AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Lyme disease is a systemic infection caused by the spirochete Borrelia burgdorferi. 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.

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 EM 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. At least one culture-positive case has been documented with this new spirochete, called Borrelia lonestari.

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 EM 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 EM 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 EM, 93 (43.7%) of 213 had spirochetemia. Some of these patients had only isolated EM and no systemic symptoms.

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 ACA 10 years after initial infection.

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 EM and patients who present with an undifferentiated febrile illness.
• Early disseminated disease refers to the secondary (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. ACA develops during this phase.

Note that while many patients present with EM, others first present with extracutaneous symptoms, either because EM never occurred or because it was not recognized by the patient or correctly diagnosed by the physician.

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.

• In 2001, the CDC reported 17,029 cases. In 2002, that number rose to 23,763 (40% increase). Year-to-year variation can be significant. 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). Even within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.
• 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.
• 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.
• BL has not been described in North America. Only a handful of cases of ACA 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, BL occurs only in approximately 1% patients with Lyme disease, and ACA occurs in 10%.

Mortality/Morbidity

• Very rarely are fatalities reported associated with Lyme disease. Many of the 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 EM 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).
• 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 BL, 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

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 EM 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 ACA, 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
• • Some patients with EM 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 EM.
  • In patients with later cutaneous manifestations of Lyme disease, BL, and ACA, 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 BL complain of 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, BL lesions occur on the scrotum, nose, and extremities. Nipple lesions tend to be painful, possibly because of rubbing against clothing.
  • EM may occur simultaneously with BL, which indicates that BL can occur very early in the disease course.
  • Patients with ACA report a rash that is acral in distribution. Initially, discoloration and inflammation of the skin are seen, and later, severe atrophy is noted.
  • ACA tends to occur more commonly in females, especially older patients. Unlike EM, ACA 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.

Physical

In many patients with early Lyme disease, physical examination alone is sufficient to establish the diagnosis of EM. 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.

• A low-grade fever is not uncommon. High fever suggests another co-infecting tick-borne organism such as Ehrlichia or Babesia species.
• Classic EM begins as an erythematous macule or papule at the site of the tick bite (within 1-33 d; median is 7-10 d). 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 ECM.
• Rashes very similar to EM 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 EM 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: EM 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 EM state that it must be greater than 5 cm in size, culture-proven cases have been occasionally documented that are smaller, and this size cut-off is only meant to be used for epidemiological purposes.
  • Shape: EM 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: EM 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. EM 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.
  • Central clearing is more common in European patients with EM 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 EM (multiple EM): Multiple EM 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).
• Borrelial lymphocytoma
• • Usually occurring on the earlobe or nipple, the lesions of BL are bluish red nodules. The earlobe is the typical location in children, while the nipple location is more commonly seen in adults.
  • Regional lymphadenopathy may be present (see Media File 2).
  • BL is a form of B-cell pseudolymphoma. Other terms used to describe BL include lymphadenosis benigna cutis, lymphocytoma cutis, cutaneous lymphoid hyperplasia, and Spiegler-Fendt lymphoid hyperplasia.
• Acrodermatitis chronica atrophicans
• • ACA 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 surfaces of the hands, feet, elbows, and knees.
  • Gradually, a central progression of the area involved occurs over months to years. 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 ACA.
• 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 BL and ACA. 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.

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.
  • 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 ACA, 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.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

