by Steven Hatch
In this chapter, however, we emerge onto the other side of the spectrum of certainty—one in which we can be fairly certain that treatments carry harm without any evidence of a corresponding benefit. For about a generation, a small group of patient advocates, along with a coterie of physicians, have theorized that chronic fatigue syndrome is caused mainly by Lyme disease. Because Lyme is a treatable disease, and because chronic fatigue is of course chronic, these patients and this small group of physicians have advocated for, in some cases, essentially indefinite courses of antibiotics. When the experts sat down to review the data in the early 2000s, there was a solid consensus that prolonged antibiotics were not only not helpful but pretty clearly harmful, and so a professional society advocated for less medicine in its Lyme disease treatment guidelines. What almost nobody could have anticipated after the publication of their fairly dry and technical paper was that they would find themselves in court, with the real possibility of financial insolvency simply by having to defend the scientific accuracy of those very guidelines.
What follows is that story, which begins in my clinic as I evaluate David Marsh. It is worth repeating that David is not “real” in the sense that he is not a single person by that name. However, he is quite real in that he is an amalgam of several patients whom I have seen, and whose stories are similar in broad outline. It is safe to say that every general infectious disease doctor, to say nothing of a good number of internists and family physicians, will be familiar with David’s story—certainly in New England, but also quite possibly across the United States.
David was twenty-four years old and had grown up in a small town in central Massachusetts. He came to my office seeking an answer to the question of why his life had gone completely awry. He was an exemplary student at his high school: he regularly made the honor roll, ran for the cross-country team, and took part in a variety of student activities. After graduation he attended a liberal arts college in the South, and four years later he came back to Massachusetts to start graduate school, about two years before our first visit.
It was midway through his first semester that something began to happen.
I say “something” because after meditating on his case for more than a year, I don’t really know what that “thing” is. What I do know is that he began to experience symptoms that most doctors would, at first glance, assume was some kind of a viral illness. He spent the better part of a week during the first semester of graduate school in bed feeling lousy, suffering from muscle pains, sweating episodes that came and went, and a bit of tenderness in his knee and ankle joints. He never sought medical help during this period so there wasn’t any specific testing done. At any rate, after that week the aches and joint pains went away, and he tried to resume his life and get back to his academic work.
But instead of picking back up, as nearly all of us have done after some brief, nonspecific bout of illness, David’s body went into a long idle that continues to this day. He never finished that first semester and couldn’t find a job. He stopped exercising, he didn’t go out and spend time with friends, he didn’t travel to try to jump-start his life again. At the time we first met, it was as if his life had just been put on a very prolonged pause.
What he did do was sleep. During college, David felt like he could function perfectly fine if he got between six and seven hours of sleep each night. Since that fateful illness, he began to sleep more and more, and by the time we met he was sleeping about twelve hours at night yet still required one to two prolonged naps during the day. He was exhausted constantly. His life had become confined largely to his father’s couch, where he would sit and watch TV after getting out of bed and spend the day dozing before returning to his room and starting the cycle all over again. I am neither Catholic nor religious, but “purgatory” seemed the most apt word for what his life had become.
He began seeking medical opinions several months later. First he made a visit to the pediatrician who cared for him as a child, who reluctantly agreed to see him as he had never established a relationship with an internist. No diagnosis was offered. Next came his father’s primary care physician, and, after a few visits, referrals to an endocrinologist, a hematologist, and a neurologist. Throughout these visits, a series of tests were ordered: routine blood work, serum chemistries, liver function studies, an HIV test, and labs for thyroid function were but a few of dozens of tests ordered to look for disease running the gamut from common to exceedingly rare. He had a CT scan done on his lungs, abdomen, and pelvis to look for some hidden cancer or infection that might be the source; the neurologist ordered a brain MRI to evaluate for any possible structural brain problems that might explain his symptoms. Every last test was normal. My office received a stack of consultation notes, lab results, and radiology reports nearly two inches thick. Not one of the doctors involved could explain what was wrong with David, and after an hour-long appointment and twice that time reviewing his records, neither could I.
Yet our visits were not, strictly speaking, aimed at finding some diagnosis for his chronic fatigue, for by the time David came to me, he had his own fairly strong ideas as to the cause. David believed he was suffering from Lyme disease. He actually had more than one Lyme test performed over the course of his prolonged evaluation, and each time it was negative. (Despite this, he had nonetheless undergone two courses of treatment with doxycycline, the gold-standard treatment for Lyme.) But David had an answer for this: the test, he said, was being interpreted incorrectly. He produced literature that backed up his claim. He noted a medical organization composed of various board-certified doctors whose website supported this interpretation of his testing. Based upon all of this, he believed that antibiotics—months of antibiotics, possibly years of antibiotics—were his best chance at turning his life around. Although we spoke in part about other causes of his illness, most of our discussion revolved around whether I felt comfortable giving him a three-month prescription for tetracycline for what he believed was his Lyme disease, which had not responded to treatment.
