Introduction
Background
Lyme disease is a systemic infection caused by the spirochete Borrelia burgdorferi.1 The bacteria are inoculated into the skin by a tick bite, nearly always from hard-bodied ticks of the genus Ixodes.
The original descriptions of the dermatologic manifestations of Lyme disease date back to 1883 in Europe, when a German physician, Alfred Buchwald, described what is now termed acrodermatitis chronica atrophicans (ACA). Several decades later in 1912, a Swedish dermatologist, Arvid Afzelius, described erythema chronicum migrans (ECM), which currently is referred to simply as erythema migrans (EM).
It was not until 1975, when a statistically improbable cluster of childhood arthritis occurred in and around the town of Lyme, Connecticut, that the full spectrum of the disease began to be elucidated. This outbreak stimulated intense clinical and epidemiologic research that led to the discovery of the causative agent and its ecology and an expanding geographic range and list of clinical manifestations. In addition, the initial antibiotic responsiveness of the cutaneous manifestations that had been described in the 1950s in the European literature was confirmed, and the findings were extended.
In 1998, the US Food and Drug Administration (FDA) approved a protective vaccine, but the manufacturer pulled it from the market a few years later.
Other eMedicine articles offer different specific foci, including Lyme Disease (Neurology), Lyme Disease (Ophthalmology), Lyme Disease (Pediatrics), and Lyme Disease (Rheumatology).
 | Clinical Image Atlas Click to view clinical images on the features, causes, epidemiology, diagnosis, and treatment of Lyme disease. |
Pathophysiology
The pathophysiology of Lyme disease is incompletely understood. Many of its manifestations are caused by active infection by the spirochete; others may be driven by immunopathogenetic mechanisms. While any part of the body can be affected, the organism shows a distinct tropism for the skin, heart, central nervous system (CNS), joints, and eyes.
The bacteria are introduced into the skin by a bite from an infected Ixodes tick. In the northeastern and upper midwestern United States, Ixodes scapularis (sometimes termed Ixodes dammini) is the vector. In the northwestern United States, Ixodes pacificus is the vector. In other parts of the world, other Ixodes ticks serve this function. Other tick species (eg, Amblyomma americanum) and insects can carry B burgdorferi, but the vast majority of cases are believed to be caused by bites by Ixodes ticks. Note that in the southern and midcentral United States, a Lyme-like disease has been reported for which the vector appears to be A americanum.
Patients with erythema migrans from Missouri and those from New York have different clinical and microbiological aspects of the disease. B burgdorferi has not been isolated from the southern patients, although a closely related spirochete is suspected to be involved. Although some cases from the southern United States are documented with this new spirochete, called Borrelia lonestari, no organism can be isolated in the vast majority of cases of erythema migrans in this geographical area.2,3
Once in the skin, the spirochete can be overwhelmed and eliminated by host defense mechanisms, can remain viable but localized at the site of inoculation, or may disseminate via blood and lymphatics. Hematogenous dissemination can occur within days or weeks of the initial infection. The organism can travel to other parts of the skin, the heart, joints, the CNS, and other parts of the body.
Early studies showed that in roughly 10% of patients with isolated erythema migrans and no systemic symptoms, B burgdorferi or its DNA, can be detected in the bloodstream. In addition, early in the course of disease and while erythema migrans still is present, spirochetal DNA has been detected in cerebrospinal fluid, indicating early CNS penetration. This can occur even in the absence of neurologic symptoms.
Importantly, one 2005 study found that if large-volume cultures (9 mL of plasma) were performed in early presenting patients with erythema migrans, 93 (43.7%) of 213 had spirochetemia. Some of these patients had only isolated erythema migrans and no systemic symptoms.4
The organism also can persist in the skin for very long periods of time. Experimentally, the spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone at concentrations well above bacteriocidal levels. While intracellular organisms have never been demonstrated in vivo, this may be one mechanism by which the organism eludes host defense mechanisms. Clinically, B burgdorferi has been cultured from skin lesions of patients with acrodermatitis chronica atrophicans 10 years after initial infection.