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• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• In most patients with EM, a carefully elicited history (including definitions of epidemiologic context) and a physical examination are all that is required to establish the diagnosis. The CDC accepts physician-diagnosed EM of greater than 5 cm in size in its case definition. No tests, including serologic tests for Lyme disease, are indicated in these patients. CBC counts and erythrocyte sedimentation rates often are normal. Antibody titers B burgdorferi may be falsely negative at this early stage of disease and should not affect the decision to treat.
• In patients in whom significant ambiguity exists concerning the diagnosis after the history and physical examination are performed, several strategies can be used.
• • Strategy one: Empiric antibiotic therapy is reasonable if EM is moderately probable. Therapy using amoxicillin or doxycycline usually is safe and inexpensive and can be initiated immediately. If the lesion is EM, prompt improvement (within a few days) and resolution is expected.
  • Strategy two: Acute and convalescent-phase serologic testing has some drawbacks. A waiting period of several weeks may be required before antibodies appear in the serum in sufficient quantities to measure; therefore, early false seronegative results are common. In addition, the notion of waiting before treatment is unappealing to many patients as there is risk that easy-to-treat localized disease will disseminate (and potentially become more difficult to treat). Physicians must understand the limitations of serologic tests.
  • • The CDC currently recommends a 2-step testing procedure consisting of a screening enzyme-linked immunoassay (ELISA) or immunofluorescent assay followed by a confirmatory Western immunoblot test on any samples with positive or equivocal results on ELISA.
    • Newer serological testing with the C6-peptide and VslE are promising new tests but are still investigational as of mid 2005.
    • Timing is important, since many patients at the EM stage are seronegative. In addition, numerous causes of false-positive ELISA test results exist, such as various infectious and immunologic diseases. Patients with past Lyme disease may be persistently seropositive. All previously vaccinated patients have positive ELISA test results.
    • For all these reasons, sequential serologic testing has serious limitations for use in individual patients with early Lyme disease, and its routine use should be discouraged.
• Strategy three: Perform skin biopsy for histology and culture or polymerase chain reaction (PCR) of the rash to obtain further diagnostic information.
• • Histologic analysis of skin biopsy specimens (see Histologic Findings) is not diagnostic for EM, and spirochetes are seen uncommonly. In some circumstances, biopsy can help exclude other diagnoses but does not include EM.
  • Culture of punch biopsy material is another method. While the organism has fastidious growth requirements, culture in the appropriate medium (BSK-II) is positive in approximately 75% of patients. This test is not universally available, but in patients with ambiguous disease, it may be useful in establishing the diagnosis.
  • PCR is growing in uses and availability. Nevertheless, as of 2005, PCR remains a research technique, in part because labs performing PCR tests must be meticulous in technique to minimize the likelihood of false-positive results. Most importantly, it is not readily available to most clinicians in routine practice. In addition, no large clinical series have been reported that assess the performance of the test in the nonresearch setting.
• Strategy four: Observing the spontaneous evolution of the rash over several days is safe and universally available. In most patients with EM, some expansion of the rash is expected over 2-3 days without antibiotics. In patients in whom disease is ambiguous, especially when culture and PCR are unavailable, this is a reasonable alternative to immediate empiric therapy.
• Most, but not all, patients with BL are seropositive for antiborrelial antibodies. This is true for all early disseminated manifestations of Lyme disease.
• In the typical patient, no tests beyond serologic testing are necessary. When the clinical syndrome is not classic (BL lesion not found on earlobe or breast, seronegative patients), biopsy may be indicated. Histopathology shows dermal lymphocytic infiltration with germinal centers, which is suggestive but not diagnostic. The organism rarely may be cultured from lesions.
• Essentially all patients with ACA are seropositive for antiborrelial antibodies. Seriously question the diagnosis in seronegative patients.
• Results of some laboratory studies may suggest some of the other co-infecting tick-borne pathogens such as ehrlichial or babesial species.
• • Most patients with ehrlichiosis have elevated levels of hepatic transaminases, leukopenia, and/or thrombocytopenia. In addition, some patients have morulae (intracytoplasmic inclusions) in white blood cells as demonstrated on peripheral blood smears.
  • Patients with babesiosis often are anemic (hemolytic type) and may have thrombocytopenia. Blood smears reveal the malarialike intraerythrocytic parasite in this disease as well.

Histologic Findings

Histologic findings in EM are nonspecific, usually showing a perivascular cellular infiltrate consisting of lymphocytes, plasma cells, and histiocytes. Occasionally, mast cells and neutrophils are seen. Central biopsies may show eosinophilic infiltrate consistent with a local reaction to an arthropod bite. Spirochetes occasionally may be identified using silver or antibody-labeled stains, although usually, a paucity of spirochetes is found in the tissues of patients with Lyme disease. In addition, cultures for B burgdorferi are positive in approximately 75% of patients.

BL biopsy specimens show a dense dermal lymphocytic infiltrate with lymphoid follicles and pseudogerminal centers. Lymphocytes with both B-cell and T-cell markers, occasional macrophages, plasma cells, and eosinophils are seen.

In ACA, biopsy specimens from early lesions show a lymphocytic dermal infiltrate, sometimes perivascular in location, with some vascular telangiectasia and lymphedema. Plasma cells also may be seen in the cellular infiltrate. Later lesions demonstrate epidermal thinning with loss of skin appendages. At this stage, plasma cells may be the only feature to distinguish ACA from morphea. The fibrotic nodules show fibrosis of the deeper dermis and sometimes, hyalinization of collagen bundles. B burgdorferi occasionally can be cultivated from the lesions; in 1 patient, cultivation was successful more than 10 years after the lesion's first appearance.

