Critical papers, part deux

Two more papers from the 1990s

Copyright 2025 Hillary Johnson. All Rights Reserved.

1992

A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus Type 6 Infection

Annals of Internal Medicine

It’s hard to understate the momentous nature of this paper when it was published on January 15, 1992. It was the most exhaustive and medically sophisticated study of the disease ever undertaken. Imagine Nevada epidemiologist Sandra Daugherty’s paper arriving with the imprimatur of the National Cancer Institute and Harvard. A sense that the tide would turn was briefly in the air.

The paper still stands as one of the largest ME studies ever undertaken, with 259 patients, healthy controls and an impressive array of investigators, among them HIV co-discoverer, Robert Gallo and HHV6 co-discoverers Zaki Salahuddin and Dharam Ablashi. Several other NIH and West Coast scientists were listed among the authors. Incline Village clinicians Dan Peterson and Paul Cheney, who together had pioneered the use of innovative new technologies for investigating the disease, provided the patients.

If Harvard’s Anthony Komaroff can be said to be a pivotal figure in the ME story of the last century, it’s because of this paper. It took a politician with laser focus, a quality Komaroff had in spades, to guide this behemoth for six years over the rocky shoals of ME politics to publication.

“Given the biopolitical nightmare that paper had to go through,” Paul Cheney said soon after the paper was published, “it wouldn’t have happened without Komaroff.”

The paper was twice rejected by the New England Journal of Medicine, Komaroff’s first choice, and once rejected by Lancet.

In the years leading up to its publication, the study acquired the casual name, “the Tahoe manuscript” among its collaborators. After the Annals accepted it for publication, the name became a big deal. Understandably, Komaroff et. al. assumed the name of the disease they were describing—at that time universally identified as “chronic fatigue syndrome”—would be in the title of the paper. To their surprise, the editors refused to allow any name to be used.

The paper synthesized an extraordinary wealth of information about an epidemic disease in urgent need of elucidation, but Annals editors were insistent. They seemed unwilling to risk their journal’s reputation by connecting the central nervous system disease Komaroff and his collaborators described to the government’s fuzzy, stigma-laden “chronic fatigue syndrome.”

It was a fight even Komaroff could not win.

In deference to the editors, Komaroff wrote in his abstract, “Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.”

A majority of patients hailed from the rustic communities near Lake Tahoe in Nevada and California. Seventy patients hailed from Los Angeles, San Francisco, and other big cities, however, patients who were provided by Paul Cheney who was then practicing in Charlotte, North Carolina. The make-up of the patient group thus rendered the idea of a “small geographic area” an understatement if not a misstatement.

By insisting that the ailment described by Komaroff and colleagues be identified solely by the generic words, “a chronic illness,” Annals editors undermined the intent of the the syndrome in question was an obscure phenomenon seen exclusively near Lake Tahoe.

Science writers were hardly misled by the journal’s hair splitting. They recognized the paper for what it was: perhaps the most significant and well-controlled study on ‘chronic fatigue syndrome’ thus far. The Boston Globe, New York Times and the Wall Street Journal all reported the story. The Times led with, “The largest study yet of chronic fatigue syndrome has found evidence of inflammation in the brains of patients, the first documentation of a neurological abnormality connected with the mysterious ailment.”

The men at CDC, too, saw through the Annals’ attempt to separate the disease Komaroff and collaborators described from the disease CDC had named ‘chronic fatigue syndrome’ four years earlier.

William Reeves, the agency’s famously ill-mannered principal investigator, and Jon Kaplan, one of two CDC investigators dispatched to Incline Village in 1985, wrote a scathing letter to the Annals, noting that, “Although the term ‘chronic fatigue syndrome’ is not used in the article title, the first two paragraphs of the discussion implicate this syndrome as the condition affecting their patients…”

One measure of this paper’s significance, in fact, was the depth of rage it engendered among CDC epidemiologists who were in charge of ME. How could they maintain their hegemony over ME if their brethren in medicine—the big boys at Harvard and in Bethesda, home of the NIH—took the paper seriously? Frankly, it was hard to miss the implications of this study: so-called ‘chronic fatigue syndrome,’ long portrayed by CDC as psychiatric, appeared to be an infectious disease of the brain.

Their letter to the Annals editors was so wrathful, in fact, that Reeves and Co. had to re-write their cri de coeur eight times before their bosses deemed the letter civil enough to send. The eighth draft wasn’t particularly civil, either, insisting as it did that Komaroff, Gallo, and fifteen other contributing scientists and clinicians were describing a disease that didn’t exist.