Because people who engage in activities that put them in risk for tick bites tend to continue those activities, reinfection is not uncommon. Patients who have had prior erythema migrans can be reinfected (meaning that the first infection has been successfully treated and they have a new infection with B burgdorferi). This has been clearly demonstrated in reinfected patients who were culture positive and had different serotypes isolated in the first and second infections. Reinfection shows similar manifestations as first infections, although a tendency towards less hematogenous spread is noted. In contrast, relapse (as opposed to reinfection) is very unusual in patients who have been treated with appropriate antimicrobials.5
Similar to syphilis, Lyme disease classically has been divided into stages; however, in individual patients, no rigid cutoffs exist between stages.
- Early localized Lyme disease refers to isolated erythema migrans and patients who present with an undifferentiated febrile illness.
- Early disseminated disease refers to the secondary (usually hematogenously spread) skin lesions and to the extracutaneous manifestations that occur during the initial weeks to months of infection. The more common of these include lymphocytic meningitis, cranial neuropathy (usually of the seventh nerve), radiculoneuritis (more common in Europe), and carditis (often with fluctuating degrees of arteriovenous block). Borrelial lymphocytoma (BL) usually occurs during this stage (see Media File 6).
- Late Lyme disease refers to manifestations, primarily rheumatologic and neurologic, that occur months to years after initial infection. Acrodermatitis chronica atrophicans develops during this phase.
Borrelial lymphocytoma of the earlobe, which shows a bluish red discoloration. The location is typical in children, as opposed to the nipple in adults. This manifestation of Lyme disease is uncommon and occurs only in Europe. Courtesy of Lyme Disease Foundation, Hartford, Conn.
The last important phenomenon to appreciate is co-infection by other organisms transmitted by the same tick bite. Co-infection by ehrlichial species and Babesia microti are reported with increased frequency; in some studies, in as many as 10-15% of patients with Lyme disease. When Lyme disease is strongly suggested but some of the manifestations are atypical, these other tick-borne infections must be considered.
Frequency
United States
The US Centers for Disease Control and Prevention (CDC) track cases of Lyme disease by using strict surveillance criteria (not designed for diagnosis of individual cases). The incidence has been increasing over time. This is not simply a result of increased recognition, since in states that perform active surveillance, true incidence and geographic range have increased. The likely causes of this increase are expansion of deer herds and the expanded range of the vector.
- From 1992-2006, approximately a quarter million cases of Lyme disease have been reported to the CDC; 70% of cases are of erythema migrans, although it is possible that cases of erythema migrans are less commonly reported than those patients with later manifestations. Over that period, the incidence has roughly doubled. Although year-to-year variation is significant, approximately 20,000 cases are reported annually in the United States. More than 95% of cases come from 12 states (Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin). Within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.6
- Overall in the United States, the prevalence is 6.0-8.2 cases per 100,000 population (2001 and 2002 data). However, in Connecticut in 2001, the rate was nearly 134 cases per 100,000 population, and, on the island of Nantucket, Massachusetts, the rate exceeds 1000 cases per 100,000 population. In other states such as Colorado or Montana, it is nearly nonexistent.
- Epidemiologic data suggest that the actual incidence of Lyme disease could be as much as 10 times higher than the CDC data indicate. This probably is a result of a restrictive case definition from the CDC, inevitable misdiagnosis, and the fact that physicians tend to underreport reportable diseases of all kinds.
- Borrelial lymphocytoma has not been described in North America. Only a handful of cases of acrodermatitis chronica atrophicans have been reported in North American patients.
