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Mystery Theater
For more than a century, Harvard physicians have stepped into the clinical sleuthing arena to test their wits against some of medicine’s most perplexing cases.
by Beverly Ballaro

Richard Cabot was irked; leafing through old patient records, he had stumbled across a case in which the sole clinical diagnosis listed was neurasthenia—a psychiatric disorder—and yet the record concluded with a note that the patient had died and an autopsy had been performed. Considered by some a “contender to sainthood,” Cabot, Class of 1892, nonetheless saw the record as an affront to his scrupulous insistence upon scientific precision.

Cabot knew from his experience as an attending physician at Massachusetts General Hospital (MGH), beginning in 1908, that, for the most part, his colleagues on the wards did not share his meticulous propensities. It was not uncommon, in the early part of the twentieth century, for clinicians to pay scant attention to autopsy reports on deceased patients, and thus to remain ignorant of the accuracy of their official diagnoses.

His consternation at “this curious blunder” immediately inspired Cabot to dig up the postmortem record. “I found,” Cabot later wrote, “that the patient had died of cancer of the pleura, but had had neurasthenic symptoms and vague intercostal pain, which had misled the clinicians.” Cabot seized upon this incident and others like it as a teaching opportunity. In 1910 he began presenting diagnostic riddles at weekly meetings with house officers and visiting doctors.

These exercises ultimately evolved into MGH’s ongoing tradition of clinicopathological conferences (CPCs) in which a guest physician—who receives a case summary four to six weeks in advance—is asked to deduce, before an audience of colleagues, the diagnosis of an anonymous, actual MGH patient based solely on the medical history and preliminary test results.

The CPCs became a popular weekly staple to which, as the late Franz Ingelfinger ’36 once wrote, “staff and students flocked to hear discusser and pathologist engage in pedagogy, histrionics, and skillful feints, attacks, and retreats.” Beginning in 1915 Cabot arranged for a stenographer to record the discussions so that any requesting physician could obtain a copy, and in 1924, the Case Records of the Massachusetts General Hospital began to appear regularly in what eventually became the New England Journal of Medicine, a publishing tradition that endures today.

Serendipitous Encounters

Although Cabot formalized the case method of teaching at HMS in 1900 when he made it part of the curriculum for third-year students, he was not the method’s only advocate at the School. While still a medical student, Walter Cannon, Class of 1900, later the George Higginson Professor of Physiology, made a detailed proposal that gained the support of Harvard President Charles Eliot for such an approach to medical education.

Cannon had a roommate who was studying at Harvard Law School, where the legal case history method had been used since the 1870s. Envious of the gusto with which the roommate tackled his subject, Cannon became convinced that in-depth examinations of actual hospital records would enliven the lecture-based medical educational process, which he found unbearably dull. Cannon’s intuition proved correct; by the 1930s, hospitals throughout the world were imitating the CPC format.

In the early decades of the CPCs, physicians pitted their skills as general diagnosticians in an arena in which exchanges sometimes grew testy. “An occasional discusser has been accused of CPC-manship in quest of the correct diagnosis,” noted a former editor of the CPCs, Robert Scully ’44, acknowledging that “discussion of the case records as unknowns introduced a challenge and, at times, a measure of discomfort for the speaker as well as zestful competition on the part of those students and physicians in the audience who chose to participate.”

In 1960, another editor of the CPCs, Benjamin Castleman, tried to quash this impulse. Castleman took pains to emphasize the value of the CPCs as “an exercise in deductive reasoning and clinicopathological correlation,” opining pointedly—and largely on deaf ears—that “it is less important to pinpoint the correct diagnosis than to present a logical and instructive analysis of pertinent conditions involved.”

The Body Eclectic

Those “pertinent conditions” invited narrow scrutiny at first; Cabot himself analyzed most of the early cases—so much so that, for many years, physicians commonly referred to the CPCs as the “Cabot Cases.” But as time went on, Cabot began to invite generalists and specialists from within MGH and from other Boston hospitals to take up the challenge.

Unlike physicians of an earlier century, who often ascribed illness to vague theories of imbalances, the disease detectives of Cabot’s era focused on pinpointing organic cause and effect. In a 1933 case, for example, Cabot exhorted his audience to consider all the possible rational explanations for the swollen right eyelid—preceded by severe heartburn, muscle pain, nausea, and vomiting—that had brought a 32-year-old Armenian housewife, with a habit of eating lightly cooked sausage, to MGH for treatment.

Cabot began by responding to the initial report, which stated that the woman had been ill with “all the typical grippe symptoms” for a week. “Of course,” Cabot grumbled, “there is no such thing as ‘typical grippe symptoms.’…In general if we see people with swollen eyelids and we don’t know why, what unusual diseases do we think of?” Delighted by a student’s response of trichinosis, Cabot enthused, “Yes. You may go a lifetime and not see a case, and then if you do see one and recognize it you are the person in that town or village for a time, because nobody else will think of it.”

And yet Cabot’s satisfaction at receiving confirmation of his hypothesis—by a biopsied piece of the patient’s muscle riddled with unencapsulated worms—was sobered, as it often was in his day, by the reality of limited options. “Of course there is no treatment in this disease,” Cabot went on to say. “We just wait for nature to cure. Death is very rare.”

Stranger than Fiction

The case indices of the 1950s and 1960s, include, as in earlier decades, a high incidence of CPCs devoted to cancer and cardiovascular disease. But they also began to explore less common conditions such as Marfan syndrome and Wegener’s granulomatosis. This trend only intensified during the 1970s and 1980s.

A curious 1984 case, for example, centered around the pain and swelling in the left forearm of a 39-year-old Florida man who had traveled to New England. Doctors quickly established that gas in the tissue of his forearm, to which he had suffered a gunshot wound some 17 years earlier, was the source of the man’s discomfort.