TREATMENT

Section 6 of 11  

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Medical Care

Cutaneous manifestations of Lyme disease are treated using antibiotics. Important considerations include the stage of the disease, presence of associated neurologic symptoms or signs (especially in BL and ACA), and patient factors (duration of symptoms, allergies, age, pregnancy status).

Consultations

• Consult physicians in the appropriate specialties in patients who may have coexisting cardiac, rheumatologic, or neurologic disease.
• In most patients with EM, no consultation is needed.
• In patients with ACA, neurologic disease is not uncommon and its presence alters the treatment plan; therefore, consultation is appropriate if neurologic signs or symptoms are present.

Activity

Limitations of activities are unnecessary in most patients and are dictated by clinical status.

MEDICATION

Section 7 of 11  

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• Follow-up
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In general, skin manifestations of Lyme disease respond promptly to appropriate antibiotic therapy. Early manifestations respond more rapidly than later manifestations. Data regarding the best route and duration of antibiotic are evolving and are, to some extent, controversial.

For solitary EM, oral antibiotics clearly provide effective therapy. The duration of recommended therapy ranges from 10-30 days. The author recommends 3 weeks of treatment, since a sizable minority of patients with solitary EM have evidence of hematogenous dissemination, even in the absence of symptoms. In addition, strong evidence indicates that patients with early disseminated Lyme disease have equally good outcomes after 3 weeks of oral antibiotics compared to 2 weeks of parenteral therapy. Therefore, patients with EM and asymptomatic disseminated disease are treated adequately using the 3-week course, although many authorities consider 2 weeks of antibiotics to be adequate therapy for EM.

For pregnant women with EM, some physicians recommend parenteral therapy, although data on this are limited. Isolated reports exist of transplacental transmission from the mother to fetus. One European descriptive study showed good results of parenteral ceftriaxone in pregnant women with EM.

BL usually is treated with 14-21 days of oral antibiotics, but when symptoms of dissemination are noted, parenteral therapy sometimes is used. BL is sufficiently uncommon that no comparative trials address the ideal duration of treatment, route of administration of the antibiotic, or the choice of medication. For the same reasons as in EM, some logic exists in using a 3-week course of antibiotics.

ACA usually is treated with 1-month course of oral antibiotics, usually a beta-lactam or doxycycline. One study showed fewer relapses with 30 days compared to 20 or fewer days of therapy. In the same study, 30 days of oral antibiotics were more effective than 15 days of IV ceftriaxone (2 g/d). Ensure that no neurologic manifestations are present before embarking on oral therapy.

Drug Category: Antibiotics

Directed against B burgdorferi sensu lato. They are indicated for all the cutaneous manifestations of Lyme disease.

Drug Name	Doxycycline (Vibramycin)
Description	DOC for adults with EM. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Advantage is that it covers co-infecting ehrlichial and rickettsial species. Dosing schedule aids in compliance.
Adult Dose	100 mg PO bid
Pediatric Dose	<8 years: Not recommended >8 years: 2-5 mg/kg PO qd or divided bid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants.
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Cefuroxime (Ceftin)
Description	Second-generation cephalosporin maintains the gram-positive activity of first-generation cephalosporins. Has explicit FDA approval for EM. For cost reasons, it is an alternate drug. In cases where bacterial cellulitis cannot be confidently distinguished from EM, this drug treats both processes.
Adult Dose	500 mg PO bid
Pediatric Dose	Children: 250 mg PO bid for 20 d Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Disulfiram-like reactions may occur when alcohol is consumed within 72 h after taking cefuroxime; may increase hypoprothrombinemic effects of anticoagulants; may increase nephrotoxicity in patients receiving potent diuretics such as loop diuretics; coadministration with aminoglycosides increases nephrotoxic potential
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Administer one-half dose if CrCl level is 10-30 mL/min and one-quarter dose if <10 mL/min (high doses may cause CNS toxicity); bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy

