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It was 1994 and life could not have been better for Alita Lyons, an aspiring biochemist from Manhattan. As a child, Lyons had dreamed of working in science, and now, at age 27, she had landed her dream job: studying hepatitis C in a laboratory at the Weill Medical College of Cornell University in New York. All day and sometimes late into the night, Lyons sat at the lab bench pipetting chemicals into test tubes and running carefully controlled experiments. “It was a typical high-end, high pressure laboratory,” Lyons says. “I loved it.”

A year or so into the job, Lyons’ experiments were humming along smoothly, but her mind

began stalling. “I began to forget,” she says. “I’d be running an experiment that I had done 1,000 times. I would get halfway through, take a break and then come back with no clue where I had left off.” Peering at the rows of test tubes she had organized just hours before, Lyons would wonder, ‘What’s inside those tubes, and why are they arranged like that?’ The memory lapses were intermittent, but other symptoms emerged, including fatigue, insomnia and involuntary muscle twitching. Most people are familiar with the abrupt muscle contractions that can happen while falling asleep, but, for Lyons, the twitches

came day and night, causing embarrassing breaks in conversations and jolting her out of deep slumber.

As the years passed, Lyons kept pushing herself in the lab, publishing studies and even becoming a first author on a well received research paper3. But her neurological problems were worsening all the time. Some days she would leave the lab to run errands, get lost on city streets she had walked hundreds of times and then have to call friends for help navigating back to work. Lyons sought medical help from distinguished doctors at Cornell University, Columbia University and

The chronic debate over Lyme diseaseA small group of doctors—and a large number of patients—say Lyme disease can sometimes manifest as a chronic illness, one that evades conventional medical tests and treatments. The physicians who support this theory flout standard medical guidelines and treat patients with long-term antibiotic therapies that mainstream researchers say are unproven and potentially dangerous. Coco Ballantyne reports on how the controversy over Lyme disease has become increasing polarized.

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private physicians in New York. Between 1995 and 2004, she says she visited approximately 20 doctors. They diagnosed her with diseases ranging from epilepsy to bipolar disorder and prescribed an assortment of medications, none of which helped.

Finally, nearly a decade after the symptoms first surfaced, a doctor asked Lyons what may have seemed to be a string of irrelevant questions: “Where did you grow up? Where did you spend your summers?” Lyons replied that she had spent nearly every summer of her life on Fire Island, a popular beach destination off the southern coast of Long Island. Travel guides highlight the island’s undulating sand dunes and pristine wilderness, but they fail to emphasize that it’s teeming with ticks. According to some sources, the 32-mile sliver of land boasts the highest density of deer ticks of any national park area in the eastern US.

The doctor ordered a blood test for Lyme disease, a tick-borne bacterial infection typically associated with a skin rash, which can lead to a variety of severe symptoms including arthritis and facial paralysis. He told her that she had tested positive for Lyme disease—that is, positive according to criteria set by the lab that ran the tests. But when judged against criteria established by the US Centers for Disease Control and Prevention (CDC), the results were negative, the doctor acknowledged. And it was the CDC she believed. “I laughed at him and called him a quack,” she says.

Scientific curiosity drove Lyons to begin reading the peer-reviewed literature on Lyme disease. She attended lectures where she met people with symptoms that were strikingly similar to her own. Eventually she returned to the doctor she had written off and agreed to take another test for Lyme disease—and this time the results came back positive according to CDC standards.

Since 2005, Lyons has been on and off oral and intravenous (IV) courses of antibiotics. She says the drugs have made her feel “95% better,” eradicating some symptoms, although others creep back when she stops treatment. “The disease had been in my body for years,” Lyons says, as she sits among members of a New York City–based Lyme support group; men and women, young and old, all of whom look perfectly healthy. “It’s a problem that we all look so well,” Lyons says. “You’d never believe it unless you had the disease.” A young woman sitting across the table nods her head in agreement; an IV pokes into her arm, pumping a steady current of antibiotics into her bloodstream. “This is really physiological,” says Lyons, offering as evidence a neuropsychological exam by doctors at Columbia University, which indicated she

has “major problems with attention, slowed processing speed and memory,” a level of impairment that “would make her unable to work at this time.”

Like Lyons, the individuals in this support group firmly believe that Lyme disease can be a chronic illness caused by a persistent infection that resists treatment. They say the scientific evidence has been spun by the mainstream medical establishment to deny the existence of ‘chronic Lyme disease’ and to invalidate the only treatment that has offered them some reprieve: long-term antibiotic therapy.

