Lyme Disease 

Updated: Aug 01, 2019
Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Lyme disease, the most common vector-borne illness in the United States, is a multisystem illness usually caused by infection with the spirochete Borrelia burgdorferi (see the image below) and the body's immune response to the infection.[1] The disease is transmitted to humans via tick bites, from infected ticks of the genus Ixodes.

The bacterium Borrelia burgdorferi (darkfield micr The bacterium Borrelia burgdorferi (darkfield microscopy technique, 400X; courtesy of the US Centers for Disease Control and Prevention).

See Lyme Disease and 4 Emerging Tick-Borne Illnesses, a Critical Images slideshow, to help identify and treat several tick-borne conditions.

Signs and symptoms

Signs and symptoms of Lyme disease vary by disease stage. Physical findings in patients with early disease are as follows:

  • Flulike illness - Fever, chills,  malaise, myalgias, arthralgia, headache
  • Tender local adenopathy (local, not diffuse)
  • Erythema migrans (EM) - Rash

Physical findings in patients with early disseminated disease are as follows:

  • EM (single or multiple lesions)
  • Headache
  • Fever
  • Tender adenopathy (regional or generalized)
  • Conjunctivitis (uncommon, never prominent)
  • Carditis (usually manifests as heart block)
  • Meningismus as a sign of aseptic meningitis
  • Cranioneuropathy, especially cranial nerve VII and Bell palsy (peripheral seventh nerve palsy with decreased unilateral function, including the forehead)

In patients with late disease, the typical physical finding is arthritis. Arthritis is located mostly in large joints, especially the knee. Warmth, swelling from effusion, and limited range of motion help distinguish arthritis from simple arthralgia.

See Presentation for more detail.

Diagnosis

In endemic areas, patients with probable erythema migrans and a recent source of tick exposure should be started on treatment without blood tests. For serologic testing, the CDC recommends the following two-tier procedure[2] :

  • Step 1: Enzyme immunoassay (EIA) or immunofluorescence assay (IFA) - Total Lyme titer or IgG and IgM titers
  • Step 2: Western blot testing

Western blot testing is performed only if step 1 test results are positive or equivocal. If signs and symptoms have been present for 30 days or less, both IgM and IgG Western blot testing are performed; if signs and symptoms have been present for more than 30 days, only IgG Western blot testing is performed.

Since Western blot testing is necessary to exclude false-positive EIA or IFA results, but unnecessary if the initial test is negative, Lyme titers should always be ordered with a reflex confirmatory test. Most commercial laboratories will perform both IgG and IgM Western blots.

In July 2019, the US Food & Drug Administration (FDA) approved the use of concurrent or sequential EIA testing for diagnosis of Lyme disease. The FDA approved the new indication on the basis of data from clinical studies showing that this alternative approach, referred to as a modified two-tier test, is as accurate as testing with EIA or IFA plus Western blot.[85]

If the patient has been in Europe, where different strains of Borrelia are more common, a C6 peptide ELISA is a more accurate confirmatory test than the Western blots, which have been developed to B burgdorferi, which is the most common strain found in the United States. The C6 peptide is less expensive than the Western blots and is as sensitive and specific for B burgdorferi; it is a reasonable alternative for the Western blots, but has not replaced it as the usual confirmatory test in the United States.

Other studies that may be used are as follows:

  • Joint aspiration - To exclude other causes of effusion (eg, septic arthritis, gout, pseudogout)
  • CSF analysis - In patients with meningitis
  • ECG - To identify Lyme carditis

See Workup for more detail.

Management

With appropriate antibiotic treatment, most patients with early-stage Lyme disease recover rapidly and completely. Antibiotic selection, route of administration, and duration of therapy for Lyme disease are guided by the patient’s clinical manifestations and stage of disease, as well as the presence of any concomitant medical conditions or allergies. 

Treatment of Lyme disease is as follows:

  • Adult patients with early localized or early disseminated Lyme disease associated with erythema migrans: Doxycycline, amoxicillin, or cefuroxime axetil

  • Children under 8 years and pregnant or nursing women with early localized or early disseminated Lyme disease: Amoxicillin or cefuroxime axetil

  • Neurologic Lyme disease: IV penicillin, ceftriaxone, or cefotaxime; oral doxycycline, when not contraindicated, in patients with Lyme-associated meningitis, facial nerve palsy, or radiculitis

Treatment of Lyme arthritis is as follows:

  • Oral antibiotics for 28 days
  • Re-treatment with oral antibiotics for mild residual joint swelling
  • Re-treatment with IV antibiotics for refractory cases
  • Oral antibiotics for another month in patients with positive PCR of synovial fluid
  • NSAIDs in patients with negative PCR, supplemented if necessary with hydroxychloroquine
  • Consideration of arthroscopic synovectomy in patients unresponsive to symptomatic therapy

Lyme carditis may be treated with either oral or parenteral antibiotic therapy for 14 days (range, 14-21 days). Hospitalization and continuous monitoring, with consideration for temporary pacing, are advisable for patients with any of the following:

  • Associated symptoms (eg, syncope, dyspnea, or chest pain)
  • Second-degree or third-degree AV block
  • First-degree heart block with prolongation of the PR interval to more than 30 milliseconds (the degree of block may fluctuate and worsen very rapidly in such patients)

See Treatment and Medication for more detail.

Background

Lyme disease is a multisystem illness usually caused by infection with the spirochete Borrelia burgdorferi and the body's immune response to the infection.[1] The disease is transmitted to humans via tick bites, from infected ticks of the genus Ixodes.

Lyme disease is the most common vector-borne illness in the United States. More than 30,000 cases of Lyme disease are reported to the US Centers for Disease Control and Prevention each year; in 2015, it was the sixth most common nationally notifiable disease.[3] Lyme disease is also endemic in other parts of North America, as well as in Europe and Asia. See Epidemiology.

Because only approximately 25-30% of US patients with early Lyme disease recall the tick bite, the clinician must direct the history toward the possibility of a tick bite. Epidemiologic context is extremely important. The probability of a tick bite—and thus, the likelihood of contracting Lyme disease—is highest in persons who spend time outdoors (particularly in wooded, brushy, or grassy habitats) in a geographically endemic area, especially from May through November.

