Numerology (Part Three): What did they know and when did they know it?

Hillary Johnson

In the 1980s, the airwaves thrummed with the sounds of The Smiths, The Cure, and Tears for Fears.  Movie-goers reveled in GhostbustersThe Breakfast Club, and Blade Runner. Two Republican presidents (Reagan and the first Bush) defined domestic and international policies for nine years of that decade. Newly homeless people haunted the streets of New York and Los Angeles. In 1986, NASA’s Challenger exploded seventy-three seconds after takeoff.  In hindsight, the 1980s seem relatively benign were it not for the shocking epidemics that emerged concurrently during the early part of the decade:  AIDS and ME.  One became important; by the decade's end, the other seemed to have dropped off the earth.

Many of the people who came down with M.E. in the Eighties, years during which the disease seemed to be spreading exponentially in every city and rural areas, too, may have missed the cultural landscape of the Eighties as a result of their profound illness, or they remember aspects of the decade in a random, disjointed fashion.  They do remember what happened to them.

This Eye View series is dedicated to the people who have survived M.E. for three or more decades. 

This series has been compiled for Millennials, too, a generation of patients who were born during the 1980s or later.  Some may be unaware that there was a time not long ago when their disease was virtually unknown in clinical settings and in the medical literature.  English-speaking investigators who studied and eventually named the disease in the decades before the early 1980s--Acheson, Richardson, Parish, Henderson, Shelokov, Gilliam, Poskanzer, Ramsay--were an iconoclastic cabal whose papers on the subject were as obscure as they were important.  All of them hypothesized the disease was caused by a transmissible virus, that no other explanation was supportable. All have died.

Epidemiologist Alexis Ioann Shelokov, famous for his expertise in polio, died just three months ago at 97.  My interview with Shelokov, conducted in the early 1990s as part of my research for my book Osler's Web, was scheduled to last an hour.  I spent an entire afternoon with the animated, white-haired Shelokov, then in his early seventies.  We parted reluctantly as the sun was sinking.  I sensed Shelokov had been waiting for someone like me whose passion for the subject matched his own to come knocking. 

His enthusiasm for our topic had begun in the early 1950s when, as a 34-year-old NIH epidemiologist, he was assigned to investigate an outbreak of a disease among student nurses at a private psychiatric retreat for the rich in Rockville, Maryland.  He was hooked. Shelokov was also well-schooled in the 1934 Los Angeles General Hospital outbreak during a massive polio epidemic in that city.  He described the investigator, epidemiologist Sandy Gilliam, who was sent to L.A. to study the outbreak from what is today the National Institutes of Health.  Even then, 83 years ago, the disease was a political football. Gilliam recognized the outbreak that had decimated the hospital's staff was distinct from polio according to Shelokov; in fact, Gilliam believed it was an entirely new disease.  Nevertheless, he was prevented from saying so in his report on the outbreak by the chief of the public health service (which would become the NIH).  Gilliam and his boss argued for four years before Gilliam was allowed to publish his monograph on the Los Angeles outbreak. When he did, he was forced to use the ambiguous phrase "atypical polio."

In a paper co-authored by Donald Henderson and Shelokov about the disease for TheNew England Journal of Medicine in 1959, the two wrote, in part, that "Repeated episodes of crying without provocation, insomnia, terrifying dreams and difficulty in concentration are probably secondary phenomena...Mild confusion, impaired memory for recent events, alterations in personality structure, euphoric behavior and tendencies to transpose and 'stumble over' words have frequently been observed during the more severe, acute phase."  Shelokov and Henderson (the latter investigated an outbreak in Punta Gorda, Florida while he was head of the Epidemic Intelligence Service at the Centers for Disease Control), called the disease "epidemic neuromyasthenia." 


We have reached the year 1989 in part three of our Numerology series.  It was a year marked by rapid-paced findings and heightened interest in the impact of M.E. upon the brain.  Researchers were motivated by a desire to sort out the overlay of psychological distress generated by overwhelming and sudden disability, the subjective aspects of the disease, from easily observable neurological components--slowed or slurred speech, short-term memory defects, diminishment of I.Q. and the like.  It is probably not coincidental that the intensified focus on the brain coincided with new brain imaging technologies that were evolving in the 1980s.  The MRI had moved brain imaging forward dramatically in 1985.  The MRI saw what it saw very well. As if staring at the landscape of a new planet, however, neuro-radiologists often lacked reference points for the never-before-seen images.  Additional imaging techniques in the second half of that decade allowed neurologists and other investigators to visualize the brain in even more specific ways.  These technologies measured blood flow, oxygen perfusion and glucose metabolism in the brain.  Separately and combined, they broadened the sometimes bewildering information provided by the MRI.

