Dianostic Frustrations in the Debate About Lyme Disease
By Rebecca Pollard
Mark S. Klempner Photograph by Frank Curran
Mary Nyman never saw the tick that started it all. The English
professor and writer knows only that one day in 1995, while
battling what she thought was a nasty version of the flu,
bull's-eye rashes appeared on her thigh and forearm. She had been
bitten by a deer tick, which had introduced into her system
Borrelia burgdorferi, the bacterum responsible for Lyme
disease. After a short course of antibiotics, the symptoms
subsided. Then a few years later it happened again. Another tick.
Another rash the size of a grapefruit. Another round of
antibiotics.
This time, however, the symptoms abated only to return a few
months later in a slightly different form. At first, Nyman
(GRS'59) of Wareham, Massachusetts, experienced muscle pain in her
knees and shoulders severe enough to waken her at night. Walking
became difficult, and names and dates began to elude her. Her
ability to articulate was drastically affected. "I just couldn't
bring forth words," she says. She began to wonder if she could
continue teaching. "This was not the kind of feeling you wanted to
have standing in front of a classroom. It would be a teacher's
worst nightmare: you open your mouth and nothing comes out.
" Nyman had joined the ranks of those suffering from chronic Lyme
disease. The vast majority of patients who develop the classic
bull's-eye rash and flulike symptoms of acute Lyme disease improve
with a short course of antibiotics. No one knows how many of these
patients go on to suffer the long-term version, because the
chronic pain, memory loss, and extreme fatigue are difficult to
diagnose as Lyme disease. Of the approximately 16,000 cases of the
acute form reported to the Centers for Disease Control every year,
more than 90 percent occur along the eastern seaboard, from
Massachusetts to Maryland. The incidence of the disease in this
region has risen steadily over the past decade, and that trend is
expected to continue.
While Nyman was considering what to do about her mysterious pain
and confusion, she saw an advertisement in her local newspaper
recruiting Lyme disease patients with the same chronic symptoms.
Mark S. Klempner, M.D., now the assistant provost for research at
Boston University's Medical Campus, wanted to study whether
antibiotics improve symptoms in patients with chronic Lyme
disease. A small minority of physicians believed that a lengthy
course of antibiotics, sometimes two to three years' worth, had
helped their chronic Lyme patients. Klempner's study would provide
the first hard evidence to the contrary.
An infectious diseases researcher for over twenty years, Klempner
has devoted the past decade to studying both the basic science and
the treatment of Lyme disease. As a researcher at the Tufts School
of Medicine, he published landmark findings in 1996 on how the
Lyme bacterium moves so quickly from the bite area to the tendons,
heart, and even the brain of its victim. Klempner reported
that the Borrelia bacterium actually stimulates the
body's cells to digest themselves, thus clearing a direct path to
its target tissues.
With a $6.5 million grant from the National Institutes of Health
in 1997, Klempner began to study patients who, like Nyman, had
received the standard two-to-three-week course of antibiotics for
acute Lyme disease. Klempner's team first ascertained whether any
of these patients still harbored traces of Borrelia
burgdorferi in their systems. They cultured the blood, urine,
and spinal fluid of each patient, and also searched for
Borrelia DNA in these samples. But Klempner and his
colleagues did not find any Lyme bacteria in the more than 700
samples collected during the trial. "It appeared that there was no
persistent infection," Klempner says. "The Lyme bacteria were
gone." Something else seemed to be making these people seriously
ill.
If there were no detectable Borrelia bacteria in any of
the study participants, it stood to reason that antibiotics would
have little or no effect on their Lyme symptoms, which is what the
researchers reported in the July 2001 New England Journal of
Medicine. Half the patients received a strong antibiotic
called ceftriaxone intravenously for thirty days, followed by
sixty days of the more standard doxycycline pills. The other half
received placebos for ninety days. Regardless of whether they took
placebo or antibiotics, by the study's end about one-third of the
participants felt better, one-third felt worse, and one-third
reported no change. These results reflect the capricious nature of
Lyme symptoms, says Klempner, which can improve or worsen. "We've
clarified a medical problem, but we haven't been able to offer a
solution," he says. "We are sympathetic to patients who are
suffering. We want to help them. Prescribing medicines that are no
more effective than placebos would not do that."
Origins of the Debate
Alan Steere, M.D., now a Tufts University researcher, unwittingly
ignited the controversy over long-term antibiotic treatment for
chronic Lyme disease. He was the first to describe the disease in the
late seventies. Over the next decade and a half, it became the most
commonly reported vector-borne disease, one spread to humans via
another organism, in the United States. But as the Lyme diagnoses
poured in, Steere began to suspect that doctors were misdiagnosing
diseases with similar symptoms. Because tests for Lyme are unreliable,
he reasoned, patients with persistent symptoms could more likely have
other illnesses, such as fibromyalgia or chronic fatigue syndrome. By
the early nineties, he had publicly voiced these concerns, as well as
skepticism about long-term antibiotic treatments.