Early localized Lyme disease refers to isolated erythema migrans, the characteristic skin rash of Lyme disease, and to an undifferentiated febrile illness. This stage occurs 1-30 days after the tick bite.

Early disseminated Lyme disease usually develops 3-10 weeks after inoculation. Musculoskeletal and neurologic symptoms are the most common; less common are symptoms from cardiac disturbances; and ocular manifestation, most often conjunctivitis.

Late or chronic Lyme disease refers to manifestations that occur months to years after the initial infection, sometimes after a period of latency. Signs and symptoms of chronic Lyme disease are primarily rheumatologic and neurologic.

See Presentation.

In endemic areas, patients with probable erythema migrans and a recent source of tick exposure should be started on treatment without blood tests. In the absence of erythema migrans, serologic testing is used. The US Centers for Disease Control and Prevention (CDC) recommends a two-step testing procedure. The first step typically consists of a screening enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA); if results are positive or equivocal, a Western immunoblot test is performed to confirm the results.[2]

Other tests and procedures (eg, electrocardiogram, cerebrospinal fluid analysis) depend on the presentation. See Workup.

Antibiotic selection, route of administration, and duration of therapy for Lyme disease are guided by the patient's clinical manifestations and stage of disease, as well as the presence of any concomitant medical conditions or allergies. First-line agents include doxycycline, penicillins, cefuroxime, and ceftriaxone; however, doxycycline is contraindicated in patients younger than 8 years and in pregnant and breastfeedingf women. See Treatment and Medication.

Several medical societies have published Lyme disease guidelines, including the Infectious Diseases Society of America (IDSA) and the American Academy of Neurology (AAN).[4, 5] The IDSA, the AAN, and the American College of Rheumatology (ACR) have drafted a joint consensus guideline for the prevention, diagnosis, and treatment of Lyme disease.[6]

Clinical Image Atlas: View clinical images on the features, causes, epidemiology, diagnosis, and treatment of Lyme disease.

Historical background

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). In 1912, the Swedish dermatologist Arvid Afzelius described the rash, then called erythema chronicum migrans, which currently is referred to simply as erythema migrans (EM).

In the 1920s, Garin and Bujadoux described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, which they attributed to a spirochetal infection. By the mid 1930s, neurologic manifestations associated with Ixodes ticks (also known as deer ticks) were recognized and were known as tick-borne meningoencephalitis. In the 1940s, Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.

In the United States, Lyme disease was not recognized until the early 1970s, when a statistically improbable cluster of pediatric arthritis cases occurred in the region around Lyme, Connecticut. This outbreak was investigated by Allen Steere, MD, and others from Yale and 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.

The recognition that the patients in the United States had erythema migrans and the initial antibiotic responsiveness of the cutaneous manifestations that had been described in the 1950s in the European literature was confirmed.[7] This led to the recognition that Lyme arthritis was one manifestation of the same tick-borne condition known in Europe.

After Willy Burgdorfer, MD, discovered a borrelial organism in Ixodes ticks, it was recovered from patients with clinical Lyme disease, confirming Borrelia as the causative agent. This led to the development of antibody tests for the disease. Different strains of Borrelia are recognized, which probably explains why the clinical manifestations of Lyme disease are different between the United States and Europe.

Lyme disease has become common in the United States from Maryland to Maine and in Wisconsin and Minnesota, with a smaller focus in northern California. The emergence of Lyme disease is probably due to the explosion of deer and tick populations with the reforestation of the northeastern United States and the subsequent contact between ticks and humans as people move into deer habitats. The pathogen itself is not new; B burgdorferi has been found in tick specimens collected in the 1940s on eastern Long Island, New York.

The spirochete Borrelia burgdorferi is introduced into the skin with a bite from an infected Ixodes tick. In the northeastern and upper midwestern United States, Ixodes scapularis is the vector. In other parts of the country and world, other Ixodes species serve that function. Other ticks (eg, Amblyomma americanum) and insects can carry B burgdorferi, but Ixodes tick bites are thought to cause the vast majority of cases.

In the southern and mid-central United States, a Lymelike illness has been reported; the vector appears to be A americanum, and the causative organism or organisms is likely to be a related spirochete.[8, 9] One such organism, named Borrelia lonestarii, has been cultured in a single case.

Borrelia burgdorferi infectious cycle

The infectious cycle of B burgdorferi involves colonization, infection of Ixodes ticks, and then transmission to broad a range of mammalian hosts, including humans. Variation in environmental and host conditions promotes different gene expression and changes in the composition of the membrane proteins of the spirochete. This adaptation is a critical step in the pathogenesis and transmission of Lyme disease.

The Ixodes tick progresses through four stages of development: egg, larva, nymph, and adult (see the following image for examples of each stage). Only larvae, nymphs, and adult female ticks require blood meals, and only ticks in the nymphal and adult stages can transmit B burgdorferi.

Magnified ticks at various stages of development. Magnified ticks at various stages of development.

The life cycle of Ixodes ticks spans 2 years (see the image below). The adult lays eggs in the spring, and the larvae emerge in the summer. The larvae feed once, in late summer, on any of a wide variety of small animals (eg, the white-footed mouse) . The following spring, the larvae emerge as nymphs. Nymphs feed once, in the spring and summer. The white-footed mouse is the preferred feeding source of nymphs, but other animals apparently suffice. Nymphs molt into adults the following fall and feed once on a larger animal, with the white-tailed deer being the preferred host.

Life cycle of the Ixodes dammini tick. Courtesy of Life cycle of the Ixodes dammini tick. Courtesy of Elsevier.

Ticks can acquire B burgdorferi from feeding on an infected animal host during any of the three life-cycle stages. Unless the tick has fed on an infected host before feeding on a person, infection cannot result from that tick bite. Even if a tick that has previously fed on an infected animal and then feeds on an infected animal, the animal may not acquire the infection. Mice do not appear to develop Lyme disease, but they do carry the bacteria. They may be considered infested rather than infected. Deer also are incompetent hosts for Borrelia.