In my personal view, cognition impairments and related neurological deficits in M.E. define the disease.  They are the disease.  Some might argue it's the immune deficits; others might argue it's the newly-discovered metabolic deficits or mitochondrial dysfunction or a "leaky" gut.  What is it about the disease that prevents a return to one's former life? I believe the neurological components prevent re-entry.  These components are not easily dealt with; they are not benign.  One cannot outfit oneself with a wheelchair or battery-powered cart and return to work after the worst has past or acquire a prosthetic limb and expect to be whole again if the brain remains damaged. One cannot meditate or pray these deficits away. 

The discoveries described below comprise a snapshot in time.  They were highly preliminary; most were never peer reviewed or published.  Several iterations of imaging technologies have surpassed those of the 1980s.  What's interesting is how much was discovered about the impact of M.E. on the brain twenty-eight years ago and the degree to which these findings were ultimately submerged or written off as unimportant, even forgotten, as a result of the federal government's intransigence.  Grants to study brain abnormalities were turned down, pilot studies dropped into some kind of netherworld of inconsequence, reports at professional conferences were, in a word, ignored.  Most of the investigators named in this report dropped from the field when it became obvious the NIH was not funding research into biological abnormalities in the disease.


All items in Numerology have been drawn from original reporting by Hillary Johnson for Rolling Stone magazine (1986) and for her book, Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic, Crown Publishing Group (1996) Penguin 1997, and IUniverse 2006.  Copyright 1996, 1997, 2006. All Rights Reserved.


After testing hundreds of M.E. sufferers hailing from all corners of the U.S.--Juneau to Miami, Bangor to San Diego--Berkeley neuropsychologist Sheila Bastien realized the pattern of intellectual abnormalities in M.E. was utterly distinct from every other category of brain injury she had studied.  That list included concussion, chemical exposures, brain tumors and dementia. 

She discovered that she could reliably identify a case of M.E. based on one particular finding.  “Verbal memory”—the capacity to remember speech—is “always more impaired than visual memory”—the capacity to recall images, Bastein said.  Any disparity between intellectual domains is considered “organic” rather than psychological by those who evaluate brain injury patients.

“I have never seen the verbal-visual memory problem before,” Bastien said that year. Los Angeles neurologist Marshall Handelman, an expert in what was then a new brain imaging technology called BEAM (brain electrical activity mapping), began performing BEAM scans on M.E. patients early in 1989.  The technology could be described as the marriage of an EEG (electroencephalogram) with a computer. BEAM’s tremendous advantage over MRI was its ability to correlate physical abnormalities seen on MRI with functional symptoms. The MRI scan revealed changes that had never been seen before, but few if anyone was certain what they meant.  Additionally, the radiologist’s skill level at interpreting MRI images introduced an element of subjectivity. BEAM scans, in contrast, drew direct and unequivocal connections between brain injury and intellectual processing defects.  The computer provided the evaluation, rendering human interpretation unnecessary.

Initially skeptical of M.E. patients referred to him, Handleman began to change his mind after performing BEAM scans on two ME sufferers in particular.  One was an engineering professor.  The other was a newly-ill oncologist who had asked Handleman for a neurology consult on a cancer patient only four months earlier.

 “To be honest, I need to know someone is smart,” Handleman said.  “And now I had two people who met my qualification of being super bright, and they were not the same—something had definitely happened to them.  I thought, ‘Jesus, there must be something here.’” 

By mid-winter, he had performed BEAM scans on nearly one-hundred Californians with M.E.  Every patient had an abnormal BEAM scan.  Many were grossly abnormal.

“This disease is getting higher on my scale,” Handleman said at the time.  “I rate it right up there with AIDS and head trauma.”

 Among the abnormalities Handleman was seeing:  acquired dyslexia with left parietal lobe involvement; paraphasias—using the wrong word such as “train” for “table;” dyscalculia (math problems), dysgraphia (writing problems); disorientation; decreased acquisition of new language resulting from left temporal and left occipital lobe involvement, and visual-spatial perception problems resulting from right parietal lobe involvement.