International
Lyme disease exists throughout much of the world including Scandinavia, Central Europe, Southern Europe, and Western Europe, the former Soviet Union, Japan, and China. Occasionally, cases are reported in more tropical locales, and Lyme diseases may exist in Australia. The ecology of Lyme disease differs in various parts of the world. In addition, different strains of the organism exist in Europe that account for differences in clinical manifestations and have implications for diagnostic testing and vaccine strategies. Even in Europe, borrelial lymphocytoma occurs only in approximately 1% patients with Lyme disease, and acrodermatitis chronica atrophicans occurs in 10%.
Mortality/Morbidity
Only extremely rarely does Lyme disease in and of itself result in a clear-cut fatality. Many of these fatalities have been in patients co-infected with other tick-borne pathogens such as Ehrlichia species and B microti, and in Europe, tick-borne encephalitis.
Morbidity usually is neurologic and rheumatic. Patients with neurologic disease who are not diagnosed and treated promptly can suffer from neurologic and cognitive dysfunction that can be difficult to treat. Some patients may have fixed neurologic deficits that are unresponsive to antibiotics. Patients with cardiac disease rarely exhibit chronic morbidity from their heart involvement. Similarly, some genetically predisposed individuals with arthritis may have ongoing joint inflammation that is not responsive to further antibiotic therapy.
Race
Lyme disease occurs in individuals of all races; however, it is diagnosed much more frequently in whites. No genetic explanation is known for this, and likely, the frequency stems from social or environmental factors (ie, whites have a higher exposure rate to ticks than do other races) and possibly to the fact that erythema migrans is more difficult to diagnose in dark-skinned individuals.
Sex
No strong preponderance of Lyme disease is noted in either sex. Risk is a function of tick exposure rather than any intrinsic difference in susceptibility.
Age
Epidemiologically, a bimodal peak in incidence of Lyme disease is seen; 1 peak occurs in patients aged 5-14 years, and the other occurs in patients aged 30-49 years. Roughly 25% of cases occur in children younger than 14 years (see Media File 8).
A toddler with erythema migrans on the right thigh. The size and location are typical of erythema migrans, as is the history of the patient vacationing on Fire Island, NY in August. No tick bite had been noted at this location. Approximately 25% of patients with Lyme disease are children, which is the same percentage of patients who do not recall a tick bite. Courtesy of Dr John Hanrahan.
The likelihood of contracting Lyme disease is related primarily to exposure to ticks, not to age, sex, or race. Therefore, the epidemiology is very important. Ascertaining where patients live, work, or vacation and what kind of activities they pursue in those locations is an important part of the history.
Age has some effect on the location of borrelial lymphocytoma, since children tend to develop lesions on the ears, while adults develop lesions on the nipples. Acrodermatitis tends to occur more commonly in older patients.
Clinical
History
- Epidemiologic context is extremely important. Since only approximately 25-30% of patients with early Lyme disease recall the tick bite, the history must be directed by the clinician towards the possibility of a tick bite.
- Determining where the patient lives, works, and vacations is important, as is asking about specific activities in which the patient participates at those locales. The likelihood of Lyme disease increases as the probability of a tick bite increases in a geographically endemic area.
- The season is important, especially in patients with early disease. Most cases of erythema migrans occurs from May through September because the nymphal stage of the tick is responsible for most cases.
- For patients presenting with later cutaneous manifestations, especially acrodermatitis chronica atrophicans, questions must be directed at assessing the risk of tick bite (or prior manifestations of Lyme disease) from many years in the past.
- Systemic manifestations are as follows:
- Some patients with erythema migrans have low-grade fever. A high fever, especially if accompanied by rigors or a toxic appearance, suggests coinfection with other tick-borne pathogens such as ehrlichial species or B microti, or it suggests an alternative diagnosis.
- Patients with early Lyme disease can present with a flulike illness (nonspecific febrile illness), although a paucity of respiratory and gastrointestinal tract symptoms may be present. Another diagnostic clue is prompt resolution using antiborrelial therapy.