Ticks carry B burgdorferi organisms in their midgut. The bacteria are introduced into the skin by a bite from an infected tick, and disease is transmitted to humans as the spirochete is translocated from the gut to the salivary glands and then to the person at the site of the bite.

The risk of Lyme disease is highest during the time of the year when Ixodes ticks in the nymphal stage are seeking a blood meal. Although the prevalence of B burgdorferi infection in adult ticks is twice that of nymph ticks, nymphs are responsible for 90% of human disease transmissions because of the great abundance of nymphs; the increase in human outdoor activity in the summer (the peak feeding season of nymphs); and the small size of nymphs, which makes them less likely to be detected and removed before disease transmission occurs.

The risk of transmission of B burgdorferi from an infected tick to a human depends on the length of exposure. It takes hours for the tick to attach fully, and experimental studies have indicated that in most cases, nymphs must feed 36-48 hours and adults 48-72 hours to transmit B burgdorferi, since the blood meal has to trigger the reproduction of the Borrelia to a large enough number to be infective .

Pathogenesis

Once the spirochete is in the skin, one of three events may occur:

  • The spirochete may be overwhelmed and eliminated by host defense mechanisms

  • The spirochete may remain viable and localized in the skin, where it produces erythema migrans (EM), the characteristic skin lesion of Lyme disease

  • Within days to weeks, the spirochete may disseminate through the lymphatics or blood,

After entering the circulation, the organism shows a distinct tropism for the skin, heart, central nervous system (CNS), joints, and eyes. Any part of the body can be affected, however; spirochetes have also been demonstrated histologically in bone marrow, the spleen, lymph nodes, the liver, testes, and the placenta during early hematogenous dissemination.

The clinical manifestations of Lyme disease generally follow three stages of disease progression: early localized, early disseminated, and chronic disseminated (see also Clinical Presentation). All are potentially curable with antibiotic therapy. The infection progresses to disseminated disease in approximately 50% of untreated patients. Only a few genotypes of B burgdorferi appear to be responsible for the large majority of cases of disseminated disease.[10]

Stage 1 disease

Stage 1 is also known as primary or early localized infection. It generally occurs within 30 days of the tick bite. Most patients present with a characteristic expanding rash (erythema migrans) at the site of the tick bite 7-14 days after the tick is removed. Nonspecific symptoms may include the following:

  • Fatigue
  • Myalgias
  • Arthralgias
  • Headache
  • Fever
  • Chills
  • Neck stiffness

Stage 2 disease

Stage 2 is also known as early disseminated disease. It generally occurs weeks to months after the bite. Musculoskeletal and neurologic symptoms are the most common; less common symptoms are cardiac and dermatologic.

B burgdorferi spreads throughout the body and produces symptoms by direct invasion (eg, erythema migrans), particularly in the early stages of the disease. Because growing B burgdorferi in culture is difficult, confirming that the organism is actually present in a specific organ that may be involved in Lyme disease is also difficult. The inflammatory response to B burgdorferi in the skin is probably the explanation for multiple lesions of erythema migrans, as almost all patients with multiple lesions are seropositive, regardless of duration.[11]

Antibodies against spirochetal protein membrane epitopes have been shown to cross-react with neural and connective tissues. This molecular mimicry possibly generates an autoimmune inflammatory reaction. The pathophysiology of early versus late manifestations of the disease is similar to that seen with syphilis.

Early studies showed that B burgdorferi or its DNA can be detected in the bloodstream of roughly 10% of patients with isolated erythema migrans and no systemic symptoms. In addition, early in the course of disease and while erythema migrans still is present, spirochetal DNA has been detected in cerebrospinal fluid (CSF), indicating early CNS penetration. This can occur even in the absence of neurologic symptoms.

Importantly, one 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.[8]

Stage 3 disease

Stage 3 or chronic Lyme disease happens months to years after infection, which sometimes involves a period of latency. Musculoskeletal (mainly joints) and neurologic systems are most commonly affected.

B burgdorferi induces an immune response that may lead to symptoms in various organs, with little evidence of bacterial invasion. Studies of Lyme arthritis have shown that the arthritis is associated with certain immunologic factors, including the production of proinflammatory cytokines and the formation of immune complexes; and genetic factors, such as carriage of human leukocyte antigen (HLA)–DR4 and HLA-DR2.

Patients with HLA-DR4 or HLA-DR2 and antibodies to OspA and OspB (outer surface protein A) proteins in their joint fluid may be more susceptible to long-term arthritis than persons without these characteristics. The presence of these genes is presumably related to the development of autoimmunity in the joint, which can lead to persistent inflammation even after the spirochete is apparently eradicated.

Animal studies have suggested a primary role of astrocytes and microglial cells in the pathogenesis of neuroborreliosis. Interleukin 6 (IL-6) production by astrocytes and subsequent oligodendrocyte apoptosis have been proposed as mechanisms of cell injury.[12]

The organism also can persist in the skin for very long periods. Experimentally, the spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone at concentrations well above bactericidal levels. Although intracellular organisms have never been demonstrated in vivo, this may be a mechanism by which the organism eludes host defenses.

Etiology

Lyme disease is usually caused by infection with the spirochete Borrelia burgdorferi (see the image below) . The complete genome of B burgdorferi was described in 1998.

The bacterium Borrelia burgdorferi (darkfield micr The bacterium Borrelia burgdorferi (darkfield microscopy technique, 400X; courtesy of the US Centers for Disease Control and Prevention).

The species Borrelia burgdorferi sensu lato has three well-characterized groups, as follows:

  • B burgdorferi sensu stricto

  • B garinii

  • B afzelii

B burgdorferi sensu stricto is a broad category of closely related but genetically distinct genospecies that constitutes most North American isolates and is found in Europe as well. B afzelii is found mainly in Europe; B garinii is found exclusively in Europe.

These subspecies are associated with different clinical presentations, probably due to genomic variation. Infection with B burgdorferi sensu stricto has a particular predilection to affect joints. In European patients with erythema migrans, B afzelii can be isolated from about 80% of lesions and B garinii from 15%.[13] B afzelii often infects the skin only but may persist in that site, causing various cutaneous manifestations including acrodermatitis chronica atrophicans.