 “They have an injury to their memory mechanism,” Handleman said, adding, “What I’m saying is that this is just an old-fashioned sub-acute viral encephalitis.  Let’s call it what it is and let’s deal with it!"

Samples of comments reported to an NIH investigator by M.E. patients during a series of interviews that winter, based on the investigator’s notes:

 * “I feel as though I am demonically possessed”* “I exist in black Jell-O.”

NIH cancer epidemiologist Paul Levine had interviewed nearly forty patients in Nevada and California.  Levine found the disease's neurologic component to be its most outstanding aspect.

"You can just feel when you're talking to someone with the cognitive disorder," he said.  "It's like a break in an electric current."Yet another brain imaging technology emerged by 1989, this one the NeuroSpect scanner, which allowed investigators to study blood flow in the brain.  In healthy people, blood perfused the brain evenly.  But Ismael Mena, a NeuroSpect expert and a professor of neurosciences at the University of California in Los Angeles, and his colleagues were using the new technology to evaluate brain blood flow in patients who weren’t healthy.  For the previous two years, they had studied people with dementia, Alzheimer’s, stoke, seizure disorders, brain trauma and HIV infection, to learn whether and in what ways blood perfusion was altered in the brain in these diseases.

“Every time function is diminished,” Mena said, “(we find) blood flow is also diminished.”

Jay Goldstein, a Los Angeles clinician who was seeking ways to treat M.E., sent a large group of his patients to Mena for evaluation.  Close to 70 percent of them “were quite abnormal,” Mena said.  He had observed areas of hypoperfusion in several regions of the brain, though the majority had unusually low blood flow to the right temporal lobe, a large lobe at the rear of the brain.

Not long after Mena made his observations of hypoperfusion in M.E. brains, he presented a paper on the subject at the Cambridge Symposium on Myalgic Encephalomyelitis at Cambridge University in England on April 12, 1990.  It was called The Study of Cerebral Perfusion by NeruoSPECT in Patients with Chronic Fatigue Syndrome.  Mena noted that during aerobic exercise, M.E. patients experienced not just a sudden drop in body temperature but a dramatic decrease in oxygen to the brain—the precise opposite of what occurs in healthy people during an aerobic workout.  Mena pointed out that the oxygen deficit in the brain could be observed for several days--after even a single episode of brief activity.  The obvious lesson to be learned was that exertion could contribute to additional brain damage in M.E. sufferers in the form of oxygen deprivation, but the message was a hard sell in a culture where exercise was accepted as a cure-all and extended bedrest was equated with sloth.

Some two decades later, the dangerous mix of aerobic exercise, however mild or brief, and the resulting physical devastation experienced by M.E. sufferers was in effect re-discovered by numerous investigators who would name it “post-exertional malaise” or PEM. Expert M.E. clinicians were long-familiar with this problem, some calling it the “push-crash” phenomenon. Well-rested patients who felt improved and then attempted even modest exertion--walking around the block, grocery shopping--inevitably “crashed” for days, weeks and even months. Patients who were forced into graded exercise regimes, a government-supported policy in the U.K. based on poorly conceived and improperly interpreted research, sometimes never regained their pre-"graded exercise" level of function. In one famous U.K. case,  a child named Ian Proctor was forced into a swimming pool by psychiatrists who believed he was malingering.  The boy was fished out of the pool only when it became evident he was drowning.

Eventually, the push-crash phenomenon was considered so universal in M.E. that an Institute of Medicine panel recommended in 2015 that PEM be considered the primary diagnostic marker for the disease.  Indeed, the panel was impressed by the abnormality to the degree that it urged the disease be renamed, “Systemic Exertional Intolerance Disease.”  The name, possibly because it focused on just one M.E. symptom exactly as the government-name “chronic fatigue syndrome” had done in 1988, as well as opened up the possibility of a renewed psychological or volitional interpretation of the disease, failed to catch on. 