It started in LymeIn the mid-1970s, doctors in Connecticut began seeing a mysterious pattern of childhood disease. Clusters of kids living in and around a town called Lyme were coming down with joint swelling, pain and other symptoms that suggested juvenile rheumatoid arthritis. The children tended to live near dense woodland areas populated by deer and field mice—animals known to harbor black-legged ticks—and the outbreaks were roughly synchronized with the tick’s feeding cycles. Before the onset of arthritis, some of the children had developed strange circular rashes where they had been bitten by ticks.

Connecting the dots, Allen Steere and his colleagues from Yale University School of Medicine realized that the mysterious childhood arthritis was caused by an infection transmitted through the bite of a tick2. But it was not until 1981 that the disease agent was

actually pinned down: a corkscrew-shaped bacterium that came to be called Borrelia burgdorferi in honor of its discoverer, Willy Burgdorfer3.

Lyme disease has since become the most common tick-borne infection in North America. Last year, the CDC received more than 27,000 reports of the disease, though the true number of cases is probably much higher, says CDC epidemiologist Kevin Griffith. The vast majority of cases occur in the Northeast, the Midwest and coastal regions stretching from California to Oregon. The disease is also relatively common in Europe, where scientists believe the Lyme bacterium originated4.

Deer ticks, particularly the poppy seed–sized immature ‘nymph’ forms, are tough to spot in the shaded woody areas they inhabit. The bites don’t hurt much, so they can easily go unnoticed, particularly if they occur on the scalp. As the tick sucks in a hearty blood meal, it may in turn infect its host with whatever microbes may be lurking in its saliva. The Lyme bacterium is just one of many disease-causing bugs that ticks can carry. There are others, such as babesiosis, a malaria-like parasite that invades red blood cells and whose symptoms range from none at all to death5.

Lyme disease announces itself in a variety of ways. Days to weeks after the initial tick bite, a person may develop a reddish skin rash called erythema migrans, often resembling a bull’s eye with a spot in the middle and a larger surrounding ring. There may be other early symptoms, including flu-like malaise

Around the clock: Jones sees patients all day and then spends the evenings handling his legal defense against the Connecticut Department of Public Health.

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and body aches. Some people experience heart block, an interruption of the electrical signals that keep the heart pumping at a steady beat. B. burgdorferi can also set up shop in the nervous system, causing temporary paralysis of face muscles or numbness and tingling in fingers and toes. The bug has a penchant for the membranes surrounding the brain and spinal cord and occasionally causes meningitis. If weeks to months go by and the disease goes untreated, sporadic attacks of joint pain and swelling, usually in the knee, may ensue—a sign that the bacterium is living in the body’s collagen-rich connective tissues. Years after the initial tick bite, some patients—including those who received treatment—say they continue to suffer from debilitating neurological problems, including oppressive fatigue and memory loss.

Some claim Lyme can be chronicOn a desolate corner in New Haven, Connecticut lies a brown apartment building housing one of the most controversial and celebrated Lyme doctors in the US. Pediatrician Charles Ray Jones says he has treated over 12,000 children for Lyme disease and other tick-borne infections. “The children come from every single state in America, from every province in Canada, from South America, Central America and every continent abroad,” Jones says, peering from behind his Coke-bottle glasses. Jones is 79 years old and walks with a limp, but the royal blue jogging suit he wears belies his age. An inscription sewn into the back of his jacket reads, “Dr. Charles Ray Jones: Keep marching to fulfill the dream”—a gift from one of the families who have rallied behind him in a rebellion against mainstream medicine.

Jones contends that the mainstream medical community does not appreciate the magnitude of the Lyme disease epidemic, and he believes that the CDC surveillance criteria commonly used for diagnosis allow many severely ill individuals to slip through the cracks. He describes some of the children he treats for Lyme disease: kids once vigorous and sharp who can no longer get out of bed or concentrate on their homework. Yet, according to the CDC, many of these kids do not have Lyme disease.

To diagnose his patients, Jones relies heavily on clinical judgment and uses laboratory analyses that diverge from CDC tests, which look for proteins produced by the immune system in response to the Lyme bacterium. Jones says the CDC diagnostic criteria leave out several key proteins that signal a Lyme infection, so he sends patient blood samples to specialized laboratories that screen for a broader array of proteins.

And as for therapy, Jones believes that patients should be given antibiotics, either orally or intravenously, for two months beyond the point at which all symptoms have disappeared. That could mean several months, or even years, depending on the individual’s infection.