“It’s not pretty,” Nevada’s Dan Peterson said after reading the government’s screed. “They’re are suggesting we are trying to legitimize hysteria.”

It’s probably not a stretch to say that this massive paper, which required, for instance, that the researchers find eighty healthy adults who were willing to submit to brain MRIs, was a turning point in the history of ME. Among other things, its appearance solidified the government’s hostility to serious inquiry and the expertise of academic scientists.

Komaroff’s team focused on a handful of critical findings: a disturbed T-cell ratio reflecting immune activation; brain lesions; and active infection with the recently discovered neurotropic herpes virus HHV6. (Two of the authors, investigators at the National Cancer Institute, had discovered HHV6 in the lymphocytes of an AIDS sufferer in 1985. At that time, the only patient group in which they found the pathogen 100% of the time were ME patients.)

In Komaroff’s paper, seventy percent of the patients were positive for HHV6 by cell culture and polymerase chain reaction, compared to 20% of controls. Seventy-nine percent had brain lesions, compared to 21 percent of controls. The neuroradiologists who studied the scans independently agreed almost 100 percent of the time, which, according to Komaroff, was an exceedingly rare concordance.

In what was perhaps the most crucial element of the paper, Komaroff dared touched the third rail: “Most of these patients became ill within a two-year period and many had close contacts who became ill…Enough cases occurred among family members, close contacts, and other close contacts to suggest the possibility of an infectious agent transmissible by casual contact,” he wrote.

Specifically, Komaroff revealed that “several groups of patients who had frequent close contact became ill within several months of each other: ten of thirty-one teachers at one local high school; five of twenty-eight teachers at another local high school; three students and one teacher at a third high school; and eleven employees at a casino. The spouses or sexual contacts of six patients were similarly affected, and there were eight instances in which at least one parent and one child both had the illness.”

Many in science had wondered whether the Tahoe disease was a unique disorder and unrelated to the increasingly common malady being documented around the rest of the country. Komaroff and his collaborators found evidence to the contrary: “Clinical and laboratory findings in the ‘clustered’ patients did not differ from those of the larger patient group.”

In addition, patients from the Tahoe epidemic and those from the large cities shared something else: "Altogether, 55 percent of the patients in the Tahoe group and 51 percent of the non-Tahoe group stated that a close contact was similarly affected.”

The seventeen authors of this paper offered the US health establishment a trove of data about a central nervous system disease that emerged in the early to mid-1980s. The data indicated the “possibility of an infectious agent transmissible by casual contact.” It was another study the CDC should have done instead of misappropriating $150 million sent to the agency by Congress to support ME research. (Per Osler’s Web, 1996)

Rather than act on this new information, the government derided the study and insisted in their rebuttal that the researchers were not describing any known illness.

Given the pristine reputations of the collaborators on this paper and the impressive, potentially paradigm-changing implications of their findings, the Tahoe manuscript might have paved the way to an aggressive response to ME akin to the response to AIDS in 1983 and 1984.

The government health establishment, instead, was enraged by the message and the messengers.

“We conclude that the disease (Komaroff) and co-workers described is not the chronic fatigue syndrome or any other clinical entity,” the CDCs Reeves and Kaplan wrote in a letter published in the Annals on August 15, 1991.

Coda:

In 1985, few in medicine or the culture at large had heard of ME. In 2023, the CDC’s conservative prevalence count of people diagnosed with ME in the U.S. was 3.3 million, or 1.3 percent of the population. The agency based its head count on a massive review of medical records. The agency noted that their number was conservative, since it represented only those who had been formally diagnosed with ME. The CDC estimated that nine out of every ten people with ME were undiagnosed due to doctors’ unfamiliarity with the disease.

1993

Memory deficits associated with chronic fatigue immune dysfunction syndrome

Biological Psychiatry

In 1990, essayist Floyd Skloot gave voice to the paradox of appearing normal while feeling “unplugged” and “like a polluted stream.” Writing in the Boston Phoenix, he explained, “The Xerox machine apparently stands for all machines in my rearranged brain. I ask my wife to reheat my coffee in the Xerox, ask my son to Xerox the lawn, explain to my daughter that the doctor will Xerox her arm. This is not the way I was before.”