- Fatigue, headache, myalgias, and arthralgias also may be seen in patients presenting early. Frank arthritis with objective joint swelling, redness, and pain is usually a later manifestation but can occur in the early disseminated phase.
- All systemic symptoms may occur in patients with erythema migrans.
- In patients with later cutaneous manifestations of Lyme disease, borrelial lymphocytoma, and acrodermatitis chronica atrophicans, other manifestations of the disease may coexist or may have occurred in the past. Thus, a history of Bell palsy, aseptic meningitis, arthritis, acral paresthesias or dysesthesias (from peripheral neuropathy), or cognitive dysfunction (from CNS involvement) may be diagnostically useful.
- Patients with borrelial lymphocytoma report a bluish red nodular swelling that is almost always on the lobe of the ear or the areola of the nipple. This symptom can occur in both the early disseminated and the late phases of Lyme disease and is seen exclusively in European patients.
- Children usually have lesions on the earlobe, while adults, both men and women, most commonly have lesions on the breast. Occasionally, borrelial lymphocytoma lesions occur on the scrotum, nose, and extremities. Nipple lesions tend to be painful, possibly because of rubbing against clothing.
- Erythema migrans may occur simultaneously with borrelial lymphocytoma, which indicates that borrelial lymphocytoma can occur very early in the disease course.
- Patients with acrodermatitis chronica atrophicans report a rash that is acral in distribution. Initially, discoloration and inflammation of the skin are seen, and later, severe atrophy is noted.
- Acrodermatitis chronica atrophicans tends to occur more commonly in females, especially older patients. Unlike erythema migrans, acrodermatitis chronica atrophicans tends to occur acrally, especially on the dorsal surfaces of the hands, feet, knees, and elbows. Early on, a minimally symptomatic erythema tends to occur in these locations.
- Progression is gradual, over months to years, from the inflammatory stage to a later atrophic stage. The latter stage is marked by a tendency towards central progression of the lesions, and more than 1 extremity may become involved. Eventually, subcutaneous fat is lost, and the skin becomes thin and wrinkled, similar to cigarette paper (see Media File 7).
- Some patients also report hypesthesia or dysesthesias characteristic of a polyneuropathy.
Acrodermatitis chronica atrophicans is found almost exclusively in European patients and comprises an early inflammatory phase and a later atrophic phase (see Media File 8). As the term suggests, the lesion occurs acrally and ultimately results in skin described as being like cigarette paper. Courtesy of Lyme Disease Foundation, Hartford, Conn.
Physical
In many patients with early Lyme disease, physical examination alone is sufficient to establish the diagnosis of erythema migrans. Careful attention to the details often makes the difference between the need to proceed with further confirmatory tests and an empiric course of antibiotics. In particular, the examination must be interpreted in the epidemiologic context; this cannot be overemphasized. The season, geography, and a patient's activities in those areas can be important diagnostic clues.
Woman with erythema migrans who presented to the emergency department after treatment with cephalexin for 2 days, which was prescribed by another physician for treatment of cellulitis. On history, she was found to live in an endemic area for ticks and to pull ticks off her dog daily. The location and size of the rash are typical of erythema migrans and the central punctum can be seen at the lateral margin of the inferior gluteal fold. The uniform color is common.
- A low-grade fever is not uncommon. High fever suggests another co-infecting tick-borne organism such as Ehrlichia or Babesia species or some other diagnosis altogether such as streptococcal cellulitis.
- Classic erythema migrans begins as an erythematous macule or papule at the site of the tick bite (within 1-33 d; median is 7-10 d).7 Vesicles may be present. Often a central punctum is seen at the site of the bite. The eruption gradually expands over days to weeks (not hours or months), sometimes leaving central clearing. Note that this phenomenon, which has been termed a bull's-eye or target lesion (see Media File 4) and was emphasized in the earlier literature, occurs only in a minority of patients (37% in one North American study). Central clearing and a more chronic course are more common in Europe, which accounts for the original European term erythema chronicum migrans.