At the crux of this open-ended treatment philosophy is the notion that the Lyme bacterium is exceedingly difficult to kill once it invades the body. B. burgdorferi has evolved to elude both antibiotics and the immune response, Jones says—“the Lyme bacterium has a lot of nifty ways of surviving, and one is to lose its outer surface protein coating and become pleomorphic [capable of changing form].” He cites studies suggesting that the bug has chameleon-like qualities, morphing between its normal spiral shape and a spherical cystic form6. And because the Lyme bug is such an adept survivor, it may cause persistent infections even after antibiotic treatment, Jones reasons. Researchers have reported finding the Lyme bacterium in the blood of individuals who have received extended antibiotic treatment7, but critics claim that other scientists have not been able to reproduce the results8.

Jones belongs to small group of self-proclaimed ‘Lyme literate’ doctors whose treatment approaches fly in the face of standard guidelines laid down by the Infectious Diseases Society of America (IDSA). The guidelines, which most doctors elect to follow, recommend no more than a few weeks of antibiotics for treating almost all cases of Lyme disease9. In the last few years, Jones’ unorthodox protocols have landed him in deep legal trouble.

Last year, the Connecticut Medical Examining Board voted to place Jones on probation and imposed a fine of $10,000 for violating standards of diagnosis and treatment for Lyme disease. The court has temporarily stayed the implementation of the order pending an appeal by Jones to reverse the decision. Meanwhile, he is fighting a new set of complaints by the Connecticut Department of Public Health. The allegations include prescribing a patient six weeks of antibiotics without first conducting a clinical examination (Jones has since ceased prescribing medications without first examining patients in his office, according to his office manager). With three lawyers working on the cases, the bill has amounted to thousands of dollars, according to Jones. But judging from the scores of pictures of smiling kids and homemade thank-you notes covering his office walls, Jones is not alone in the fight. Patients and supporters have donated over $200,000 dollars to his legal fund, Jones claims.

Chronic Lyme—a hoax?A few miles from the rainbow-decorated walls of Jones’ office, a giant Lego elephant ushers visitors into the Yale-New Haven Children’s Hospital. Children with Lyme disease come to this institution to see Eugene Shapiro, a professor of pediatrics, epidemiology and investigative medicine. Shapiro helped write the IDSA guidelines, and his perspective on Lyme disease could hardly be more different from that of Jones.

According to Shapiro, the CDC criteria are reliable for diagnosis, and Lyme disease is almost always easy to treat with a few weeks

Look for the signs: Ticks hide in marsh areas among other places outdoors

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of antibiotics. “B. burgdorferi is highly sensitive to antibiotics,” both in vitro and in the body, Shapiro says. “Most of the patients with ‘chronic Lyme’ have no evidence of ever having had Lyme disease,” he says. And although they may complain of subjective symptoms such as pain and fatigue, they often lack objective signs that a doctor needs for diagnosing a disease. “This does not mean these people are not suffering, only that active infection with B. burgdorferi is not the cause,” Shapiro says.

Then what do these people have? “Medically unexplained symptoms,” Shapiro says—symptoms such as fatigue and pain that are relatively common in the general population but are not caused by a persistent Lyme infection. In fact, some research suggests that up to 15% of the general population may suffer from chronic pain and 8% from chronic fatigue10. As far as treatment goes, there is “no evidence that long-term antibiotics for people with ‘chronic Lyme disease’ is of any benefit and much evidence of harm to both the individual and society,” says Shapiro, noting that overuse of antibiotics can set the stage for the evolution of drug-resistant bacteria.

There are now four double-blind, placebo-controlled clinical trials testing long-term antibiotic therapy on subjects who have been treated for Lyme disease but still suffer from ongoing symptoms. One of those studies found that prolonged therapy with the antibiotic ceftriaxone boosted cognitive function for subjects, but they relapsed when they stopped taking it11. Another trial suggested that ceftriaxone might reduce fatigue, but some critics question whether that trial was

truly double blinded12. Considering the risks associated with taking potent antibiotics, the overall message from these four studies is that there is no sustained benefit from long-term antibiotics, concludes Adriana Marques, chief of clinical studies at the Laboratory of Clinical Infectious Diseases at the US National Institute of Allergy and Infectious Diseases13.