B garinii has some neurotropism and is the isolate that accounts for most cases of lymphocytic meningoradiculitis (Bannwarth syndrome) and white matter encephalitis, which is rare in North America. However, this organism can also cause all the various cutaneous manifestations of Lyme disease.

Other strains, which may be sufficiently different in their genetic structure to be considered separate strains, exist; however, most of these are nonpathogenic to humans. This is an area of active research.

In 2016, Mayo Clinic researchers reported the discovery of a novel species of bacteria, provisionally named Borrelia mayonii, isolated in six patients in the upper Midwest of the US with suspected Lyme disease. Clinically, disease from B mayonii is similar to that from B burgdorferi, except that B mayonii is associated with nausea and vomiting, diffuse rashes, and unusually high spirochetemia. Polymerase chain reaction (PCR) testing targeting the oppA1 gene of B burgdorferi sensu lato proved useful in diagnosis.[14]

B burgdorferi is transmitted by ixodid tick species. 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. See the images below.

This patient's erythema migrans rash demonstrates This patient's erythema migrans rash demonstrates several key features of the rash, including size, location, and presence of a central punctum, which can be seen right at the lateral margin of the inferior gluteal fold. Note that the color is uniform; this pattern probably is more common than the classic pattern of central clearing. On history, this patient was found to live in an endemic area for ticks and to pull ticks off her dog daily.
Amblyomma americanum is the tick vector for monocy Amblyomma americanum is the tick vector for monocytic ehrlichiosis and tularemia. An adult and a nymphal form are shown (common match shown for size comparison). Image by Darlyne Murawski; reproduced with permission.

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. 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 lonestarii, no organism can be isolated in the vast majority of cases of erythema migrans in this geographic area.[9, 15]

Epidemiology

Lyme disease is endemic in North America, Europe, and Asia, and the distribution of the vectors directly affects the incidence of the disease. Ixodes scapularis is the principal vector found in the Northeast and Central United States and Canada, whereas Ixodes pacificus is more common on the Pacific coast. Ixodes ricinus is the principal vector in Europe. The vector in Asia is the taiga tick, Ixodes persulcatus.

United States statistics

Lyme disease is the most common vector-borne illness in the United States. Over 30,000 cases of Lyme disease are reported each year.[3]  In 2017, a total of 42,743 cases of Lyme disease—29,513 confirmed and 13,230 probable— were reported to the US Centers for Disease Control and Prevention (CDC), an increase of more than 17% over 2016 figures.[3]  Lyme disease led the list of a record number of tickborne disease cases that state and local health departments reported to the CDC In 2017: 59,349 cases, up from 48,610 in 2016.[16]

From 2008 (when the national surveillance case definition was revised to include probable cases) to 2012, the incidence ranged from 9.86-12.71 cases per 100,000 population in the US.[17] In 2015, Lyme disease was the sixth most common nationally notifiable disease.[3]

The CDC tracks 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, because 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.

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.

The risk of Lyme disease follows a general geographic pattern, with concentrations in the Northeast, mid-Atlantic, and upper Midwest. In 2017, 3-year average incidence of confirmed cases was high (ie, at least 10 per 100,000) in the following states[3] :

  • Connecticut  – 41.8
  • Delaware – 40
  • Maine –  89.2
  • Maryland – 20.6
  • Massachusetts – 16.6
  • Minnesota – 23.4
  • New Hampshire – 51.9
  • New Jersey – 40.5
  • New York – 15.8
  • Pennsylvania – 66.7
  • Rhode Island – 53.4
  • Vermont – 86.7
  • Virginia – 12.3
  • Wisconsin – 26.6

Washington, DC was also a high-incidence area, at 10.1 cases per 100,000 population. Note that Massachusetts uses a surveillance method that relies primarily on laboratory reports, and information on most Lyme disease cases occurring in that state is not sent to the CDC.[3]

In addition, infected ticks have also been found in states neighboring those, as well as in some areas of Northern California, Oregon, and Washington.[3] In 2017, confirmed cases of Lyme disease were reported from every US state except Oklahoma and Hawaii.[16]

The map below shows the county of residence for each reported case of Lyme disease in 2017. This does not indicate where each case of Lyme disease was acquired.

Lyme disease in the United States is concentrated Lyme disease in the United States is concentrated heavily in the northeast and upper Midwest; it does not occur nationwide. Dots on the map indicate the infected person's county of residence, not the place where they were infected. Courtesy of the US Centers for Disease Control and Prevention (CDC).

In the states where Lyme disease is most common, the average incidence is 39.5 cases per 100,000 persons.[3] Within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.[18]

Lyme disease has a seasonal influence that reflects the feeding pattern of the Ixodes tick and human outdoor activity. Infection occurs most often between May and November, with a peak incidence in June through August; 75% of cases occur during the summer months.

International statistics

Lyme disease exists throughout much of the world, including Canada, Europe, and Asia. Occasionally, cases are reported in more tropical locales, and Lyme disease may exist in Australia.

In Asia, Borrelia burgdorferi infection has been reported in countries including China, Korea, Japan, Indonesia, Nepal, and eastern Turkey. In Europe, most Lyme disease is reported by Scandinavian countries, Germany, Austria, and Slovenia. Lyme disease in Europe is primarily caused by B afzelii and B garinii.

A rate of 69 cases of Lyme disease per 100,000 persons was reported in southern Sweden, with peaks at ages 5-9 years and 60-69 years. In one publication, the estimated incidence of Lyme disease was as high as 206 cases per 100,000 population in Slovenia and 135 cases per 100,000 population in Austria, which are among the highest reported rates in Europe.[19] Increases in prevalence have been also observed in Poland, Germany, Bulgaria, Norway, and Finland.

Racial differences in incidence

Lyme disease is reported primarily in whites, although it occurs in individuals of all races. No genetic explanation is known for this; the disparity most likely stems from social or environmental factors (ie, a higher exposure rate to ticks in whites than in members of other races) and possibly to the fact that erythema migrans is more difficult to diagnose in dark-skinned individuals.