Drug Name	Erythromycin (E-Mycin, Eryc, Ery-Tab)
Description	Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes arresting RNA-dependent protein synthesis. For treatment of staphylococcal and streptococcal infections. In clinical studies, did not perform as well as other oral antibiotics despite good in vitro sensitivities. Not recommended except in unusual circumstances (eg, pregnant patient with severe allergy to beta-lactam antibiotics).
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) PO q6h, or 500 mg q12h (1 h ac or 2 pc) Alternatively, 333 mg PO q8h; increase to 4 g/d depending on severity of infection
Pediatric Dose	30-50 mg/kg/d (15-25 mg/lb/d) PO divided q6-8h; double dose for severe infection
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI tract adverse effects are common (administer doses pc); discontinue if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Azithromycin (Zithromax)
Description	Second-line drug. Like erythromycin, has excellent in vitro sensitivities but has underperformed compared to amoxicillin in 1 large study. Conversely, in several European studies, has been shown to be equal to beta-lactam and tetracycline group antibiotics. Because of once-daily dosing, should be considered in pregnant patients who are allergic to beta-lactams and in patients where compliance is a major issue.
Adult Dose	500 mg PO qd for 15 d, 500 mg PO qd for 5 d, followed by 5-day hiatus, then second course of 500 mg PO qd for 5 d
Pediatric Dose	10 mg/kg PO once on day 1; not to exceed 500 mg/d, followed by 5 mg/kg PO on days 2-5; not to exceed 250 mg/d Alternatively, 5-12 mg/kg/d PO for 15 d
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Drug Name	Ceftriaxone (Rocephin)
Description	Third-generation cephalosporin with broad-spectrum gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins. Generally reserved for extracutaneous manifestations of Lyme disease, especially neurologic. Data on use in pregnant women with EM shows excellent outcomes. While oral therapy also may be effective, many physicians recommend parenteral therapy for pregnant patients with EM.
Adult Dose	1-2 g IV qd; not to exceed 4 g/d
Pediatric Dose	50 mg/kg/d IV; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections, and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding and patients with allergy to penicillin

Drug Name	Penicillin VK (Ledercillin VK, Pen-Vee K, Veetids)
Description	Inhibits biosynthesis of cell wall mucopeptide. Bactericidal against sensitive organisms when adequate concentrations are reached, and most effective during the stage of active multiplication. Inadequate concentrations may produce bacteriostatic effects only. Can be used to treat EM, since it is safe in both pregnant and pediatric patients, although amoxicillin is used more commonly these patients.
Adult Dose	500 mg PO qid
Pediatric Dose	50 mg/kg/d PO divided tid/qid; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in impaired renal function

Drug Name	Tetracycline (Sumycin)
Description	Treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). Used as alternative to doxycycline. Because of dosing schedule, doxycycline is preferred for compliance reasons; however, tetracycline may be less expensive.
Adult Dose	250-500 mg PO qid
Pediatric Dose	<8 years: Not recommended >8 years: 25-50 mg/kg/d (10-20 mg/lb) PO qid
Contraindications	Documented hypersensitivity; severe hepatic dysfunction; breastfeeding
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients with cutaneous manifestations of Lyme disease (without concurrent extracutaneous disease) do not require hospitalization.

Further Outpatient Care

• Follow-up monitoring is indicated for all patients with Lyme disease until complete resolution of all signs and symptoms. In early Lyme disease, lack of prompt resolution should lead the physician to question the original diagnosis. Later manifestations tend to clear more slowly.
• Follow-up monitoring by the primary care physician or an appropriate specialist is indicated for patients with extracutaneous manifestations.
• Importantly, note that the standard serologic tests, with initial positive results, may remain positive for long periods and should not be used as a test of cure. Recent data suggest that the new test, the C6-peptide, may return negative results after treatment with antibiotics.