Classic target lesion with concentric rings of erythema, which often show central clearing. Although this morphology was emphasized in earlier North American literature, it only represents approximately 40% of erythema migrans lesions in the United States. This pattern is more common in Europe. Courtesy of Lyme Disease Foundation, Hartford, Conn.
- Rashes very similar to erythema migrans have been reported in the southern United States from which B burgdorferi cannot be cultured. This disease is called southern tick-associated rash illness (STARI), or Master disease. As a group, distinctions can be made between classic erythema migrans and this illness, but significant overlaps exist such that the differences are not useful in diagnosing individual patients.
- A number of important details are diagnostically useful.
- Size: Erythema migrans varies in size (lesions are up to 70 cm; median is 16 cm). Some of the differential diagnoses (eg, bacterial cellulitis) become more unlikely with larger lesions, especially in a patient who does not appear ill. Although the CDC surveillance criteria for erythema migrans state that it must be greater than 5 cm in size, culture-proven cases have been occasionally documented that are smaller,8 and this size cut-off is only meant to be used for epidemiological purposes.
- Shape: Erythema migrans typically is round or oval and monocyclic. Occasionally, lesions can be triangular or linear, but this is seen less frequently.
- Associated symptoms: A paucity of pain or pruritus exists in most patients. When present, these localized symptoms tend to be mild. Associated systemic symptoms include low-grade fever, chills, fatigue, and neck stiffness. Very high fever or toxicity suggests an alternative diagnosis or an additional tick-borne infection such as babesiosis or ehrlichiosis.
- Location: Location of the bite is an important diagnostic clue. Ticks tend to feed in areas in which natural barriers prevent their forward progress, such as the popliteal fossa, groin, and axilla, or in areas in which elastic clothing or bra straps impede their journey. The thorax and trunk also are common spots. In children, the hairline and scalp are especially common locations.
- Evolution: Erythema migrans usually enlarges by a few centimeters per day and eventually fades within a few weeks, even without antibiotic treatment. Occasionally, the rash can be fleeting. Erythema migrans does not enlarge over hours, and it very rarely remains constant over weeks to months.
- Color and morphology: Most lesions are red (see Media File 10). While central clearing has been emphasized in the past, the color of the lesion more commonly is uniform. Occasionally, the center is darker than the periphery. Lesions usually are flat but may be slightly raised (see Media File 3). Scaling does not usually occur. In some patients mistakenly treated with topical steroids, the rash may be quite pale.
In this patient, the rash on the ankle is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (July presentation in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin and clavulanate combination) is one effective strategy.
Patient who had pulled a tick from the left side of his neck 7 days previously. Note the raised vesicular center, which is a variant of erythema migrans. The patient had a Jarisch-Herxheimer reaction approximately 18 hours after the first dose of doxycycline.
- Other: Central clearing is more common in European patients with erythema migrans than in North American patients. Thus, while most lesions are flat erythemas, several variations are important to recognize, in particular, vesicular and centrally necrotic lesions.
- Regional lymphadenopathy may be seen.
- Early disseminated erythema migrans (multiple erythema migrans): Multiple erythema migrans lesions occur in approximately 20% of patients. Secondary lesions tend to be more uniform in morphology than the primary lesion. Necrosis and vesicles do not occur, nor does a central punctum. Since they are spread hematogenously, the locations of secondary lesions are not as restricted as in the primary lesion (see Media File 9).
Multiple lesions of erythema migrans occur in approximately 20% of patients. This patient, a carpenter from Nantucket who worked predominantly outside, had been treated with Lotrisone for 1 week prior to presenting to the emergency department with this rash. The patient had no fever and only mild systemic symptoms. He was treated with a 3-week course of oral antibiotics.
