movie in three acts. The only research I saw at this conference that suggested a way of staging M.E. over time was Marci Zinn's EEG analysis of "neuronal degeneration" in the disease.  She suggested that her research findings had "promise in the understanding of disease progression" and "could potentially aid in staging of the illness."

One other study that addressed at least one aspect of illness duration, even if indirectly, came in the form of a poster presentation from Hemispherx Biopharma, which has struggled for years for federal approval for the drug for treatment of M.E.  The Food and Drug Administration, which has turned down every request for approval of the drug to treat people suffering from M.E. since 1991, more recently asked the company if M.E. sufferers could be stratified based on the strength of their response to the drug.  

David Strayer, an oncologist and the clinical director at Hemispherx since 1986, and now its chief scientific officer, and colleagues produced a retrospective study that found patients who had been sick for more than two years but less than eight years were so-called "high responders." Fifty-one percent of this group were able to improve their exercise time by at least 25 percent versus patients who received placebo after 40 weeks of treatment. However, a finding that would come as a surprise to ampligen patients who fall outside the "high responder" category yet who have found salvation in this drug was that patients who had been ill less than two years or more than eight years showed "no significant exercise effect vs. placebo" according to this data. FDA seems to be seeking to reduce the potential clientele for ampligen to the smallest possible number.  A potential outcome: minimizing the window to gain access to ampligen should FDA ever cave to sanity and approve the drug.  If Hemispherx had utilized tests of IQ instead of treadmill tests over the years to assess response to ampligen, one wonders if the outcome might have been different. Thank CDC for its 1980s fatigue-paradigm that curtailed other avenues of research for so long. 

Maureen Hanson, director of the Cornell Center for Enervating NeuroImmune Disease, Cornell University, Ithaca and David Strayer, chief scientific officer, Hemispherx Biopharma, Inc., Philadelphia.

Jose Montoya's career has been about listening to patients, a hallmark of those few doctors whose professional lives have become enmeshed in M.E.  As M.E. whisperer Paul Cheney commented to me many years ago, "If you believe in this disease, when you get a negative result you say, 'Well, that was a negative result,' and you keep going." Those with doubts about the disease tended to flee when confronted with a negative result, as if their fears had been confirmed, Cheney added. Montoya, professor of medicine, was never among the latter. Instead, beginning in the mid-2000's he found ways to, in effect, sneak patients into Stanford's infectious disease clinic, a place Stanford bio-med executives had decreed M.E. patients were not allowed in the 1980s and 1990s. (Same for UCLA and UCSF.)  Call it "Jim Crow M.E.," a phenomenon still extant throughout American medicine. 

Montoya presented new cytokine data in Ft. Lauderdale, adding to the plentiful if sometimes contradictory studies of cytokine abnormalities.  At least one reason for the contradictions already may have been explained by Mady Hornig at Columbia, who in early 2015 reported that duration of illness may be a variable in cytokine activity; after three years, in that particular study, cytokine activity began to dip, as if the immune system was wearing out. Hers was the first study I am aware of in which duration of illness emerged as significant but it has not been replicated. Montoya provided evidence that cytokine profiles are most abnormal in M.E. patients when measured 24 hours after M.E. patients are asked to bicycle to their energy limit. 

In the same session, Montoya presented a second cytokine study that was particularly high-powered in part due to the sheer numbers of patients and controls, 192 vs. 393. His group at Stanford measured a panel of 51 cytokines in an effort to determine whether this "profile of circulating cytokines" could both create an M.E. signature and correlate with the severity of the disease.  The Stanford team identified seventeen cytokines with a "statistically significant upward linear trend" that correlated with disease severity, thirteen of which were pro-inflammatory.  These findings, he concluded, were "likely (causing) many of the symptoms experienced by patients" and proved the immunological nature of the disease.

Jose Montoya, professor of medicine at Stanford University, greeting patient Mary Schweitzer.  Neuropsychologist Gudrun Lange (leopard scarf) is between them.

Not emphasized in any cytokine discussions was the the fact that cytokines are immune modulating proteins largely produced in response to infection and inflammation.  I had dinner one evening with one exemplary bug hunter who left the field years ago and did not attend the conference.  With something like incredulousness in his voice, he asked me, "Were there any microbiologists there?" "One," I said. Mangalathu Rajeevan, a Ph.D. research microbiologist from the CDC works with Beth Unger.  