Initial concerns focused on the man’s occupation as a shrimper; commercial fishermen, the presenter pointed out, face a risk for cellulitis from various sea organisms as well as other hazards of their trade: “If…this patient had been bitten by a seal,” the presenter noted, “so-called seal finger would have been included in the differential diagnosis.” But the lack of systemic toxicity and the patient’s confusing history deepened the mystery—and the doctors’ suspicions.

Two different hospitals in which the shrimper claimed to have been treated could find no record of him. When more checking revealed that the man went by several false identities, the diagnostic trail shifted to psychiatry. The gas in the patient’s arm tissue, the presenter concluded, was there because the man had deliberately injected air into his own arm. In a bid for attention, he had engineered his own symptoms, the desperate act of a patient in the throes of Munchausen syndrome.

Unusual Suspects

Throughout their history, the CPCs have mirrored changes not only in the science of medicine but also in the increasingly specialized medical profession and in society at large. In the 1980s and 1990s, as genetics came to assume more and more importance in the understanding of disease, and as international travel increasingly transformed previously localized outbreaks of illness into potentially global concerns, the content of the CPCs shifted in response: presenters from these years wrangled with such cases as incontinentia pigmenti—a rare genetic disease of the skin, hair, teeth, and central nervous system—and Dengue hemorrhagic fever, a flu-like viral illness spread by the bite of infected mosquitoes, common in most tropical regions of the world.

In another reflection of changing times, irresoluble diagnostic puzzles became increasingly scarce. But when such riddles did come up at the CPCs, presenters sometimes proved ominously prescient. By the early 1980s, discussers were puzzling their way through what would eventually be identified as AIDS-related diseases. Discussing the unlikely 1982 case of a 29-year-old patient with Kaposi’s sarcoma—a form of skin cancer until then seen primarily in elderly Italian and Jewish men—the presenter noted that his diagnosis “should be placed in the context of an emergence of a series of remarkable observations concerning diseases among homosexual men.

“The major unanswered question, which looms over this entire discussion,” he worried, “is what accounts for this extraordinary cluster of cases of Kaposi’s sarcoma and opportunistic pathogens in this population. Are we dealing with activation of a latent agent that induces immunosuppression that itself has pluripotential expressions of disease?”

In more recent years, presenters methodically combing through patients’ histories for clues have arrived at diagnostic deductions that technology alone failed to yield. A brain lesion, for example, in a researcher was linked not to the man’s work experience on a HIV vaccine trial in East Africa, as first feared, but rather to schistosomiasis, a disease caused by parasitic worms found in Lake Victoria, where the researcher had unwisely chosen to swim.

In another case, a toxic reaction in a young man, carried incoherent and incontinent into the emergency department after a round of drinking, was connected to the man’s attempt to heighten alcohol’s effects by gulping down cleaning fluid intended for laser printer toner cartridges.

Yet another case traced a painful shinbone infection in a liver transplant recipient to an inhalation of Cryptococcus neoformans, which the man’s weakened immune system could not stop from disseminating to the skin and bone of his leg. This yeast-like fungus is ubiquitous in nature, the discusser noted, because it characteristically inhabits soil contaminated by pigeon feces or the debris that surrounds pigeon roosts. The patient, who enjoyed cultivating roses, had come into contact with soil that, the presenter theorized, was most likely the origin of his terrible infection.

Ghosts of Litmus Past

When the current editor of the CPCs, pathologist Nancy Harris, took over the position in 2003, she conceded that “changes in the practice of medicine mean that cases involving diagnostic mysteries suitable for the traditional CPCs are becoming more esoteric and less relevant to practice.” Yet, in her view, an updated version of Cabot’s original vision of using real patient cases to teach physicians remains as valuable as ever.

While Harris has retained the classic diagnostic-mystery format in some cases, many others contain both differential-diagnosis and management components, with an emphasis on prevention, diagnosis, prognosis, or therapy. In their new form, the CPCs’ rarified—yet profoundly pragmatic—ethos endures. In one recent case, an Indonesian teenager was treated by volunteer MGH physicians aboard the USNS Mercy after she survived a 65-foot-high wall of water, mud, and debris that devastated her hometown of Banda Aceh. The December 2004 tsunami had swept the girl more than a mile inland, nearly drowning her, and claimed the life of her mother, whose body was never recovered.

The CPC at which the girl’s case was presented to a packed amphitheater was a far cry from the conferences of Cabot’s era; an array of specialists armed with the latest databases of knowledge in pediatrics, neurology, and infectious diseases solved the mystery of the girl’s symptoms deftly and decisively—and with the live participation, via videoconferencing satellite connection, of physicians on board the Mercy, afloat in the Indian Ocean, thousands of miles and multiple time zones removed from MGH.

And yet, for all its cutting-edge quality, this CPC reverberated with an echo of the tradition’s original spirit. In the absence, on the ship, of some of the highly refined diagnostic technology to which physicians have routine access at MGH, some of the presenters recounted the roles that improvisation, deduction, and intuition had played in helping them to arrive at a successful diagnosis and treatment. The elegance—and compassion—with which the MGH physicians presented the Indonesian teenager’s case would have gratified Cabot, who, despite being a staunch champion of the emerging biosciences of his time, never lost sight of the human stakes at the center of the CPCs. After all, Cabot wrote in his later years, “I was not interested in Disease but rather in spotting it and getting people over it.”

Beverly Ballaro was associate editor of the Harvard Medical Alumni Bulletin from 2001 to 2005; before that, she served as assistant editor for one year.

This article appeared in the Spring 2005 issue of the Harvard Medical Alumni Bulletin.

Photo: Department of Pathology, Massachusetts General Hospital