Meanwhile, many physicians continue to support the use of antibiotics
for chronic Lyme disease. Sam Donta, M.D., is a professor of medicine
at Boston University's School of Medicine. Every week he sees about
five new patients with chronic Lyme symptoms at the Boston Medical
Center Lyme Disease Center, which he directs, and at his clinic on
Cape Cod. Donta has prescribed lengthy courses of antibiotics for
patients for the past fifteen years. About 75 percent of the patients
he treats show improvement, he says, and a quarter of them remain
symptom-free.
The debate among physicians over the proper diagnosis and treatment of
Lyme disease leaves patients confused about their options. Before he
founded the Lyme Education and Research Network in 1997 to raise
public awareness of the disease, Todd Summer (SMG'86) of Carlsbad,
California, had battled chronic Lyme disease for about three years. "I
was tested many times for Lyme disease," he says. "Some tests were
negative, some were positive. Some doctors told me I had Lyme, others
disagreed."
Summer, who was living in New Jersey when his symptoms began, doesn't
recall whether or not he had the classic bull's-eye rash. He knows
only that what started out as tremendous fatigue quickly progressed to
blurry vision, memory problems, and heart tissue inflammation. Then in
the summer of 1995, he started having trouble recognizing familiar
faces. One night he lost his way while driving the familiar route to
his uncle's house. "That's when I knew that something was terribly
wrong," he says.
Summer found a doctor in New York who prescribed seven months of
intravenous antibiotics and three years of antibiotic pills. His
symptoms fluctuated at first, then gradually improved. He says that he
is one of the few patients he knows whose insurance covered the costly
intravenous treatment, which can run some $200 to $300 per day.
"Without a definitive test that says this person has Lyme disease,
it's easy for insurance companies to justify refusing treatment," he
says. "That needs to change."
Would Summer have improved if he had never taken antibiotics?
Klempner's study suggests that he would have. But Donta believes that
Klempner's ninety-day trial was not long enough to adequately test
whether the antibiotics work. "It takes eighteen months of treatment,
on average, to cure the disease," says Donta, who was the chief of
infectious diseases at the University of Connecticut before coming to
Boston University in 1993.
In his experience, he says, relapses are common in the first several
months of treatment. "My observations support that antibiotics work,"
Donta says, "but I know that that has to be proven with clinical
trials. I hope we will get the support to do longer trials."
The Genetics of Lyme
Klempner and coauthor Arthur Weinstein, M.D., director of rheumatology
at Washington Hospital Center in Washington, D.C., believe that their
study offers quite enough evidence against long-term antibiotics. "It
is very important that we found no persistent infection," says
Weinstein. "That means that even patients who improve when they take
antibiotics are improving for other reasons." Klempner and Weinstein
are now looking into the possibility that persistent symptoms after
Lyme disease occur in people with certain genetic characteristics. If
this is true, then a Borrelia infection behaves like one type
of Salmonella infection. In patients with a certain kind of immune
system, Salmonella bacteria can trigger an autoimmune
response that leads to arthritis long after the infection has gone.
Klempner has found evidence that patients with chronic Lyme disease
have genetically similar immune systems. After studying the DNA of the
first fifty-one participants in the trial, he and Weinstein found that
many share a certain gene that controls their immune type. They did
not find a high incidence of the gene in a random sample of healthy
people.
The researchers are also considering the possibility that the
Borrelia bacterium alters the neural pathways that transmit pain
in the spinal cord or brain in patients with a certain genetic
predisposition. They found a chemical associated with nerve damage and
chronic pain in 75 percent of spinal fluid samples from ninety chronic
Lyme disease patients. "These results are preliminary, but they give
us clues into how the disease may actually work," says Klempner.
It's no wonder that Klempner's study has met some resistance. As Mary
Nyman says, "The public wants it black or white. They don't accept the
gray areas." But she is less concerned with knowing exactly what
alleviated her wandering muscle pain and memory loss than with the
fact that they have for the time being vanished as mysteriously as
they came. She has started working on a novel again, and has resumed
her favorite outdoor pastimes but with a hint of caution. These days
she prefers to hike on roads instead of trails, and at the beach, she
tries to spend most of her time in the water. Just to be on the safe
side.
Rebecca Pollard (COM'99) is a writer for publications of
the Harvard University Graduate School of Education.