During a workshop on data so-far collected from the CDC's Multi-Site Clinical Assessment of ME (MCAM), Rajeevan reported that the MCAM biorepository, as of April 2016, is among the largest specimen collections in the M.E. world, consisting of saliva samples (because they are easy to collect) and blood. At least the specimens are being shipped to the agency by doctors who know how to diagnose a case. Rajeevan said the repository would allow research on "biologic differences in pathogenesis." If that's code for, "looking for pathogens," I cheer him on. It's a disgrace that there aren't hoardes of microbiologists collaboratively or individually engaged in a bug hunt, but given the fates of those who have tried in the past, it's not surprising.

Ben Natelson, a neurologist at Mt. Sanai in New York City who has published 141 papers on M.E. and related issues since 1993, presented the results of a study in which he had originally hypothesized there would be a difference in brain abnormalities between M.E. patients with co-morbid psych diagnoses and those without. His results revealed there were no differences between the two groups. Differences arose between healthy controls and M.E. patients.  Areas of significant difference between patients and healthies included "the number of abnormal spinal fluids, ventricular lactate, cortical glutathione and cerebral blood flow."  You know--the usual.

One of the most interesting studies, perhaps because it offered a novel treatment approach, was presented by Dikoma Shungu, a radiology and MRI expert at Weill Cornell in New York City. Shungu used MRI technology to show that providing M.E. patients with the supplement N-Acetlcysteine (NAC) corrects a glutathione deficit in the brain's occipital cortex.  Glutathione is the primary tissue antioxident and the lack of it suggests oxidative damage is occurring.  In a previous study, Shungu found a 36 percent deficit of occipital cortex glutathione in M.E. patients.  Thus, he sought to discover whether providing patients with supplemental N-acetylcysteine--a synthetic precursor to glutathione--daily for four weeks would elevate glutathione in the brain. He used proton magnetic resonance spectroscopy, an imaging system that allows the investigator to observe metabolic changes at the cellular level, to assess changes.  The answer was yes--"NAC supplementation markedly improved symptoms in CFS." The study also provided, according to Shungu, "the very first evidence that NAC crosses the blood-brain barrier to spur in situ synthesis and elevation of cortical glutathione."  And while the supplementation ameliorated symptoms, Shungu cautioned that more studies evaluating the optimal dose and treatment duration are needed.

Although impossible to be everywhere and at every meeting in Ft. Lauderdale, in my experience the most cringeworthy quote came from Beth Unger, who leads the M.E. research program at the CDC.  She was responding to a surprisingly direct, anonymous query at the end of the pre-conference conference, a day of presentations mostly by investigators at the Institute for Neuro Immune Medicine, begun in 2013 at Nova Southeastern University in Ft. Lauderdale.  Asked simply, "Why study M.E.?" Unger thought for a moment and said, "I ask myself that a lot--why are you going to work on CFS?"  After a moment, she continued, "It will teach us about some biology we don't know yet."  

No concession from this public health servant that some untold number of citizens have been disabled by and left untreated for decades with a disease that emerged in the late 1970s-early 1980s without any clear understanding of transmission modes other than apparent close contact.  Isn't that enough reason for the Centers for Disease Control and Prevention to study M.E.?  She spent time defining "public health" for patients during a Solve CFS/ME Initiative webinar last fall, yet emphasized in response to a query then that ME will never be a reportable disease and that it makes no difference to CDC whether it is or is not.  Must study of M.E. simply be a means to an end, unrelated even to public health? And shouldn't CDC be worrying about epidemiology and risk factors instead of learning new biology, given their history of incompetence in that area?