- Borrelial lymphocytoma usually occur on the earlobe or nipple, and the lesions are bluish-red nodules. The earlobe is the typical location in children (as is the scrotum), while the nipple location is more commonly seen in adults. Borrelial lymphocytoma tends to occur in areas of prior (or concurrent erythema migrans). The size is up to a few centimeters. Regional lymphadenopathy may be present (see Media File 2). Borrelial lymphocytoma is a form of B-cell pseudolymphoma. Other terms used to describe borrelial lymphocytoma include lymphadenosis benigna cutis, lymphocytoma cutis, cutaneous lymphoid hyperplasia, and Spiegler-Fendt lymphoid hyperplasia.
Young man who had been working outdoors in northern New Jersey in late June. He was under treatment for a spider bite, although he did not have a history of a bite and had no pain, as is typical in a spider bite. The location, size, and epidemiologic context favor a diagnosis of erythema migrans. Examination was remarkable for a palpable right axillary lymph node. His symptoms resolved within 48 hours of initiating doxycycline.
- Acrodermatitis chronica atrophicans begins as an inflammatory phase marked by edema and erythema, usually on the distal extremities. At times, a faint bluish discoloration is found predominantly on extensor surfaces. The lesions have a predilection for the posterior heels and dorsal (extensor) surfaces of the hands, feet, elbows, and knees.
- Gradually, a central progression of the area involved occurs over months to years. The lesions also tend to become symmetric. The buttocks often become involved.
- Later, atrophy supervenes and thin cigarette-paper skin is seen. Because of the loss of subcutaneous fat, underlying venous structures are more visible, and the skin becomes thin, atrophic, and dry.
- Fibrous juxtaarticular nodules or bands may be seen on the extensor surfaces of the elbows and knees.
- Signs of peripheral neuropathy may coexist with acrodermatitis chronica atrophicans.
- Other skin lesions have been associated with B burgdorferi infection, but whether they are part of the syndrome of Lyme disease is controversial. The lesion for which the most evidence of causality has been reported is morphea (localized scleroderma), which develops in roughly 10% of European patients with borrelial lymphocytoma and acrodermatitis chronica atrophicans. B burgdorferi has been isolated from these lesions but not from North American patients with morphea. Other European reports less commonly link lichen sclerosis et atrophicans, progressive facial hemiatrophy (Parry-Romberg syndrome), and eosinophilic fasciitis with B burgdorferi infection.
Borrelial lymphocytoma of the earlobe, which shows a bluish red discoloration. The location is typical in children, as opposed to the nipple in adults. This manifestation of Lyme disease is uncommon and occurs only in Europe. Courtesy of Lyme Disease Foundation, Hartford, Conn.
Causes
- The cause of Lyme disease is infection by the spirochete, B burgdorferi. This organism, whose complete genome was described in 1998, has several distinct genetic groupings; as well, there is evidence that additional strains or closely related Borrelia species also exist.
- The generic species is B burgdorferi (eg, sensu lato). Within this species exists several well-characterized groupings that account for the different clinical manifestations seen in North America and Europe. Three groups are well established, including B burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. Many other strains exist, but most are not pathogenic to humans. This is an area of active and constantly evolving research.
- B burgdorferi sensu stricto is the strain that constitutes all North American isolates and is found in Europe as well. In European erythema migrans, B afzelii can be isolated from about 80% of lesions and B garinii from 15%.9
- B garinii, found exclusively in Europe, has some neurotropism and is the isolate that accounts for most cases of the neurologic syndrome lymphocytic meningoradiculitis (Bannwarth syndrome) and a white matter encephalitis, which is rare in North America. However, this organism does cause all the various cutaneous manifestations described above.
- Although B afzelii is the most common organism causing acrodermatitis chronica atrophicans, all 3 groups have been isolated from these patients.
- The primary risk factor for developing cutaneous manifestations of Lyme disease is exposure to Ixodes ticks.