The same year, neuropsychologist Curt Sandman emerged as a new player in the field with the expertise, not to mention gravitas, to provide insight into the workings—and deficits—of the ME brain. Today, he is a professor emeritus of psychiatry at the University of California at Irvine with 257 scientific papers to his name. At the time, Sandman was the vice chairman of the Department of Psychiatry and Human Behavior at UC Irvine. He was also chief of research for the State Developmental Research Institute, a small group of select scientists employed by the state to research brain and behavior. He had developed a group of computerized measures of memory skills, useful in assessing brain dysfunction in patients with frank neurological diseases like Alzheimer’s, traumatic head injuries, learning disabilities, stroke, and people with psychiatric diagnoses like schizophrenia and depression.

ME couldn’t have had a better ally. Sandman was the rare researcher who undertook his research despite serious reservations about the disease itself.

“I must admit,” he told me, “I was one of the enemy. I was convinced that the first three or four patients I saw had hysteria or conversion neurosis. I assumed they were giving me psychogenic, non-specific complaints. I refused to believe they were actually suffering from anything profound or real. I'll never really forget my total lack of interest in those first patients.”

He began a serious research effort only after unrelenting pleas by Los Angeles clinician Jay Goldstein, whose practice was focused on ME.

Ultimately, Sandman performed his tests on forty ME patients, 23 depressed patients, and 129 age- and sex-matched controls. Far from exaggerating, Sandman realized, ME sufferers profoundly underestimated the extent of their impairment. He was also surprised by the severity of the memory and processing deficits he measured. In his abstract, he wrote, “The overall pattern indicated that (ME) patients had a significant memory deficit, far worse than implied by CDC criteria. The pattern for (ME) patients was consistent with temporal-limbic dysfunction and significantly different than depressed patients and control subjects.”

There existed, Sandman concluded, a “CFIDS dementia.

(In the early 1990s, the CFIDS name was pushed by a patient organization, but its use was temporary. The acronym stood for “chronic fatigue immune dysfunction syndrome.”)

Sandman’s research was among the first to identify a distinct pattern of brain dysfunction in ME that prevented patients from holding a job or attending school. It was a profoundly disabling symptom, one that undermined the sufferer’s sense of identity in multiple ways. In modern times, the intellectual disablement of ME has been relegated to the specious phrase “brain fog.” The term has been applied to everything from premenstrual syndrome (PMS) to hay fever and myriad relatively mild conditions. “Brain fog” would never be applied to Alzheimer’s or Lewy body dementia or ALS or even MS. The terms is profoundly inadequate to describe the severe and disabling cognitive disorder that defines ME, as well.

Sandman was fully engaged and intended to pursue his investigations into ME brain damage in 1993. What happened next was perhaps unsurprising, given the times.

“I was told it would hurt my career,” he told me some years later. “Someone in a real position of power warned me that I was making a terrible mistake and that I should disassociate myself from the people studying this disease, that it was a fringe disease. I argued, ‘We can either accept the politics and the PR that this disease doesn’t exist or is a flaky illness, or we can prove or disprove the disease.’”

Reasonable words indeed, but as things turned out, Sandman never returned to ME. Nevertheless, Sandman’s 1993 paper stands as an important contribution to the field. His research is as relevant today as it was thirty years ago.

Blue Sky

Years ago, ME investigators dreamed of an ME Czar who would monitor and guide research from inside the NIH. The perfect candidate, they believed, would be someone with a deep familiarity with the literature, which goes back at least to the early 1930s. They would coordinate research efforts by steering researchers in promising new directions, especially pathogen research, and discourage repetitive studies. So far, the approach feels scattershot. A Czar would seek to consolidate what is known already into a coherent plan of attack. As things stand now, the US government seems to want scientists to continue proving until the end of time that ME is a discrete disease rather than a mood disorder.

Science is not working as philosophers have said it should in this case.

How often must researchers interrogate the microbiome of ME sufferers, for instance? Just now, scanning entries in PubMed, I stopped counting at one hundred. How many studies are required to measure the deleterious effect of exercise on the immune system, heart, brain, muscles, and mitochondria of ME patients? And is any of this moving the ball down the court to resolution?

Of course, I am describing what can only be considered a pipe dream, not least because NIH has so rarely funded ME research, whether in flush times or austere times, as now.

Maybe European scientists or UK scientists ultimately will solve ME. I heard through the grapevine that a recent international conference in Berlin was impressive, although not without its poignant moments, such as when a German researcher reported his observation: misshapen red blood cells.