Deterrence/Prevention

• Basic strategies for preventing Lyme disease include environmental and personal. Environmental strategies are beyond the scope of this article and are not discussed. Personal strategies fall into 2 categories including personal habit modification and vaccination.
• • Personal habit modification methods to prevent Lyme disease include the following:
  • • Lyme disease can be prevented by avoiding tick bites or by removing ticks before they can transmit disease. Staying to centers of trails, applying DEET (diethyl toluene) to the skin or permethrin to clothing, and wearing long pants and sleeves when outdoors (tucking pant legs into socks) decrease the likelihood of tick bites.
    • Wearing clothing with white colors improves the odds of seeing ticks on clothing before they attach. Performing daily tick inspections and removing ticks before they have been attached for 24 hours is another important way to diminish the risk of contracting Lyme disease.
    • Several studies have shown that the likelihood of infection is related to the duration of tick attachment. Infection is much less likely, but not impossible, with tick attachment durations of less than 24 hours. Proper tick removal technique is important too, ie, grasping the tick with fine tweezers close to the skin and pulling gradually outwards.
    • The degree of engorgement of the tick can be used as an indicator for tick attachment duration. For patients with unattached ticks or with ticks that are not engorged, no prophylactic therapy is recommended. The author's recommendation is to treat patients using oral antibiotics for 10 days if an Ixodes tick's bite is engorged (in an endemic area) or if the patient is pregnant.
    • An article published in 2001 suggests that a single dose of 200 mg of doxycycline may be used for tick bite prophylaxis. The investigators also corroborated that the degree of engorgement was an important variable in transmission of disease and that female nymphal ticks accounted for all cases of Lyme disease.
• Vaccination to prevent Lyme disease involves the following:
• • In December 1998, the FDA approved a vaccine directed against the outer surface protein A of B burgdorferi after trials indicated efficacy. In 2002, this vaccine was pulled off the market by the manufacturer.
  • After 3 doses, using a dosing schedule at 0, 1, and 12 months, the vaccine is approximately 80% effective in preventing Lyme disease. Data indicate that a 0-, 1-, and 2-month schedule is equally effective. Pediatric and pregnant patients were excluded from the study. Unpublished data show that children have an excellent antibody response to the vaccine, suggesting that the vaccine may be effective in these patients as well.
  • Adverse effects in the studies were minimal and the vaccine probably is very safe. No increase in arthritis was reported in vaccine recipients. This was a concern because a population of patients with antibiotic-resistant Lyme arthritis have high levels of antibodies against Osp A, the antigen used in the vaccine. Whether the high levels are causal is unknown, and to date, this concern remains theoretical.
  • Educating vaccinated patients that the vaccine does not protect against other tick-borne diseases (and is imperfect against Lyme disease) is important. Therefore, other standard tick prevention strategies remain important. In addition, the vaccine is not anticipated to be effective in European patients.
  • The CDC has not issued firm guidelines for the Lyme vaccine. Contrary to other diseases with routine vaccination protocols, Lyme disease is (1) rarely, if ever, fatal, (2) treatable in most patients when diagnosed early, (3) preventable by other means, and (4) not communicable from person to person. In hyperendemic regions and in patients who, by nature of their activities, have a high tick exposure, the physician should strongly consider the vaccine.
  • In the absence of infection, vaccinated patients all have falsely positive ELISA test results but have negative Western blot test results.

Complications

• In early Lyme disease (EM), treatment is highly effective and complications are unusual. Complications consist of later manifestations of Lyme disease.
• In patients with late-stage cutaneous disease, the physician must look for additional, especially neurologic, manifestations. Neurologic disease constitutes an indication for parenteral therapy.

Prognosis

• Prognosis for treated patients with EM is excellent. Careful follow-up monitoring is very important in patients with Lyme disease in the later stages to ensure that patients have responded to treatment and do not develop extracutaneous symptoms and signs.

Patient Education

• Educate patients regarding ticks and tick avoidance. Instruct patients regarding other tick-borne diseases and how to take appropriate precautions.
• Provide patients with instructional material about additional manifestations of Lyme disease. Patients who have EM can get EM again; one episode does not necessarily confer immunity.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center and Arthritis Center. Also, see eMedicine's patient education articles Lyme Disease and Ticks.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to diagnose Lyme disease correctly can result in legal ramifications, since malpractice cases have been brought centering on missed diagnoses of Lyme disease. Carefully complete the process of differential diagnosis. Monitor patients to ensure that the disease resolves in both early-stage and late-stage disease. Lack of resolution with antibiotics suggests an error in diagnosis, lack of compliance with the treatment by the patient, or inadequate therapy.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
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Media file 2:  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.
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Media file 3:  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.
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Media file 4:  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.
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Media file 5:  Hematoxylin and eosin stained section from a biopsy performed at the periphery of an eruption (same patient as in Media File 1). Note the perivascular lymphocytic infiltrate, a pattern that is not specific for, but is characteristic of, erythema migrans.
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Media file 6:  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.
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Media file 7:  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.
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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.
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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.
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Media file 10:  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.
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Media file 11:  Blood smear showing likely babesiosis. Babesiosis can be difficult to distinguish from malaria on a blood smear.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• 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].
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Article Last Updated: Jan 25, 2007