Sexual and age-related differences in incidence

No strong preponderance of Lyme disease is noted in either sex. Reports from Europe indicate that, among children, the rate of Lyme disease is slightly higher in boys than in girls aged 5-19 years,[20] but, in adults over 30 years of age, the disease is more common in women than in men. In the United States from 1992-2006, 53.1% of reported Lyme disease cases occurred in males.[18]

Age distribution in Lyme disease is bimodal: the first peak is in children aged 5-14 years and the second in adults aged 45-54 years.[21] In general, this pattern is related to increased levels of outdoor activity and environmental exposure in these age groups rather than any intrinsic difference in susceptibility.

Prognosis

The prognosis for patients with Lyme disease is generally excellent when they are treated early with appropriate antibiotic regimens. However, recurrent infection is possible if the patient is again bitten by an infected tick; these infections are usually due to a different strain of the local Borrelia.[22]

Patients, especially adults, who receive late treatment or initial treatment with antibiotics other than doxycycline or amoxicillin may develop chronic musculoskeletal symptoms and difficulties with memory, concentration, and fatigue. These symptoms can be debilitating and hard to eradicate.

Some patients develop chronic arthritis that is driven by immunopathogenic mechanisms and not active infection. This condition is more prevalent among individuals with HLA-DR2, HLA-DR3, or HLA-DR4 allotypes. The arthritis is resistant to antibiotic treatment but typically responds to symptomatic treatment and shows eventual resolution.[23]

Cardiac involvement in Lyme disease is rarely chronic. However, patients with third-degree heart block often require a temporary pacemaker insertion and, on rare occasions, a permanent pacemaker insertion.

Lyme disease appears to rarely be fatal. Many of the fatal cases reported have been in patients co-infected with other tick-borne pathogens such as Ehrlichia species and B microti, and in Europe, tick-borne encephalitis. A US Centers of Disease Control and Prevention (CDC) study of death records from 1999-2003 found that only one of 114 total records listing Lyme disease as an underlying or multiple cause of death was consistent with clinical manifestations of Lyme disease.[24] .

Extremely rare cases of neonatal death or stillbirth have been reported after pregnancies complicated by untreated or inadequately treated symptomatic maternal Lyme borreliosis. Subsequent findings from CDC studies suggest that congenital infection with B burgdorferi is unlikely and that it is not directly responsible for adverse fetal outcomes.

Post-treatment Lyme disease syndrome

Lingering symptoms, which may persist for more than 6 months, affect 10-20% of patients who receive recommended treatment for Lyme disease.[3] Common complaints include cognitive disturbances, fatigue, joint or muscle pain, headaches, hearing loss, vertigo, mood disturbances, paresthesias, and difficulty sleeping. This condition is often termed chronic Lyme disease, but is more appropriately called post-treatment Lyme disease syndrome (PTLDS).

No evidence suggests that prolonged antibiotic therapy is effective for PTLDS. Almost all patients recover with time, but recovery may take more than 6 months in some cases.[3]

In one study, many patients who had been diagnosed with Lyme disease 1-11 years previously reported increased symptoms, difficulties with typical daily activities, or both. However, the frequencies of these reports were similar to those in age-matched controls without Lyme disease.[25]

Another study found no difference in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance between control patients and Lyme disease patients examined a mean of 6 years after infection. However, patients with previous Lyme disease had more joint pain and memory impairment, and had poorer functional status due to pain.[26]

Patient Education

Clinicians should educate parents and children who live in endemic areas about the risk of Lyme disease. Education and awareness are the best means of preventing Lyme disease. Anticipatory guidance should focus on prevention measures and post–tick exposure counseling on watching for symptoms and signs of Lyme disease. Personal strategies for preventing Lyme disease fall into two categories: personal habit modification (eg, avoiding ticks/tick habitats, inspecting clothing and pets, using repellents) and prophylaxis.

Educate patients with early stages of Lyme disease about symptoms that can develop later. Development of these symptoms necessitates re-examination and may indicate treatment failure or incorrect diagnosis. Advise patients receiving doxycycline that this antibiotic can cause severe cutaneous photosensitivity. Caution patients to use sunblock with a sun protection factor (SPF) of at least 30 and to wear wide-brimmed hats for further protection.

Patients who have had Lyme disease should be advised that antibodies induced by the infection are not protective against further exposures to Borrelia burgdorferi; one episode of erythema migrans does not always confer immunity to the next. Consequently, preventive strategies remain important for these patients.

For patient education information, see Lyme Disease. Additional information can be obtained from the American Lyme Disease Foundation, Inc., PO Box 466 Somers, Lyme, CT 06371.

Avoidance

Educate patients regarding ticks and tick avoidance. Backyard patios, decks, and grassy areas that are mowed regularly are unlikely to have ticks present. This may be because of the lack of cover for mice from owls and other raptors that prey on mice. In addition, these areas do not provide moisture, which ticks need. The areas around ornamental plantings and gardens are more hospitable for mice and ticks.

The highest concentration of ticks is found in wooded areas. Staying to centers of trails and applying repellents to the skin or to clothing helps avoid contact with ticks (see Repellents, below). In addition, wearing long-sleeved shirts and tucking long pants into socks and long hair under a hat when outdoors is recommended. Wearing light-colored clothing improves the odds of seeing ticks on clothing before they can attach.

Inspection and tick removal

Because recommendations for avoidance are not always practical, particularly for children and during the summer, daily close inspection for ticks should be performed each time one has been outdoors. Parents of children in endemic areas must be vigilant to check for ticks—especially the nymphs, because of their smaller size (approximately that of a poppy seed)—from the spring to the fall. Checking inside skin folds, behind ears, the umbilicus, groin, axilla, hairline, and scalp must be routine. If one tick is found, search thoroughly for others.

See the image below for a tick removal diagram and instructions.

To remove a tick, use fine-tipped forceps and wear To remove a tick, use fine-tipped forceps and wear gloves. Grasp the tick as close to the skin surface as possible, including the mouth parts, and pull upward with steady, even traction. Do not twist or jerk the tick because this may cause the mouth parts to break off and remain in the skin; however, note that the mouth parts themselves are not infectious. When removing, wear gloves to avoid possible infection.