More on Lyme Disease |
 Overview: Lyme Disease |
| Differential Diagnoses & Workup: Lyme Disease |
| Treatment & Medication: Lyme Disease |
| Follow-up: Lyme Disease |
| Multimedia: Lyme Disease |
| References |
| Further Reading |
| Next Page » |
References
Feder HM Jr. Lyme disease in children. Infect Dis Clin North Am. Jun 2008;22(2):315-26, vii. [Medline].
Masters EJ, Grigery CN, Masters RW. STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Infect Dis Clin North Am. Jun 2008;22(2):361-76, viii. [Medline].
Varela AS, Luttrell MP, Howerth EW, et al. First culture isolation of Borrelia lonestari, putative agent of southern tick-associated rash illness. J Clin Microbiol. Mar 2004;42(3):1163-9. [Medline].
Wormser GP, McKenna D, Carlin J, et al. Brief communication: hematogenous dissemination in early Lyme disease. Ann Intern Med. May 3 2005;142(9):751-5. [Medline].
Wormser GP, Brisson D, Liveris D, et al. Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. J Infect Dis. Nov 1 2008;198(9):1358-64. [Medline].
Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease--United States, 1992-2006. MMWR Surveill Summ. Oct 3 2008;57(10):1-9. [Medline].
Dandache P, Nadelman RB. Erythema migrans. Infect Dis Clin North Am. Jun 2008;22(2):235-60, vi. [Medline].
Weber K, Wilske B. Mini erythema migrans--a sign of early Lyme borreliosis. Dermatology. 2006;212(2):113-6. [Medline].
Stanek G, Strle F. Lyme disease: European perspective. Infect Dis Clin North Am. Jun 2008;22(2):327-39, vii. [Medline].
Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for lyme disease. Clin Infect Dis. Jul 15 2008;47(2):188-95. [Medline].
Aguero-Rosenfeld ME. Lyme disease: laboratory issues. Infect Dis Clin North Am. Jun 2008;22(2):301-13, vii. [Medline].
Johnson L, Stricker RB. Attorney General forces Infectious Diseases Society of America to redo Lyme guidelines due to flawed development process. J Med Ethics. May 2009;35(5):283-8. [Medline].
Stricker RB, Johnson L. Chronic Lyme disease and the 'Axis of Evil'. Future Microbiol. Dec 2008;3(6):621-4. [Medline].
Kemperman MM, Bakken JS, Kravitz GR. Dispelling the chronic Lyme disease myth. Minn Med. Jul 2008;91(7):37-41. [Medline].
Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am. Jun 2008;22(2):341-60, vii-viii. [Medline].
Baker PJ. Perspectives on "chronic Lyme disease". Am J Med. Jul 2008;121(7):562-4. [Medline].
Hassett AL, Radvanski DC, Buyske S, et al. Role of psychiatric comorbidity in chronic Lyme disease. Arthritis Rheum. Dec 15 2008;59(12):1742-9. [Medline].
Cameron DJ. Clinical trials validate the severity of persistent Lyme disease symptoms. Med Hypotheses. Feb 2009;72(2):153-6. [Medline].
Cameron DJ. Insufficient evidence to deny antibiotic treatment to chronic Lyme disease patients. Med Hypotheses. Jun 2009;72(6):688-91. [Medline].
Nau R, Christen HJ, Eiffert H. Lyme disease--current state of knowledge. Dtsch Arztebl Int. Jan 2009;106(5):72-81; quiz 82, I. [Medline].
Maraspin V, Cimperman J, Lotric-Furlan S, Pleterski-Rigler D, Strle F. Treatment of erythema migrans in pregnancy. Clin Infect Dis. May 1996;22(5):788-93. [Medline].
Aberer E, Breier F, Stanek G, Schmidt B. Success and failure in the treatment of acrodermatitis chronica atrophicans. Infection. Jan-Feb 1996;24(1):85-7. [Medline].
