Chronic Lyme disease (CLD) is a generally unrecognized medical diagnosis that contains a broad number of disorders or symptoms that are supposedly related to a Lyme disease infection. There is no reproducible or convincing scientific evidence of any relationship between the symptoms and Lyme disease. There is no evidence that chronic Lyme disease is caused by a persistent Lyme disease infection. In fact, there’s little evidence that CLD “patients” ever had Lyme disease itself.
Despite this lack of scientific, medical and clinical evidence, a whole cottage industry has arisen to promote the myth of chronic Lyme disease along with selling expensive treatments that have shown little or no clinical efficacy. Furthermore, a whole activist movement that argues that CLD is a real disease, and they can be a vociferous and radical as your every day anti-vaccine activist. In fact, a lot of the arguments are similar between the CLD and anti-vaccine groups – over-reliance on anecdotes, cherry-picking scientific articles, and claims of some sort of conspiracy.
But we’re going to ignore all of that. This article will take a look at the best scientific evidence that has examined the claims about chronic Lyme disease. Because the only thing that matters is scientific evidence.
- 0.1 What is Lyme disease?
- 0.2 The Chronic Lyme disease myth
- 0.3 Refuting the chronic Lyme disease myth
- 0.4 More science refuting the myth of CLD
- 0.5 The CDC and chronic Lyme disease myths
- 0.6 One article that supports the existence of CLD
- 0.7 Summary, the TL;DR version
- 0.8 Key citations
- 1 Don’t miss each new article!
What is Lyme disease?
Lyme disease is an infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Of the three species, Borrelia burgdorferi is the main cause of Lyme disease in North America, whereas Borrelia afzelii and Borrelia garinii are more prevalent in Europe. The disease is named after the towns of Lyme and Old Lyme, Connecticut, where a number of cases were initially identified in 1975.
Borrelia is transmitted to humans when bitten by infected ticks belonging to a few species of the genus Ixodes, called “hard-bodied” ticks. Although deer ticks, Ixodes scapularis, Ixodes pacificus, or Ixodes ricinus, are commonly considered to be the vectors for Borrelia infection, some of the other species in the Ixodes genus can transmit the disease. Lyme disease is the most common tick-borne disease in the United States, and it appears to be spreading far outside of the northeastern USA.
The initial symptoms of Lyme disease include fever, headache, fatigue, depression, and a circular skin rash called erythema migrans (EM). If the Borrelia infection is not treated quickly, later symptoms may involve the joints, heart, and central nervous system. There is generally only one known treatment for the infection–antibiotics including doxycycline, amoxicillin, and cefuroxime. The symptoms usually disappear after antibiotic treatment.
From this rather straightforward disease, a whole industry has arisen around the chronic Lyme disease myth – it claims that the Lyme disease is never really killed by antibiotics, and it persists for months or years. Let’s look at the evidence.
The Chronic Lyme disease myth
The problem with the delayed or inadequate treatment of Lyme disease is that it can lead to the more serious symptoms, which can be disabling and difficult to treat. Difficult, but science-based medicine provides sufficient evidence that it can be successfully treated, especially with antibiotics.
And this is where the pseudoscience begins. There is a vocal group, the International Lyme And Associated Diseases Society (ILADS), made up of patients, doctors and other advocates, that is pushing a belief that the Borrelia bacteria can hide out in the body and persist even after treatment, causing a vague list of symptoms, from night sweats and depression to back pain and vertigo. They call this disorder by the catchy name, chronic Lyme disease.
This group, and others who share this belief, vehemently argue that a cure requires not weeks but months or years of strong antibiotics. And they also believe that the disease sometimes just goes into remission, with frequent relapses. The ILADS attempts to portray the disease as an almost impossible disease to treat:
Chronic Lyme disease patients may face a long hard fight to wellness. People with chronic Lyme can have many debilitating symptoms, including severe fatigue, anxiety, headaches, and joint pain. Without proper treatment, chronic Lyme patients have a poorer quality of life than patients with diabetes or a heart condition.