But how does one reconcile this clinical trial evidence with the myriad people like Alita Lyons claiming that antibiotics are their only recourse from crushing fatigue, unbearable pain and other disabling symptoms? “Antibiotics tend to have other effects,” including anti-inflammatory and neuroprotective properties that could potentially mitigate arthritic and neurological symptoms, says CDC epidemiologist Kevin Griffith14. Furthermore, symptoms of chronic illness naturally tend to wax and wane, which may lead patients to attribute ups and downs to changes in their antibiotic regimens. And, finally, many infections leave enduring effects on the body after they are cleared up, Griffith says—“it’s not unique to Lyme.”

But Lyme advocacy groups insist that antibiotics are helping kill off the bacteria still living in the bodies of individuals with chronic Lyme. “The notion that patients are responding to anti-inflammatory effects rather than antibacterial effects of antibiotics is just an unproven theory,” says Pat Smith, president of the US Lyme Disease Association (LDA). “On the other hand, we do know that antibiotics are effective for treating infection”—and infections are know to cause inflammation, Smith adds. Studies suggesting that long-term antibiotics are no more effective than the

placebo had small sample sizes and only lasted for up to 90 days, says Smith, noting that other complex infections such as tuberculosis and leprosy require treatments ranging from 6 to 36 months.

The LDA and other Lyme advocates have rejected the IDSA guidelines and embraced an alternative set created by the International Lyme and Associated Diseases Society (ILADS), a nonprofit medical society headquartered in Bethesda, Maryland. The authors of the ILADS guidelines recognize chronic Lyme disease and condone the use of antibiotic therapy lasting several months, and they have a library of scientific literature to back them up. However, other researchers assert that studies frequently referenced by ILADS have not been subjected to rigorous peer review. “Much of what they cite is in more obscure journals,” and contains data “difficult for an outsider to interpret,” says infectious disease specialist William Bowie of the University of British Columbia in Vancouver, British Columbia.

Lyme disease groups have sharply criticized the IDSA guidelines, which they say restrict doctors’ ability to treat the illness and provide insurance companies with a basis for refusing coverage for long-term antibiotic therapy. In fact, the LDA says that 38,000 people signed a petition on its website protesting the IDSA guidelines. And when the Lyme community rallied for an investigation, the Connecticut Attorney General delivered.

Trouble in the courtIn 2006, Connecticut Attorney General Richard Blumenthal launched an antitrust investigation of the IDSA’s process for writing its Lyme disease guidelines. The probe, which ended in a settlement this May, unearthed “undisclosed financial interests held by several of the most powerful IDSA panelists,” including ties to insurance companies, according to statements released by Blumenthal’s office. The link is important since insurers often refuse Lyme disease patients coverage for long-term antibiotic treatments. And, at the end of the 2006 IDSA guidelines, one comes upon a “potential conflicts of interests” section where authors offer disclosures. But documents obtained by Nature Medicine through a Freedom of Information Act request indicate that certain panel members failed to reveal potential conflicts of interest. The Connecticut Attorney General’s office found multiple financial links between panelists and companies that make Lyme disease diagnostics. This is important because the guidelines say that there is no convincing after treatment evidence that the Lyme bacterium causes persistent symptomatic infections, or Spiraling out of control: The Borrelia burgdorferi bacterium causes Lyme disease

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‘chronic Lyme’—an assertion that hinges on the assumption that the standard diagnostic tools are adequate.

Additionally, according to a statement from the attorney general’s office, “the IDSA’s guideline panel improperly ignored or minimized consideration of alternative medical opinion and evidence regarding chronic Lyme disease,” excluding evidence suggesting the existence of chronic Lyme disease and blocking participation by scientists and doctors with alternative views. The attorney general’s office “has no opinion on the science” itself, emphasizes spokesman Christopher Hoffman.

The IDSA, meanwhile, stands by its guidelines. “We don’t think there is anything wrong with the way the panel was assembled or the way they conducted their deliberations,” says IDSA spokesman Steve Baragona. “We don’t agree at all that there is anything wrong with these guidelines,” he says. The evidence we have now is pretty solid that long-term antibiotics are not the answer.”

Nevertheless, the IDSA has agreed to cooperate with Blumenthal in assembling a review panel to reassess the 2006 Lyme disease guidelines and amend or change them if necessary. A neutral ombudsman chosen by the attorney general’s office and the IDSA will oversee the selection of the panel members to ensure they have no conflicts of interest.

Moving forwardFew medical issues have been as rife with controversy and bitter feelings as Lyme disease.