Is PEM really exclusive to M.E.?  According to one scientist I have asked, PEM exists in AIDS, however, there have been no supporting studies.  One wonders:  are there other severe diseases in which exercise inflicts post exertional malaise upon the sufferer? Given that, as far as I know, PEM has not been studied in any other serious diseases to the degree it has been studied in M.E., if at all, that question remains unanswered. Controls in PEM-ME studies tend to be sedentary but otherwise healthy people.
It has always struck me as barbarous that in order to prove their disability to insurance companies, M.E. patients are offered an aerobic exercise challenge that makes them even more ill--to the degree they may in the end be rushed to the hospital with cardiac symptoms.  Short of that outcome, they likely will accrue additional damage to their brains.  It's hard to imagine this option being offered to people suffering from multiple sclerosis, cancer, and other untreated infectious diseases as a means to establish their illness.  Personally, I believe the exercise challenge in order to prove the existence of "PEM" should be abolished as it amounts to torture and inflicts further damage.  As I hope this column proves, evidence for brain damage in M.E. has been available to the government and to extramural researchers for decades.  It is well past time to put investigative efforts into finding out the cause of the disease and pharmacological interventions, as well as establishing prevention strategies.


M.E. clinician Jay Goldstein was on the faculty at the University of Irvine.  In the winter of 1989 he enlisted yet another colleague to help him understand what he believed was an organic brain disease.  He called upon Steven Lottenberg, who was the clinical director of the brain imaging center at UC Irvine.  The latter’s evolving expertise was in a two-year-old imaging technique called positron emission tomography, or PET.  The technology measured glucose metabolism.  When compared to the MRI, the BEAM, and the NeuroSpect, the PET scanner was emerging as the most sensitive of the three. 

Marshall Handleman characterized the BEAM scan as the Chevrolet of brain imaging and the PET scan as the Cadillac.

Lottenberg liked to cite the example of a stroke victim whose MRI scan appeared to be normal, but whose PET scan revealed “a huge lesion” indicating an area where metabolism simply was not occurring, suggesting a large region of cell death.  PET scanning was able to provide “a real, objective evaluation of these patients rather than just a visual evaluation, which is a bit more subjective,” Lottenberg said.

Lottenberg agreed to perform PET scans on just six M.E. patients, supplied by Goldstein.  All six had abnormally low glucose metabolism in portions of their brains, but three of them had frank abnormality in the right middle frontal region.

“The frontal lobe is a good one to look at in terms of any cognitive problems that might exist in these patients,” Lottenberg said.

Goldstein made plans with Lottenberg, Handelman and Mena to pursue a larger study of M.E. sufferers using all three technologies.

The new scanning techniques complemented the MRI and standardized neuropsychiatric evaluations that reflected organic disease as opposed to emotional dysfunction.  They offered physiologic data--information about the way the brain was working--not just what the brain looked like. They furnished evidence of functional problems even in the absence of obvious lesions. They helped to remove subjective elements from brain evaluation in the disease.  No one could argue, for instance, that a black hole in a patient’s brain that was bright red in the brains of fifty healthy age and sex-matched controls was a normal result or even a variance of normal.


On Friday, February 15, the NIH released a press release about Stephen Straus’s latest research.  Straus was the NIH’s expert in M.E.  In fact, he was the only clinician-scientist at the NIH who was interested in M.E. He lectured medical societies around the world on the subject, advised the FDA on the disease, as well as served on review committees judging extramural scientists' grant applications.  In bold-faced, all caps, the press release announced, “LIFETIME HISTORY OF PSYCHIATRIC ILLNESS IN PEOPLE WITH CHRONIC FATIGUE SYNDROME.” 

Straus' conclusions about the disease were met without question by the nation’s media, who in every case failed to interview anyone but Straus for their stories on TV, in newspapers and magazines.  Straus' supporting data for this claim went unexamined and unquestioned by the press, as well.

If anyone could have more effectively killed the intellectual curiosity about the disease that until then had been percolating throughout academia, it would be difficult to imagine.  Clinician Paul Cheney predicted Straus’ study would end investigation into therapeutic interventions in the disease for a generation.  His prediction turned out to be 100 percent correct with one exception: ampligen, a drug that had raised I.Q levels in patients by twenty to forty points.