How David and I came to that point, with that specific question on the table, is a story that probably could not have happened were it not for the quirky biology of the Lyme bacteria, which produces illness ranging from something that looks like the flu to chronic arthritis to a state where the heart muscle becomes inflamed to any number of neurological problems and, of course, to chronic fatigue. It could not have happened if it were not for the difficulty in diagnosing Lyme, which at the time of this writing relies on a testing algorithm that is not without its problems. Finally, it could not have happened without the Internet, which has spread both an abundant amount of medical knowledge to laypeople as well as an equal amount of misinformation.
Thus far, this book has discussed uncertainty by emphasizing the underestimated imperfection of results. My goal has been to show that these results, whether those of an individual blood test or those of a 10,000-person study five years in the making, need to be approached with varying levels of caution. I’ve tried to highlight some areas in which doctors or patients or both have gotten themselves into trouble by neglecting uncertainty when they interpret results, not realizing that a positive test may sometimes be negative in reality.
In the case of chronic fatigue syndrome, however, this has been turned on its head so that negative tests have been interpreted by some to be positive. An entire medical subculture—one might, in fact, call it an alternate medical universe—has evolved, and it has exploited the complicated dynamics of Lyme disease testing, convincing thousands of patients who don’t suffer from Lyme that they do, and that they will benefit from ever-longer courses of antibiotics when no study has ever shown this to be true. Indeed, the lack of benefit of prolonged antibiotics is often taken as evidence by particular practitioners that more antibiotics are required, with the very failure of patient improvement serving to reinforce their belief that they haven’t stamped out the infection that so-called mainstream physicians can’t find in the first place.*
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br /> What’s in a name? The sharply divergent views of different communities involved in the treatment of Lyme disease lead to two competing sets of nomenclature, which can be dizzying in its confusion, especially for outsiders trying to make sense of the controversy. Thus, for the sake of simplicity I refer to each of these groups by commonly used names—“alternative” and “mainstream,” mainly—and won’t spend much time analyzing why people have chosen that vocabulary or complain that they are misleading. What’s important is that they really do refer to two distinct groups with very different assumptions about Lyme disease.
If all of this sounds confusing, it is, and yet it is the state of affairs in doctors’ offices across the country. Lyme tends to be concentrated in three parts of the United States: New England, the upper Midwest, and the Pacific West. Nevertheless, this has not stopped a small industry of physicians convinced of the ubiquitous menace of Lyme from cropping up across the country, all running clinics focused on patients with chronic fatigue. They also believe chronic fatigue is caused by other exotic infections as babesiosis, anaplasmosis, and bartonellosis. Their common denominator is that they are tick-borne illnesses, but Lyme takes center stage for these doctors, and their patients reflect these concerns. The notion that Lyme plays the starring role in the world of chronic fatigue is reflected in the name of the principal advocacy group known by the acronym ILADS, or the International Lyme and Associated Diseases Society.
There is nothing especially controversial about having specialized clinics that cater to certain patient populations; a typical infectious disease practice routinely cares for patients with such infections. But these particular chronic fatigue Lyme clinics—let’s call them the ILADS group—have a very different approach than that of mainstream physicians. They interpret Lyme testing differently, often avoiding the labs and tests used by such mainstream physicians. They utilize treatment protocols that their mainstream colleagues shun. They have their own professional organization in ILADS, and ILADS engages in very little dialogue with the broader medical world. They are, in every meaningful sense of the phrase, alternative medicine: they have alternative theories about the causes of chronic fatigue, they have alternative laboratories who perform alternative tests not approved by government agencies, and they have alternative treatments.
For their part, mainstream physicians often react to the ILADS practitioners with a mixture of bewilderment, exasperation, and contempt. Most believe that the entire approach of ILADS relies on shoddy science and that these doctors do more harm than good in at least two ways. First, they prescribe treatments that carry genuine risk without any evidence of a corresponding benefit in symptoms. (I’ll discuss some of these risks later in the chapter.) Second, they offer false certainty about the cause of chronic fatigue, and thus false hope, to their patients.
Normally these two mostly distinct worlds would just function in parallel, with one set of doctors choosing to go their own way, and the other set doing otherwise, each largely rejecting the baseline assumptions of the other group. This is the case with many of the philosophies that undergird the movement of alternative medicine, whether it be Qi Gong, reflexology, acupuncture, or the like.* But, in the case of Lyme disease, a series of guidelines issued by a mainstream physicians’ organization brought the two groups into direct conflict, leading not merely to the usual heated accusations of unprofessionalism, but a full-fledged legal attack on the largest organization of infectious disease physicians in the world.
There is much more to be said about so-called alternative medicine that is beyond the scope of this book. What distinguishes ILADS from many other alternative movements is that it seems to accept certain baseline assumptions of “Western medicine.” It appears to accept the evidence of germ theory, the molecular biology that forms the basis of Lyme testing, and the usefulness of antibiotic therapy, for instance. However it does differ, and differs mightily, with mainstream medicine on the ground rules concerning scientific evidence in how to assign causes to symptoms and how to know whether a given therapy is working and should be stopped.