While these instructions may represent the optimal method for removing the tick, it is more important to remove it promptly than to delay removing it while obtaining forceps or gloves.

A common misperception is that pressing a hot match to the tick or trying to smother it with petroleum jelly, gasoline, nail polish, or other noxious substances is beneficial. This only prolongs exposure time and may cause the tick to eject infectious organisms into the body. Finally, do not squeeze, crush, or puncture the body of the tick because its fluids (saliva, hemolymph, gut contents) may contain infectious organisms.

Once the tick is removed, wash the bite area with soap and water or with an antiseptic to destroy any contaminating microorganisms. Additionally, the person who removed the tick should wash his or her hands.

The likelihood of infection is related to the duration of tick attachment.[27] Infection is much less likely, but not impossible, when ticks have been attached for less than 24 hours. The degree of engorgement of the tick (see the following image) can be used as an indicator for tick attachment duration.

Normal and engorged Ixodes ticks. Normal and engorged Ixodes ticks.

Repellents

Chemical repellents with DEET (N,N-diethyl-3-methylbenzamide), picaridin, IR3535, and oil of lemon eucalyptus are available in numerous over-the-counter skin preparations as sprays or lotions. Permethrin is an acaricide that can be applied to clothing and is used in conjunction with chemical repellents.

The use of tick repellents, sprayed on clothing or directly on the skin, may be appropriate for adults. In children, increased absorption and resultant toxicity is a concern. The American Academy of Pediatrics issued a recommendation that children not be exposed to products containing more than 10% DEET because of case reports of neurotoxicity in children exposed to high concentrations.[28] To prevent accidental exposure to the mucous membranes, repellents containing DEET should not be applied to children's hands.

Tick repellent containing DEET or permethrin are appropriately used when exposure to an endemic environment is imminent. DEET is available in 5-100% concentrations as sprays, creams, gels, lotions, solutions, towelettes, and other formulations. In most circumstances, products containing 10-35% DEET are sufficient to provide adequate protection from ticks.

The degree of protection is proportionally related to the concentration of DEET. That is, products with a high DEET concentration provide a long duration of protection. Extended-release liposphere microdispersion DEET preparations (6.5% and 10%) may decrease exposure to high concentrations of DEET while maintaining a relatively long (2-4 h) duration of activity.

Other recommendations to reduce DEET exposure include the following[28] :

  • Use a minimal amount of product to cover the exposed skin and clothes
  • Avoid contact with mucous membranes, open cuts, or irritated skin
  • Wash treated areas with soap and water immediately after returning indoors

Antibiotic prophylaxis

In general, avoiding exposure and removing ticks promptly is a much better strategy than using prophylactic antibiotics. Even in endemic areas, the risk of transmission from a tick bite is estimated to be only 1-2%. For patients with unattached ticks or with ticks that are not engorged, no prophylactic therapy is recommended. For a description of criteria for prophylactic antibiotic use, see Treatment.

Animals

Because pets can develop Lyme disease and can carry ticks, making sure they are wearing tick collars seems prudent. Applying the suggestions concerning skin inspection may also be prudent after playing with outdoor pets. Any ticks found on pets should be removed promptly. In animal studies, a preferred method of removing ticks is not clearly evident. Removal by holding on to the body of the tick does not increase the transmission rate.

 

Presentation

History

Because only approximately 25-30% of United States patients with early Lyme disease recall the tick bite, the clinician must direct the history toward the possibility of a tick bite. (In Europe, 64% do not remember being bitten.) Patients are generally unaware of a tick bite because these ticks are extremely small (nymphal Ixodes ticks are approximately the size of a poppy seed) and their bites are often painless.

Epidemiologic context is extremely important. The clinician should determine where the patient lives, works, and vacations, and should ask about specific activities in which the patient participates at those locales. The probability of a tick bite—and thus, the likelihood of contracting Lyme disease—is highest in persons who spend time outdoors (particularly in wooded, brushy, or grassy habitats) in a geographically endemic area.

Endemic areas can be defined as those with established populations of Ixodes scapularis or other vector ticks and evidence of enzootic transmission of Borrelia burgdorferi between the tick and the resident animal population. (See Epidemiology.)

The season is important, especially in patients with early disease. Most cases of erythema migrans occur from late spring through early fall, because that is when ticks in the nymphal stage are seeking a blood meal, and nymphs account for 90% of Lyme disease cases. For patients presenting with later cutaneous manifestations, especially acrodermatitis chronica atrophicans, questions must be directed at assessing the risk of tick bite (or previous manifestations of Lyme disease) from many years in the past.

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 previously had 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.

Reinfections manifest in much the same ways 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.[10]

Certain manifestations of Lyme disease are related to the particular strain of Borrelia involved. In the United States, isolates from the East Coast are known as B burgdorferi sensu stricto, and infection with this organism has a particular predilection to affect joints, whereas other strains are more common in Europe, such as B burgdorferi afzelii, which is associated with acrodermatitis chronica atrophicans.

Similar to syphilis, the manifestations of Lyme disease have been divided into three stages: localized, disseminated, and persistent. However, in individual patients, no rigid cutoffs exist between stages. The first two stages are part of the early infection, whereas persistent disease is considered late infection. Unlike syphilis, stage 3 disease may occur within 1 year of infection, not many years later.

Stage 1 Lyme disease

Early localized Lyme disease refers to isolated erythema migrans and to an undifferentiated febrile illness. This stage occurs 1-30 days after the tick bite.

Erythema migrans, the characteristic skin rash of Lyme disease, occurs in two thirds of patients with Lyme disease and develops at an average of 7 days after the tick bite.[3] The rash typically occurs at or near the site of the tick bite, which may be an area not normally visualized by individuals, such as the axilla, groin, or popliteal areas. It may be asymptomatic or it may itch or burn.

The rash typically expands over days and is not evanescent. It may not be observed until it is already full size. Clearing of portions of the rash as it expands may result in concentric rings of erythema, producing the classic bull’s-eye rash (see the image below). In the United States, however, erythema migrans is more likely to have a uniform color.