The fact is Lyme is a complex disease that can be highly difficult to diagnose. Reliable diagnostic tests are not yet available which leaves many—patients and physicians alike—relying on the so called “telltale signs” of Lyme disease: discovery of a tick on the skin, a bull’s eye rash, and possibly joint pain. However, ILADS research indicates that only 50%-60% of patients recall a tick bite; the rash is reported in only 35% to 60% of patients; and joint swelling typically occurs in only 20% to 30% of patients. Given the prevalent use of over the counter anti-inflammatory medications such as Ibuprofen, joint inflammation is often masked.
Based on these statistics, a significant number people who contract Lyme disease are misdiagnosed during the early stages, leading to a chronic form of the disease which can prove even more difficult to diagnose and treat. Lyme disease is often referred to as the “great imitator” because it mimics other conditions, often causing patients to suffer a complicated maze of doctors in search of appropriate treatment. ILADS is committed to the prevention of chronic Lyme disease.
The blogosphere is filled with stories, always anecdotal, about this chronic form of Lyme disease. In an article from a few years ago, Laurie McClellan described how her husband got ill from an unknown disease in 2009. She wrote:
Pat (her husband), who’d been climbing mountains a few years ago, now struggled to walk a city block. Two doctors were telling us that he had a certain disease, that it was treatable, and that he could recover. But the standard medical authorities were telling me that this condition didn’t exist and that the proposed treatment was ineffective and harmful.” With no improvement in his condition over a year, they went to a Lyme disease clinic, where, despite negative tests for Lyme disease, Pat “was given prescriptions for a sophisticated regimen of drugs to control his symptoms, plus multiple antibiotics to fight the infection. He would need to take the drugs for the next year or so. He started swallowing some twenty-five pills a day, and the pace of his recovery picked up.
McClellan also tells the story of a friend’s daughter:
(She was) an honor-roll student who took several dance classes each week, she became so fatigued that she had to sit out much of her senior year of high school. She suffered from joint pain so severe that she sometimes just lay on the sofa and wept, and she lost her ability to read. One neurologist declared that she was merely anxious, but another doctor diagnosed chronic Lyme disease. After a year of antibiotics, she was well enough to start college.
Although this anecdote is compelling and seems like it indicates some serious disease, it is purely subjective. She’s not describing a diagnosis, just general complaints that can be indicative of many other disorders or diseases.
Using her own anecdotes and that infamous University of Google research, McClellan chose to accept a diagnosis of chronic Lyme disease for her husband, despite the lack of a positive diagnostic test.
Laurie McClellan is a science writer, so my expectations for her critical thinking skills is high, so why would she accept a diagnosis of chronic Lyme disease despite the evidence that it doesn’t exist? Why wouldn’t she consider alternative diagnoses that make more sense? Whatever the reason, the pull of the simplistic pseudoscience is too hard to resist, even for a science writer.
Refuting the chronic Lyme disease myth
According to an article in The Lancet by a group of infectious disease physicians from Johns Hopkins, who generally eschew pseudoscience, has stated that:
…these (chronic Lyme disease) advocates have created a pseudoscientific and alternative selection of practitioners, research, and publications and have coordinated public protests, accused opponents of both corruption and conspiracy, and spurred legislative efforts to subvert evidence-based medicine and peer-reviewed science.” The Hopkins group even go as far as stating that “advocacy for Lyme disease has become an increasingly important part of an antiscience movement that denies both the viral cause of AIDS and the benefits of vaccines and that supports unproven (sometimes dangerous) alternative medical treatments.
Here’s what we know. Almost all infectious disease researchers agree that the Borrelia bacteria causes Lyme disease and can stay in the body for years, if not treated correctly. However, nearly all of these researchers state that a short course of antibiotics is enough to wipe out the infection. There is absolutely no evidence that, in some mysterious way, Borrelia “hides” somewhere in the body to avoid the antibiotics. There is no evidence that Borrelia is antibiotic-resistant (especially since the reservoir for the bacteria is not humans, but other animals like rodents and deer).