The story of Lyme disease and patients suffering from chronic fatigue syndrome reveals much about the limits of what doctors can know through testing. It highlights the problems associated with modern medicine when a patient has obvious illness but a diagnosis for it remains elusive. It illustrates the influence that the business of medicine can have on patients’ perception of doctors. And it displays the impact of the Internet on doctor-patient interactions—or at least one aspect of it. To say that the Internet alone is responsible for the false prophets who trumpet “chronic Lyme” as the source of so many ills not only goes too far, it ignores the significant benefits that the Internet has had on the doctor-patient encounter. But it might not be a stretch to say that, with respect to Lyme, the Internet has allowed a certain kind of anti-intellectual and antiscientific set of ideas to spread much more efficiently, and for like-minded advocates to join forces and spread confusion in the process.
Although there were descriptions in the medical literature throughout the twentieth century of the disease we now call Lyme, we typically date its discovery to 1975, when physicians working for the Centers for Disease Control and Prevention (CDC) in Atlanta came to Lyme, Connecticut, to investigate a cluster of cases of what appeared to be the fairly uncommon condition of juvenile rheumatoid arthritis. Several of these patients, and subsequent others like them, were also found to have a distinctive bull’s eye rash that had been described in European medical journals as early as 1909 and was called erythema migrans.
What was known about erythema migrans rashes is that they were associated with tick bites, and that became a critical clue in unwrapping the Lyme mystery. Over the next several years a variety of clinical and laboratory studies were carried out, and a researcher named Willy Burgdorfer isolated from deer ticks a type of corkscrew-shaped bacteria known as a spirochete that eventually was understood as the causative agent of Lyme, and the organism was named Borrelia burgdorferi in his honor.
It would become clear over the course of the 1980s that Borrelia burgdorferi was an odd organism. It was incredibly difficult to grow in culture, which was and remains the mainstay laboratory technique for the diagnosis of bacterial disease. Moreover, the clinical symptoms that B. burgdorferi produced were protean—that is, they could frequently change form, first appearing as the painless rash, then progressing to fevers and muscle pains, then to headaches or neurologic abnormalities or arthritis or a combination of these symptoms. The arthritis notwithstanding, most of the complaints were nonspecific and could be associated with dozens of diseases. Because there was no direct method for testing for Lyme infection, and because Lyme could mimic so many other conditions, it was difficult from the start to know whether Lyme was, or was not, the cause of someone’s illness.
During the 1980s and 1990s, as suburbanization was bringing more and more people into direct contact with traditional deer habitat, and thus the ticks that spread Lyme, scientists began developing other tools besides culture for detecting Borrelia burgdorferi. The two most important types of tests that were developed for Lyme, which are still used today, were the ELISA and the Western blot. Both of these tests diagnose Lyme not by finding direct evidence of the presence of Borrelia in the patient (as a culture would) but by indirectly noting the presence of the patient’s immune response to Borrelia. It’s a bit like stumbling upon a crime scene. If you see a body lying there with a knife in the chest, then you can be pretty confident a murder took place. That’s the equivalent of culturing Borrelia from the patient. But in the case of Lyme, the body typically is nowhere to be found. Instead, you can infer that a patient had Lyme (i.e., that there was a murder) by seeing a pool of blood and a nearby knife—the metaphor for the ELISA and Western blot.
Of course, occasionally you find blood and a knife in a room and there really wasn’t a murder, but rather there was some innocent explanation for the mess: someone cut themselves shaving, it was an anim
al who bled rather than a person, or it wasn’t even blood in the first place and merely looked like it. The combination testing of ELISA and Western blot, of which I’ll discuss the biological details in a moment, is designed to minimize these overinterpretations. But the believers in chronic Lyme argue that it’s the mainstream physicians who are ignoring the evidence and that they are in collusion with one another to deprive patients of care. At the heart of the dispute is how to interpret Lyme tests and what degree of uncertainty is acceptable in diagnosing a disease that often has very nonspecific symptoms.
The origins of the ELISA test date to the mid-1960s, but it became available for commercial use more than two decades later. The ELISA can be used in a variety of ways, but to keep things simple I’ll discuss it mostly in relation to Lyme. The Lyme ELISA is based on the idea that the body responds to Borrelia infection by developing antibodies that “catch” the organism and direct it to specialized immune cells that devour and destroy the bacteria. Antibodies are made by a different set of immune cells, and what makes the ELISA work is that these cells make antibodies that are organism specific. That is, after being infected by Lyme, the body will mount an immune response by making antibodies that target unique surface molecules (mostly proteins) of Borrelia burgdorferi. This is true for nearly all infectious agents: infections with bacteria, or viruses, or fungi all produce antibody responses specific to that organism.