Bulls-eye rash. Bulls-eye rash.

Although many patients present with erythema migrans, others first present with extracutaneous symptoms. In those cases, erythema migrans may have never occurred or may not have been recognized by the patient or correctly diagnosed by the physician.

Untreated, the rash may persist for 2-3 weeks. Eighty percent of patients with Lyme disease have only one episode of erythema migrans, whereas 20% may have recurrent episodes. Multiple lesions may occur in 20% of patients with Lyme disease; they result from hematogenous dissemination and are not the result of multiple tick bites (see the following image).

Multiple lesions of erythema migrans occur in appr Multiple lesions of erythema migrans occur in approximately 20% of patients. A carpenter from Nantucket who worked predominantly outside had been treated with clotrimazole/betamethasone for 1 week for a presumed tineal infection, but the initial lesion grew, and new ones developed. He then presented to the emergency department with the rashes seen in this photo. The patient had no fever and only mild systemic symptoms. He was treated with a 3-week course of oral antibiotics.

Approximately 50% of patients describe flulike symptoms within days to 1 week of infection, characterized by fever, chills, and malaise. Fever is generally low grade. Other symptoms include fatigue and myalgia (80% of patients with Lyme disease in the US but < 35% in Europe), as well as arthralgia, headache, and neck stiffness, which may resolve spontaneously even if specific therapy is not initiated. A paucity of respiratory and gastrointestinal tract symptoms may also be present.[29]

The most common ocular manifestations of stage 1 Lyme disease are redness and tearing.

Approximately one third of all patients with erythema migrans develop no further manifestations of Lyme disease. Two thirds of patients develop further symptoms (stages 2 and 3).

It is also important to consider co-infection by other organisms transmitted by the same tick bite, in areas where those are endemic. Co-infection with Ehrlichia species and Babesia microti are reported with increased frequency; in some studies, co-infection occurs in as many as 10-15% of patients with Lyme disease. When Lyme disease is strongly suggested but some of the manifestations are atypical (eg, a high fever, especially if accompanied by rigors or a toxic appearance) these other tick-borne infections or an alternative diagnosis must be considered.

Stage 2 Lyme disease

Early disseminated Lyme disease usually develops 3-10 weeks after inoculation. Approximately 25% of individuals infected with B burgdorferi have signs and symptoms of disseminated disease at presentation.

Systemic manifestations may include fever and malaise. One or more organ systems become involved as hematologic or lymphatic spread disseminates spirochetes to distant sites. Musculoskeletal and neurologic symptoms are the most common; less common are symptoms from cardiac disturbances, such as dizziness, syncope, dyspnea, chest pain, and palpitations.

Ocular manifestations include diplopia secondary to a cranial neuropathy or Bell palsy. Blurred vision and eye pain can occur from keratitis and iritis. Unilateral blindness from panophthalmitis has been reported as well.

Musculoskeletal manifestations

Intermittent inflammatory arthritis often begins as a migratory polyarticular process involving bursae, tendons, and joints, which evolves over 1-2 days into a monoarticular process involving the knee, ankle, and wrist, in decreasing frequency. When asked about symptoms after they have resolved, patients with Lyme disease are less likely to remember those symptoms that occurred before the monoarthritis. Polyarticular episodes may also occur.

In two thirds of patients, the first episode occurs within 6 months of the erythema migrans lesion. Untreated, the episodes last approximately 1 week. Two thirds of patients have three recurrences approximately 2.5 months apart. The recurrences are more likely to involve more than one joint. With time, these episodes become less frequent and severe and involve fewer joints. Even without treatment, the recurrent episodes usually resolve over a 10-year period.

Some patients may present with intermittent joint pain without inflammatory findings. This is more common in Europe, where arthritis was not recognized as a manifestation of Lyme disease until the early reports from the United States.

Neurologic manifestations

Neurologic involvement, also known as Lyme neuroborreliosis, is reported in 5-20% of cases. In the United States, cranial neuropathy is the most common manifestation of early neurologic Lyme disease. Other manifestations include meningitis and encephalopathy.

Cranial neuropathies, especially facial nerve palsy (Bell palsy), develop in approximately 3% of Lyme disease patients. In endemic areas, Lyme disease is the most commonly identified cause of acquired facial palsy, especially in children.[30] Headache, absence of previous herpetic lesions, and meningeal symptoms are noted in most pediatric Lyme disease patients with facial palsy.[30]

When meningitis is involved, symptoms usually occur 2-10 weeks following infection. Headache, neck pain or stiffness, and photophobia typically indicate meningeal irritation. The headache of Lyme disease typically is described as waxing and waning, and the severity varies from mild to severe, even in patients with frank meningitis. Persistent headache alone is a rare presentation of Lyme disease but should be considered in patients in endemic areas during summertime.

Borrelia encephalopathy most commonly manifests as a mild confusional state accompanied by disturbances in memory, concentration, mood, sleep, personality, and/or language occurring months to years after the infection. Depression and irritability are also common.

Cutaneous manifestations

In patients with cutaneous involvement, multiple erythema migrans lesions are present. These are relatively small erythematous macules (1-5 cm) and are often oval. Unlike primary single erythema migrans rashes, these lesions can be evanescent and do not show the typical expansion over days.

Borrelial lymphocytoma is an uncommon manifestation of early disseminated Lyme disease (though it may also occur very early in the disease course) that has been reported only from Europe. It is a bluish-red nodular swelling that typically occurs on the lobe of the ear in children (see the following image) or the areola of the nipple in adults. Occasionally, borrelial lymphocytoma lesions occur on the scrotum, nose, and extremities. Nipple lesions tend to be painful, possibly because of rubbing against clothing.

Borrelial lymphocytoma of the earlobe, which shows 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.

Stage 3 Lyme disease

Late or chronic Lyme disease refers to manifestations that occur months to years after the initial infection, sometimes after a period of latency. Signs and symptoms of chronic Lyme disease are primarily rheumatologic and neurologic. Acrodermatitis chronica atrophicans, the cutaneous feature of late-stage Lyme disease, is found almost exclusively in European patients.