The advocacy for CLD has been around for a few years, but there just is no peer-reviewed evidence in support of an epidemic of persistent yet invisible Lyme disease infections. One of the hallmarks of pseudoscience is the failure to progress towards additional evidence of its claims.
Furthermore, the internet has been flooded with false information about Lyme disease, and, by extension, the so-called chronic Lyme disease.
More science refuting the myth of CLD
However, it’s more than the fact that there is little science supporting the claims, we have solid evidence that refutes the claims regarding the existence of chronic Lyme disease. For example, the National Institute of Allergy and Infectious Diseases (NIAID) has funded three clinical trials that failed to show any benefit of long-term antibiotic therapy in individuals who have no evidence of an active Borrelia infection.
- Klempner et al. concluded that “there is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.
- Krupp et al. concluded that “this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS (post-Lyme syndrome).”
- Fallon et al. published an article discussing research where chronic Lyme disease patients were treated for Lyme disease and presented with objective memory impairment tests. The group that received antibiotic therapy showed slightly greater improvement than the placebo group at 12 weeks, but at 24 weeks, both the antibiotic and placebo groups had similar improvement from the baseline results. However, because of the adverse effects of the IV antibiotic therapy, which afflicted about 26% of the antibiotic group, the authors concluded that because of the limited and minor improvement in cognitive function in combination with the adverse effects, the antibiotic therapy was not an “effective strategy for cognitive improvement in these patients and more durable and safer treatment strategies are still needed.”
NIAID concludes that “carefully designed, placebo-controlled studies have failed to demonstrate that prolonged antibiotic therapy is beneficial. Although isolated success stories are always good to hear, such reports alone are not sufficient grounds to support a therapeutic approach.” In other words, not only is there no evidence that chronic Lyme disease exists, but there is extremely high-quality evidence, published in high impact, peer-reviewed journals, that the accepted therapy for chronic Lyme disease, long-term antibiotic therapy, doesn’t work.
Another study published in the New England Journal of Medicine found “that repeat episodes of erythema migrans (the typical rash) inappropriately treated patients were due to reinfection and not relapse.” They examined the genetic makeup of the bacteria found in these rashes to determine that they were new, not recurrent, infections. In other words, these particular patients, who had claimed to have a chronic Lyme disease probably were bitten by another tick.
In a review article, published in 2011, seven studies were conducted in endemic areas that included nearly 2,000 patients with suspected Lyme disease. It was determined that “only 7–31% had active Lyme disease and 5–20% had previous Lyme disease. Among the remainder, 50–88% had no evidence of ever having had Lyme disease.” These patients probably had alternative medical diagnoses like chronic fatigue syndrome or fibromyalgia.
In a recent review of research into Lyme disease (and again, chronic Lyme diseases), the author, Dr. Eugene Shapiro of the Departments of Pediatrics, Epidemiology of Microbial Diseases, and Investigative Medicine, Yale University Schools of Medicine and of Public Health, states:
In a minority of patients who receive recommended treatment for Lyme disease, objective signs resolve, but subjective symptoms such as fatigue, arthralgia, and myalgia persist for weeks, months, or longer. These are classified as post– Lyme disease symptoms if they persist for less than 6 months and as post–Lyme disease syndrome if they are disabling and persist for 6 months or longer.
The cause and frequency of this problem are unclear. Such nonspecific symptoms are common in the general population without Lyme disease. The positive predictive value of serologic tests for Lyme disease in patients with only nonspecific symptoms is poor, so misdiagnosis based on false positive serologic test results is common.
Moreover, extensive publicity as well as misinformation on the Internet about “chronic” Lyme disease, a condition for which there is no clear definition or scientific evidence of its existence, may increase anxiety on the part of patients about the consequences of the illness and may confound assessments of treatment outcomes. In patients with two or more episodes of erythema migrans, often occurring years apart, it has been shown that the episodes were caused by different strains of bacteria, indicating reinfection rather persistence of infection with the original organism.
Let me summarize what Dr. Shapiro wrote:
- The symptoms described by the CLD suffers are no different than general complaints made by the general population without Lyme disease.