People like Lyons feel cast aside by doctors who tell them their disease is psychosomatic and insurance companies that deny them antibiotic treatment. Jones and his compatriots believe they are helping patients in dire need and that their standards of practice are supported by sound science. Shapiro, on the other hand, thinks the IDSA guidelines were formulated with unbiased peer-reviewed research, whereas the science frequently cited by ILADS and Lyme literate physicians is not rigorous or easily reproducible. Meanwhile, some researchers have criticized the media for fanning the flames of controversy by feeding the public uncritical accounts of individuals rebuffed by mainstream medicine but then saved by a sympathetic doctor willing to prescribe long-term antibiotic therapy15.

“No one is absolutely correct on this. There is some truth to everybody’s story,” says Stephen Barthold, who directs the Center for Comparative Medicine at the University of California, Davis. But sadly, Barthold says, the discussion about Lyme disease has devolved into an ‘it’s them against us’ mentality. “This disease is difficult,” he notes. “Further studies are needed.”

Barthold has hit upon the one—and perhaps the only—point that most everyone agrees upon: research is paramount. The Lyme advocacy community is clamoring for more research. “I think there needs to be more medical research on medically unexplained symptoms,” Shapiro says.

Lately, scientists studying Lyme disease have been churning out interesting results. Earlier

this year, Barthold and his colleagues published a study suggesting that a nondividing but infectious form of B. burgdorferi may persist in mammals even after one month’s treatment of antibiotics. After giving ceftriaxone to mice infected with B. burgdorferi, the researchers exposed those mice to ticks. Not only did the ticks become infected; they transmitted the Lyme bacterium to other mice that had never been exposed to it before16.

Another study published this summer by Benjamin Luft’s team from Stony Brook University in New York identified the most common strain of the Lyme bacterium in the US17. On the basis of his findings, Luft suspects that “different strains have different capacities to cause disease,” and the diversity in strains could potentially explain why certain antibiotics don’t work well for some people, he adds.

A recent study published this month by Mario Philipp and his colleagues from the Tulane National Primate Research Center in Covington, Louisiana suggests that the Lyme bacterium provokes cell death in the nervous system18. When Philipp’s team cultured B. burgdorferi in brain tissue taken from nonhuman primates, the bacteria induced inflammation and caused cell death. “This is the best evidence we have that B. burgdorferi can induce death in neuronal tissues,” Philipp says.

The clinical implications of such research—if there are any—have yet to be determined. But Lyons is convinced that she and other patients will be vindicated. “When the truth comes out, it’s really going to be one of the most astounding stories in science.”

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2. Steere, A.C., Broderick, T.F. & Malawista, S.E. Am. J. Epidemiol. 108, 312–321; 1978.

3. Burgdorfer, W. et al. Science 216, 1317–1319; 1982.4. Margos G. et al. Proc. Natl. Acad. Sci. 105, 8730–8735;

2008.5. Vannier, E., Gewurz, B.E. & Krause, P.J. Infect. Dis. Clin.

North Am. 3, 469–488; 2008.6. Brorson, O. & Brorson, S.H. Infection 25, 240–246;

1997; Alban, P.S., Johnson, P.W. & Nelson, D.R. Microbiology 146, 119–127; 2000.

7. Phillips, S.E., Mattman, L.H., Hulínská, D. & Moayad, H. Infection 26, 364–367; 1998.

8. Feder, H.M. Jr. et al. N. Engl. J. Med. 357, 1422–1430; 2007.

9. Wormser, G.P. et al. Clin. Infect. Dis. 43, 1089–1134; 2006.

10. Aggarwal VR, et al. Int. J. Epidemiol. 35, 468–476; 2006.

11. Fallon, B.A. et al. Neurology 70, 992–1003; 2008.12. Krupp L.B. et al. Neurology 60, 1923–1930; 2003.13. Marques, A. Infect. Dis. Clin. North. Am. 2, 341–360;

2008.14. Rothstein, J.D. et al. Nature 433, 73–77; 2005.15. Bowie, W.R. Drugs 67, 2661–2666; 2007; Feder, H.M.

Jr. et al. N. Engl. J. Med. 357, 1422–1430; 2007.16. Hodzic, E. et al. Antimicrob. Agents Chemother. 52,

1728–1736; 2008.17. Qiu, W.G. et al. Emerg. Infect. Dis. 7, 1097–1104;

2008.18. Ramesh, G. et al. Am. J. Pathol., doi:10.2353/

ajpath.2008.080483; 2008.

All suited up for fighting Lyme: Parents from Florida gave this jogging suit to Charles Ray Jones to thank him for treating their two children.

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