Straus’ conclusions were based on a series of interviews performed by a single unblinded psychiatrist (he knew patients had a diagnosis of "chronic fatigue syndrome").  The psychiatrist queried 28 M.E. patients who were hospitalized at the NIH clinical center and enrolled in an Acyclovir trial.  Acylovir is an anti-herpes virus drug (there are newer anti-herpes drugs on the market today). A few patients needed to stop the trial because Straus failed to adequately hydrate them according to the drug manufacturer’s directions.  Most of the “pre-disposing” psychiatric diagnoses the NIH psychiatrist recorded in his one-on-one interviews with the remaining patients were simple phobias--fear of spiders, snakes and heights.  An independent psychiatrist who evaluated the study post-publication commented on the study in a letter to the journal in which Straus' article appeared.  Phobias relating to spiders and snakes, as well as fear of heights, were so common in the general population “it is very misleading to call them a ‘predisposing psychiatric problem'" the psychiatrist wrote in his published comments.

At the time, I asked the NIH press officer why the NIH deemed it necessary to Fed-Ex or Fax a press release about a study of just 28 patients to more than 500 reporters and news outlets around the country.  After a long pause, the agency’s press officer responded, “Well, for chronic fatigue syndrome, there aren’t that many studies that come out of the National Institutes of Health.  But it’s our second most popular inquiry from the public.  It’s just behind AIDS.  We know there’s a lot of interest in it.”

Straus' study was a line of demarcation in the contemporary history of the M.E. epidemic.  His research was a reassuring balm for the public: citizens now had it on highest authority that the disease was neither contagious nor deserving of significant tax payer-supported research.  Straus' work, with an elaborate assist from the NIH public affairs office, further alienated mainstream practitioners from the disease and its victims, as well.


On the very day Straus’ paper appeared in an obscure psychiatric journal, a letter co-authored by doctors Paul Cheney and David Bell appeared in the Annals of Internal Medicine. They reported finding exceedingly high—fifty times normal in many cases—amounts of interleukin 2 in the blood serum of 54 adults and 53 children with M.E. 

In the late 1970s and mid-1980s, cancer researchers had touted synthetic interleukin-2 as a magic-bullet cancer therapy.  By the end of the 1980s, however, the drug had been dropped due to its extreme toxicity.  In addition to “severe cognitive changes (with) evidence of cognitive deterioration” and mood changes, researchers had observed decreased energy, anorexia, disorientation, ataxia, heart arrhythmias, chills and even coma. 

“Many patients likened their symptoms to an influenza-like syndrome,” one group of researchers wrote. 

Cheney’s search of the literature found just four other diseases with the same marker:  chronic progressive multiple sclerosis, tropical spastic paraparesis, T-cell lymphoma and AIDS.  The latter three were linked to retroviruses; the first two were frank neurological diseases.  The M.E. patients Cheney and Bell tested had levels of interleukin-2 that were higher than any recorded in patients with each of these four diseases, sometimes ten times higher and in the most severe of their M.E. cases, higher than any values Cheney could find in the medical literature.

Their finding received no publicity whatsoever upon its publication, though I reported it in Osler's Web in 1996.



In the spring of 1989, clinician Dan Peterson obtained a brain sample from a living M.E. patient who had been sent to Stanford for a “skinny needle” brain biopsy.  A brain sample from a living person is rare indeed. The patient had severe cognitive deficits, ataxia (abnormal gait), transient blindness and a range of additional neurological symptoms.  Peterson sent the sample, along with a clinical summary, to Stephen Straus’ lab at the NIH for evaluation.  Straus returned the sample to Peterson without opening it, explaining in the letter that he had neither the time nor the resources to analyze it.  Straus was receiving $800,000 a year for M.E. research. 


New York Multiple sclerosis expert and neurologist Carolyn Warner presented findings of neurologic abnormalities in fourteen patients at a national neurologic conference in Chicago in 1989.  She reported that based on spinal fluid samples, something, possibly a virus, had broken the blood-brain barrier in M.E.; that abnormal brain waves were seen on EEGs; that multiple lesions were found on MRI scans of the brain.

Later, Warner speculated, “MS was always a diagnosis of exclusion.  But now you’ve got another ‘by exclusion’ neurologic disease with many similarities. With (M.E.) on the horizon, you were probably safer five years ago making an MS diagnosis than you are now.  I don’t think anything is definitive in the interface between (M.E.) and MS now.”


Twenty-Eight Years ago...


What are today's M.E. scientists studying?  Among other things, spinal fluid abnormalities; interleukin/cytokine patterns. They are also experimenting with more sophisticated brain imaging techniques.  They continue to investigate the myriad side-effects of exercise, as well as the differences between MS and M.E. In the months ahead, Eye View will report on the new generation of brain and cognition research underway at universities in the U.S.    

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