- Because tests for Lyme disease can cause false positives (but rarely, false negatives), some people who are diagnosed with Lyme disease and treated for the disease, may not have an improvement in symptoms, because they never had the disease in the first place.
- There is so much misinformation for CLD on the internet, it may actually cause an increase in anxiety for patients leading to the confounding of patient assessments post-treatment.
- Many individuals who complain that they have CLD actually have a reinfection of Lyme disease from a different strain of bacteria. They got another tick bite.
Finally, in a recent meta-review, considered the pinnacle of the hierarchy of scientific evidence, Lantos et al. wrote,
Our primary literature search identified 6 studies that reported round morphologic variants of B. burgdorferi in specimens obtained from 32 total patients. No study described these forms in patients who had purely subjective symptom complexes (eg, fatigue or pain). No study investigated a causal relationship between morphologic variants and clinical disease or evaluated treatment of morphologic variants in vivo. Of 29 additional studies that described the morphology of B. burgdorferi from patients with Lyme disease, the organism was invariably described as having spirochetal morphology.
Their systematic review found no study that showed a causal relationship, and no study showed B. burgdorferi in patients with subjective symptoms, such as fatigue and pain. They concluded that “in the context of the broader medical literature, it is not currently possible to ascribe a pathogenic role to morphologic variants of B. burgdorferi in either typical manifestations of Lyme disease or in other chronic disease states that are often labeled chronic Lyme disease.”
The CDC and chronic Lyme disease myths
The Centers for Disease Control and Prevention is probably the best science-based fountain of information about all infectious diseases. The CDC, in it’s best objective tone of voice, states this about CLD (or what they call Post-Treatment Lyme Disease Syndrome or PTLDS):
It is not uncommon for patients treated for Lyme disease with a recommended 2 to 4 week course of antibiotics to have lingering symptoms of fatigue, pain, or joint and muscle aches at the time they finish treatment. In a small percentage of cases, these symptoms can last for more than 6 months. Although sometimes called “chronic Lyme disease,” this condition is properly known as “Post-treatment Lyme Disease Syndrome” (PTLDS).
The exact cause of PTLDS is not yet known. Most medical experts believe that the lingering symptoms are the result of residual damage to tissues and the immune system that occurred during the infection. Similar complications and “auto–immune” responses are known to occur following other infections, including Campylobacter (Guillain-Barre syndrome), Chlamydia (Reiter’s syndrome), and Strep throat (rheumatic heart disease). In contrast, some health care providers tell patients that these symptoms reflect persistent infection with Borrelia burgdorferi. Recent animal studies have given rise to questions that require further research. Clinical studies are ongoing to determine the cause of PTLDS in humans.
Regardless of the cause of PTLDS, studies have not shown that patients who received prolonged courses of antibiotics do better in the long run than patients treated with placebo. Furthermore, long-term antibiotic treatment for Lyme disease has been associated with serious complications. The good news is that patients with PTLDS almost always get better with time; the bad news is that it can take months to feel completely well.
If you have been treated for Lyme disease and still feel unwell, see your doctor to discuss how to relieve your suffering. Your doctor may want to treat you in ways similar to patients who have fibromyalgia or chronic fatigue syndrome. This does not mean that your doctor is dismissing your pain or saying that you have these conditions. It simply means that the doctor is trying to help you cope with your symptoms using the best tools available.
The CDC does state that there continues to be research into PTLDS. This is normal, and it doesn’t indicate that the CDC believes that CLD or PTLDS exists, it just wants to find out what may be the causes, beyond the thoroughly debunked chronic infection.
The CDC does state that many bacterial infections have lingering symptoms past the original infection. That’s science, but it does not support the chronic Lyme disease myth – in fact, it dismisses it.
Finally, the CDC states, about as emphatically as I’ve ever seen it state, that “prolonged courses of antibiotics” do not help. They’re no better than placebos.
One article that supports the existence of CLD
A paper, often cited by the CLD activists, from Embers et al. and published in PLoS One in 2012, examined the persistence of B. burgdorferi infection in Rhesus macaques after antibiotic therapy for 4-6 months. They claimed that B. burgdorferi infection developed some resistance to antibiotics, and persists in the body. These would seem to support the claims of those who advocate for the existence of chronic Lyme disease. But there are a number of problematic issues with this study.