Vicky Whittemore, Ph.D., Program Director, Channels, Synapses and Circuits, National Institute of Neurological Disorders and Stroke

‍Vicky Whittemore of the National Institute of Neurological Diseases and Stroke (NINDS) is currently enjoying a honeymoon-like popularity in the M.E. cosmos as a friendly and committed-seeming program director for extramural grants in this field.  In a sign this optimism, so far, is not misplaced, Whittemore was present and accessible at both Nova and at the IACFS conferences. Not present were the director of NINDS, Walter Koroshetz, or the scientist Avindra Nath, in charge of the NIH-in house study of 40 M.E. patients, or Brian Wallitt, the study's clinical coordinator who seems to have a great deal to learn about M.E. As recently as October 2016, Wallit described Candadian denialist and hater Edward Shorter as "a distinguished historian" in a publication and apparently invited Shorter to lecture NINDS investigators about M.E. on November 5th, 2016.  

Not surprisingly, Whittemore clearly wanted to turn the page on the history of the disease and move forward.  

"I've been involved for a couple of years," Whittemore told the audience at the Nova pre-conference. In the closest mention to a government apology M.E. patients may ever get she added, "It's my understanding that (M.E.) was moved to the Office of Research on Women's Health after being at NIAID.  But they do not have a research budget and they really don't have the ability to move forward with a research plan and no ability to implement a research program."  

In fact, it was NIAID chief Anthony Fauci's decision to stash M.E. in this dead zone about fifteen years ago, an act akin to pouring the disease down the janitorial sink where Fauci seemed to think it belonged.  Whittemore can't be blamed for Fauci's despicable act and I was impressed she was willing to publicly acknowledge, without thoroughly trashing either Fauci or the Office of Women's Health Research, of course, that the OWHR had been perhaps the worst imaginable place for M.E. in Bethesda, resulting in the waste of at least a decade that could have been spent moving closer to resolving the disease.  As far as I know, she's the only government bureaucrat to have ever identified in a public forum one of the most enduring boondoggles (though hardly the worst) in M.E. history.

I asked her anonymously on the index card provided to me during a Q & A session if the NIH might ever consider issuing a formal apology to M.E. sufferers for its sins of the past. Rather than defend NIH, she read the question aloud and said, "That's an interesting question.  I'm going to show it to Francis Collins."   

When someone else in the audience asked how the M.E. community could move their cause forward at NIH, Whittemore said, "I'm not allowed to tell you how to lobby the government." And then she smiled as if to say, "But that doesn't mean you can't learn." The real test will be Whittemore's shepherding of the grant process at NINDS. Especially after observing her in Ft. Lauderdale, I certainly wish her well.

Interesting discoveries and ideas that for one reason or another may not deemed worthy of oral presentations or show up too late for inclusion in the public sessions are left for poster sessions at conferences.  The best part is that the author or authors of the posters are usually present to "defend" their findings and hypotheses one-on-one.  Three posters in Florida out of a total of 80 posited what has already been demonstrated in previous studies: M.E. is a greatly more disabling disease than multiple sclerosis.  

There were no fewer than nine posters on Gulf War Illness. Veterans have political clout in Congress and the Department of Defense (DOD) dedicated $20 million to study Gulf War Illness in 2016, approximately 8 times the amount NIH dedicated to M.E., even if 250,000 have Gulf War Illness versus a million or more with M.E.  An entire session of the IACFS conference was devoted to Gulf War Illness with four presenters, two of them from the local Nova Southeastern University, many of whose researchers are funded by the DOD and/or Veterans Administration.  Whether Gulf War Illness and M.E. are the same or different diseases still seems to be an unanswered question but there was an appearance of some kind of mashup of the two.  If you call both Gulf War and M.E. "neuro-immune" diseases, a vague phrase that could apply to any number of maladies, you can suggest you're doing M.E. sufferers a service by studying Gulf War Illness, which unlike M.E. pays the bills, an ideology that was implied at both the Nova pre-conference and the IACFS conference.

Below, a few snapshots from the IACFS conference poster sessions:   

Tom Equels, a Florida native who has been president of Hemispherx Biopharma since 2015 and CEO since February 2016, in front of his company's poster at the IACFS/ME conference in Ft. Lauderdale.  Hemispherx Biopharma has been seeking FDA approval for its nearly curative drug (in some patients) ampligen since 1991.  Recently, ampligen received approval for use in M.E. in Argentina, the first time the drug has been approved by a government for treatment of M.E.  This paper attempts to satisfy FDA's latest demand:  how to differentiate people who will respond to ampligen from people who will not.  Hemispherx employed a treadmill exercise test. 