Sood SK, Salzman MB, Johnson BJ, et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. Apr 1997;175(4):996-9. [Medline].
Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. Jul 12 2001;345(2):79-84. [Medline].
Nardelli DT, Munson EL, Callister SM, Schell RF. Human Lyme disease vaccines: past and future concerns. Future Microbiol. May 2009;4(4):457-69. [Medline].
Demicheli V, Debalini MG, Rivetti A. Vaccines for preventing tick-borne encephalitis. Cochrane Database Syst Rev. Jan 21 2009;CD000977. [Medline].
[Guideline] Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jul 3 2007;69(1):91-102. [Medline].
[Guideline] Cameron D, Gaito A, Harris N, et al. Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther. 2004;2(1 Suppl):S1-13. [Medline].
[Guideline] Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. Nov 1 2006;43(9):1089-134. [Medline].
Dattwyler RJ, Luft BJ, Kunkel MJ, et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med. Jul 31 1997;337(5):289-94. [Medline].
Edlow JA. Bull's Eye - unraveling the medical mystery of Lyme disease. 2nd edition (paperback). Yale University Press; 2004.
Edlow, JA. Erythema migrans. Medical Clinics of North America. 2002;86(2):239-260.
Feder HM Jr, Hunt MS. Pitfalls in the diagnosis and treatment of Lyme disease in children. JAMA. Jul 5 1995;274(1):66-8. [Medline].
Feder HM Jr, Whitaker DL. Misdiagnosis of erythema migrans. Am J Med. Oct 1995;99(4):412-9. [Medline].
Kirkland KB, Klimko TB, Meriwether RA, et al. Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease?. Arch Intern Med. Dec 8-22 1997;157(22):2635-41. [Medline].
Malane MS, Grant-Kels JM, Feder HM Jr, Luger SW. Diagnosis of Lyme disease based on dermatologic manifestations. Ann Intern Med. Mar 15 1991;114(6):490-8. [Medline].
Nadelman RB, Nowakowski J, Forseter G, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med. May 1996;100(5):502-8. [Medline].
Nadelman RB, Wormser GP. Lyme borreliosis. Lancet. Aug 15 1998;352(9127):557-65. [Medline].
Steere AC. Lyme disease. N Engl J Med. Jul 12 2001;345(2):115-25. [Medline].
Strle F, Maraspin V, Pleterski-Rigler D, et al. Treatment of borrelial lymphocytoma. Infection. Jan-Feb 1996;24(1):80-4. [Medline].
Strle F, Nadelman RB, Cimperman J, et al. Comparison of culture-confirmed erythema migrans caused by Borrelia burgdorferi sensu stricto in New York State and by Borrelia afzelii in Slovenia. Ann Intern Med. Jan 5 1999;130(1):32-6. [Medline].
Strle F, Pleterski-Rigler D, Stanek G, Pejovnik-Pustinek A, Ruzic E, Cimperman J. Solitary borrelial lymphocytoma: report of 36 cases. Infection. Jul-Aug 1992;20(4):201-6. [Medline].
Tibbles CD, Edlow JA. Does this patient have erythema migrans?. JAMA. Jun 20 2007;297(23):2617-27. [Medline].
Wormser GP. Clinical practice. Early Lyme disease. N Engl J Med. Jun 29 2006;354(26):2794-801. [Medline].
Wormser GP, Masters E, Nowakowski J, et al. Prospective clinical evaluation of patients from Missouri and New York with erythema migrans-like skin lesions. Clin Infect Dis. Oct 1 2005;41(7):958-65. [Medline].
Further Reading
Clinical guideline summaries
- Practice parameter: treatment of nervous system Lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology 27
- Evidence-based guidelines for the management of Lyme disease 28
- Infectious Diseases Society of America practice guidelines for clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis 29
Keywords
Lyme disease, erythema migrans, erythema chronicum migrans, borrelial lymphocytoma, acrodermatitis chronica atrophicans, tick,