GP Wormser et al. wrote a critical review of the PLoS One article, focusing on these points:
- None of the Rhesus macaques were described as having objective clinical manifestations of infection (such as erythema migrans, neurologic dysfunction, or arthritis), either during or after treatment. Therefore, there was no objective assessment of antibiotic efficacy, and it’s difficult to conclude whether the persistence of the B. burgdorferi infection is due to some resistance to the antibiotics or ineffective treatment.
- In the study that compared antibiotic and placebo-treated monkeys for the persistence of B. burgdorferi infection used “IFA, a procedure which in tissues is highly subjective and poorly reproducible.” In other words, IFA is not the best way to determine persistent infection.
- The study only included 17 animals, a very small number to make any statistical claims.
- Embers et al. could not subculture the spirochetes that may indicate B. burgdorferi infection. This means that the possible persistent infection did not include viable bacteria, which would put the results in question.
- Embers et al. inoculated the subject animals with several injections of the bacteria, which does not parallel real-world infections. Extending this to naturally occurring B. burgdorferi infections in humans is problematic.
- The most important point is that the infection of Rhesus macaques is difficult to extrapolate to humans, especially when the other issues listed above are included. Finally, this research contradicts all of the high-quality research done in humans over the past 15 years. Again, we have no evidence of a persistent and chronic Lyme disease in humans. None. If someone presents an animal model that contradicts the vast body of literature, we need more evidence than a animal model.
One more thing – there have been 69 published articles that mention Embers et al., and none of them repeated the Rhesus study. None. So, in the six years since Embers et al. was published, we have no repeated experiments, with improvements that were suggested above, that might show us an important new piece of evidence in chronic Lyme disease.
Summary, the TL;DR version
Many public health and infectious disease specialists, using evidence published in the best journals, are troubled by the claims made about these chronic Lyme disease myths – they are being pushed by charlatans who have less than honorable intentions for these patients.
The Johns Hopkins group stated rather harshly, “the relations and actions of some activists, medical practitioners, and commercial bodies involved in Lyme disease advocacy pose a threat to public health.”
Furthermore, the one group that almost always looks for ways to prevent paying out long-term medical costs, the health insurance industry, refuses to pay for treatment of chronic Lyme disease (pdf). You might believe it’s because they want to save money from paying for these treatments, but since they state that “CLD does not exist”, those treatments are useless, like paying for homeopathy or acupuncture. They’d rather have the physician find the real diagnosis, and treat that.
There is no evidence that chronic Lyme disease exists. Real research says so. The CDC says so. The best research says so. There is no evidence that long-term antibiotic therapy does anything for those who have the symptoms associated with the nonexistent chronic Lyme disease.
To be fair, there are some articles, always published in low-quality journals, that try to argue, without scientific evidence, that CLD is real. However, unless evidence is published in strong, peer-reviewed publications that support the existence (and subsequent treatment methods) for this disease, then standard treatment of Lyme disease should be considered the gold standard.
There is no chronic Lyme disease. And we should quit wasting money trying to treat a nonexistent disease.
Editor’s note: This article was originally published in March 2017 based on a previous version of this article that was published in 2015. It has been extensively revised and updated to include more comprehensive information, fix broken links, do some copyediting, and add current research.
- Auwaerter PG, Bakken JS, Dattwyler RJ, Dumler JS, Halperin JJ, McSweegan E, Nadelman RB, O’Connell S, Shapiro ED, Sood SK, Steere AC, Weinstein A, Wormser GP. Antiscience and ethical concerns associated with advocacy of Lyme disease. Lancet Infect Dis. 2011 Sep;11(9):713-9. PubMed PMID: 21867956.
- Bratton RL, Whiteside JW, Hovan MJ, Engle RL, Edwards FD. Diagnosis and treatment of Lyme disease. Mayo Clin Proc. 2008 May;83(5):566-71. Review. PubMed PMID: 18452688.