Bruce and Pat Fero next to Pat Fero's poster presentation, "An Observational Case Study of Chronic Fatigue Syndrome: Potential indicators of onset in a preschool child starting at birth through age 23."  In one of the few "lay" posters at the conference, Fero provided a detailed documentation of her son Casey's medical history from premature birth complications up to his sudden death at 23, which included 71 doctor visits before the age of five.   "There are no scientific studies or proposals that would suggest to a pediatrician that a child could have early onset CFS," she wrote.  Their son suffered from M.E. from early childhood. "The possibility of genetic or in utero maternal transmission is apparent with the mother's diagnosis of chronic fatigue syndrome in 1987...eight years after the original viral onset in July 1980," Fero added.

James Baraniuk, MD, Department of Medicine, Georgetown University. Baraniuk looked for spinal fluid abnormalities in both Gulf War illness and M.E., as well as sedentary controls. At rest,  he saw no differences among the three groups.  After exercise, brain neurotoxicity could be measured in Gulf War vets; data on M.E. was unreported in this poster.

John Chia, (left) the clinician-researcher from Torrance, CA, held scientists and doctors rapt with his occasionally emotional narrative of enterovirus infection in a 23-year-old severe M.E. patient.  Stomach and colon biopsies taken 5 months after illness onset had been positive for enterovirus infection.  Six years after myriad efforts to regain his health, the man committed suicide.  Within 24 hours of his death, the patient's brain was frozen for a pathology evaluation for chronic viral infection. After some detective work, Chia and his colleagues found both enterovirus protein and enterovirus RNA in the brain.  "Enterovirus is clearly one of the causes of M.E.," Chia wrote in his abstract. In near full agreement?  Byron Hyde, MD of Ottawa, Ontario and chair of the Nightingale Research Foundation, whose own poster, "Precise Scientific Diagnoses of Myalgic Encephalomyelitis, Based on SPECT Brain Mappping and Recovery of Enterovirus," claimed EV as the sole cause of the disease.  Above, Dr. Chia talked with UCSF's Jon Kaiser, MD, board member of the IACFS and Medical Director, K-Pax Pharmaceuticals.

Leonard Jason, Ph.D., DePaul University and Lucinda Bateman, medical director of the Bateman Horne Center of Excellence in Salt Lake City. Friends and lifetime members of the IACFS, Dr. Batemen was showing off her crazy socks, a staple of her campaign to raise M.E. awareness and funds and Dr. Jason was just goofing around.  Write your own caption!

Vincent Lombardi, Ph.D., Director of Research, Nevada Center for Biomedical Research, Reno, NV (left) and Dan Peterson, clinician-researcher, Simmaron Research scientific advisor, Incline Village, NV.  Lombardi and long-time M.E. researcher Kenny DeMerlier, who is medical director at the Nevada Center, have been collaborating to identify M.E. biomarkers.

Alexandara H. Mandarano, a Ph.D. student in the Hanson Lab at Cornell University, standing in front of her poster about additional microbiome abnormalities.  Mandarano found an abnormal shift in the ratio of one type of fungal phyla to another, a shift that is also seen by researchers during flares in irritable bowel syndrome.  "Overall, our results are consistent with an existing inflammatory state in M.E," Mandarano concluded.

Lucinda Batemen, MD (left) and Marcie Zinn, Research Project Director for Electrophysiology at the Center for Community Research, DePaul University, Chicago.  Zinn, who presented neuropsychological data revealing brain dysfunction in M.E. at Stanford in 2014, brought two posters to Ft. Lauderdale. Her collaborators were Mark Zinn and Leonard Jason, also at DePaul. Both studies utilized EEG (electroencephalography), in the first case looking at functional connectivity in the M.E. brain.  In Alzheimer's disease, functional connectivity abnormalities have been postulated as potential biomarkers for Alzheimer's. Zinn et. al. found functional connectivity disruptions in the "attention network" in M.E. and suggested the finding might be a useful biomarker. Zinn's second poster described "significantly decreased connectivity" in parts of the brain in M.E. patients and noted that the the connectivity problems correlated with neuronal degeneration and disease duration. If her research was replicated, she said the findings might "potentially aid in staging the illness".

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