- Cooper JD, Feder HM Jr. Inaccurate information about lyme disease on the internet. Pediatr Infect Dis J. 2004 Dec;23(12):1105-8. PubMed PMID: 15626946.
- Embers ME, Barthold SW, Borda JT, Bowers L, Doyle L, Hodzic E, Jacobs MB, Hasenkampf NR, Martin DS, Narasimhan S, Phillippi-Falkenstein KM, Purcell JE, Ratterree MS, Philipp MT. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS One. 2012;7(1):e29914. doi: 10.1371/journal.pone.0029914. Erratum in: PLoS One. 2013;8(9). doi:10.1371/annotation/f84663e3-0a2c-4243-8f97-3a58133c1b0f. PLoS One. 2012;7(4):10.1371/annotation/4cafed66-fb84-4589-a001-131d9c50aea6. PubMed PMID: 22253822; PubMed Central PMCID: PMC3256191.
- Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, Nelson DR, Sackeim HA. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008 Mar 25;70(13):992-1003. Epub 2007 Oct 10. PubMed PMID: 17928580.
- Feder HM Jr, Johnson BJ, O’Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc International Lyme Disease Group., Agger WA, Artsob H, Auwaerter P, Dumler JS, Bakken JS, Bockenstedt LK, Green J, Dattwyler RJ, Munoz J, Nadelman RB, Schwartz I, Draper T, McSweegan E, Halperin JJ, Klempner MS, Krause PJ, Mead P, Morshed M, Porwancher R, Radolf JD, Smith RP Jr, Sood S, Weinstein A, Wong SJ, Zemel L. A critical appraisal of “chronic Lyme disease”. N Engl J Med. 2007 Oct 4;357(14):1422-30. Review. Erratum in: N Engl J Med. 2008 Mar 6;358(10):1084. PubMed PMID: 17914043.
- Fell E. An update on Lyme disease and other tick-borne illnesses. Nurse Pract. 2000 Oct;25(10):38-40, 43-4, 47-8 passim; quiz 56-7. Review. PubMed PMID: 11068777.
- Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M, Weinstein A. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001 Jul 12;345(2):85-92. PubMed PMID: 11450676.
- Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler R, Chandler B. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003 Jun 24;60(12):1923-30. PubMed PMID: 12821734.
- Lantos PM. Chronic Lyme disease: the controversies and the science. Expert Rev Anti Infect Ther. 2011 Jul;9(7):787-97. PubMed PMID: 21810051.
- Lantos PM, Auwaerter PG, Wormser GP. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin Infect Dis. 2014 Mar;58(5):663-71. doi: 10.1093/cid/cit810. Review. PubMed PMID: 24336823; PubMed Central PMCID: PMC3922218.
- Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010 Jan;10(1):13-20. Review. PubMed PMID: 20425509.
- McClellan L. Chronic Lyme disease: it’s time to solve the medical mystery inside an enigma. Health Aff (Millwood). 2012 Mar;31(3):647-9. PubMed PMID: 22392677.
- Nadelman RB, Hanincová K, Mukherjee P, Liveris D, Nowakowski J, McKenna D, Brisson D, Cooper D, Bittker S, Madison G, Holmgren D, Schwartz I, Wormser GP. Differentiation of reinfection from relapse in recurrent lyme disease. N Engl J Med. 2012 Nov 15;367(20):1883-90. doi: 10.1056/NEJMoa1114362. PubMed PMID: 23150958.
- Shapiro ED. Clinical practice. Lyme disease. N Engl J Med. 2014 May 1;370(18):1724-31. doi: 10.1056/NEJMcp1314325. Review. PubMed PMID: 24785207; PubMed Central PMCID: PMC4487875.
- Wormser GP, Baker PJ, O’Connell S, Pachner AR, Schwartz I, Shapiro ED. Critical analysis of treatment trials of rhesus macaques infected with Borrelia burgdorferi reveals important flaws in experimental design. Vector Borne Zoonotic Dis. 2012 Jul;12(7):535-8. doi: 10.1089/vbz.2012.1012. Review. PubMed PMID: 22620495; PubMed Central PMCID: PMC3398392.