Most patients presenting with late disease do not have a history of erythema migrans, because the rash typically leads to earlier treatment, which prevents the development of late disease. However, 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.

Lyme arthritis is the hallmark of stage 3 Lyme disease. It tends to involve large joints (the knee is involved in 90% of cases). Arthritis must be differentiated from arthralgia, which is common in early disease.

The neurologic abnormalities of stage 3 Lyme disease involve both the central and peripheral nervous systems. Typical presentations include subacute encephalopathy, chronic progressive encephalomyelitis, and late axonal neuropathies, as well as symptoms consistent with fibromyalgia. Radicular pain can occur and present as acute disk disease. More common in European patients, radicular pain may be associated with lymphocytic pleocytosis (Bannwarth syndrome).

Borrelia encephalomyelitis is a rare but severe syndrome. Symptoms can progress gradually or in a relapsing-remitting pattern, with partial improvement after the attacks. The most common clinical manifestations of Borrelia encephalomyelitis are hemiparesis, ataxia, seizures, cognitive impairment, bladder dysfunction, and hearing loss. Myelitis is present in 50% of patients with late neuroborreliosis. Progressive spastic paraparesis or quadriparesis is common.

Acrodermatitis chronica atrophicans most commonly affects older women. 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. Initially, there is discoloration and inflammation; later, severe atrophy is noted.[13] See the image below.

Acrodermatitis chronica atrophicans is found almos Acrodermatitis chronica atrophicans is found almost exclusively in European patients and comprises an early inflammatory phase and a later atrophic phase. 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 Examination

In many patients with early Lyme disease, identification of erythema migrans (EM) on physical examination alone is sufficient to establish a working diagnosis of Lyme disease. 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 findings must be interpreted in the epidemiologic context; this cannot be overemphasized. The location, time of year, and patient's activities can be important diagnostic clues.

Regional lymphadenopathy may be seen, and 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.

Erythema migrans

EM is the characteristic rash of Lyme disease. Classic EM is a flat to slightly raised erythematous lesion that appears at the site of the tick bite after 1-33 days bite (average, 7-10 days).[31] Without therapy, erythema migrans typically fades within 3-4 weeks.

EM usually is round or oval, but can be triangular or linear. Often, a central punctum is evident at the bite site.

EM enlarges by a few centimeters per day; single lesions typically achieve a diameter of approximately 16 cm (approximately 5-6 inches), but lesions as large as 70 cm have been reported. The case definition for Lyme disease used by the US Centers for Disease Control and Prevention (CDC) specifies that EM be greater than 5 cm in size. This size cutoff is only meant to be used for epidemiologic purposes, however; EM smaller than 5 cm has occasionally been documented in culture-proven cases.[32]

The entire lesion may be uniform in color or have central darkening. Central clearing is more common in European patients than in North American patients. More proximal to the clearing may be additional erythema leading to a so-called bull's eye or target appearance; however, this phenomenon, emphasized in the earlier literature, occurs only in a minority of patients (37% in one North American study of culture-proven EM).[33] See the images below.

This patient's erythema migrans rash demonstrates This patient's erythema migrans rash demonstrates several key features of the rash, including size, location, and presence of a central punctum, which can be seen right at the lateral margin of the inferior gluteal fold. Note that the color is uniform; this pattern probably is more common than the classic pattern of central clearing. On history, this patient was found to live in an endemic area for ticks and to pull ticks off her dog daily.
Classic target lesion with concentric rings of ery 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.
The rash on the ankle seen in this photo is consis The rash on the ankle seen in this photo is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (presentation in July, in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin-clavulanate) is an effective strategy.
The thorax and torso are typical locations for ery The thorax and torso are typical locations for erythema migrans. The lesion is slightly darker in the center, a common variation. In addition, this patient worked outdoors in a highly endemic area. Physical examination also revealed a right axillary lymph node.

Atypical manifestations of EM include vesicular (see the image below) and centrally necrotic lesions. Scaling is unusual, but may be seen, especially in the center of the lesion.

Photo of the left side of the neck of a patient wh Photo of the left side of the neck of a patient who had pulled a tick from this region 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.

Rash location is another important diagnostic clue. Unlike spider and other arthropod bites, EM rarely is found on the hands or feet. Rather, ticks tend to bite where natural barriers impede their forward motion (eg, popliteal fossa, axillary or gluteal folds, hairline, areas near elastic bands in bra straps or underwear). In children, the scalp, face, and hairline are especially common locations.[8, 34]

Approximately 20% of patients with EM have secondary lesions (see the image below). These lesions generally are smaller than the primary one, lack the central punctum, and are not necrotic or vesicular. They also tend to be more uniform in morphology than the primary lesion. Because secondary lesions result from hematogenous spread, their locations are not as restricted as those of the primary lesion.

Multiple lesions of erythema migrans occur in appr Multiple lesions of erythema migrans occur in approximately 20% of patients. A carpenter from Nantucket who worked predominantly outside had been treated with clotrimazole/betamethasone for 1 week for a presumed tineal infection, but the initial lesion grew, and new ones developed. He then presented to the emergency department with the rashes seen in this photo. The patient had no fever and only mild systemic symptoms. He was treated with a 3-week course of oral antibiotics.

Note that rashes very similar to erythema migrans, but from which Borrelia burgdorferi cannot be cultured, have been reported in the southern United States. 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.

An erythematous skin lesion present while an Ixodes tick is still attached is most likely a hypersensitivity reaction rather than EM. Hypersensitivity reactions also tend to produce lesions that are smaller and more transient than EM; typically, the lesions are less than 5 cm in size and begin to resolve within 2 days.

Borrelial lymphocytoma

Less than 1% of patients with stage 2 Lyme disease, almost all of them European, develop Borrelia lymphocytoma, described as a small, bluish-red nodule or plaque. The earlobe and scrotum are the typical location in children (See the image below), whereas the nipple is the more common location in adults.

Borrelial lymphocytoma of the earlobe, which shows 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.

Borrelial lymphocytoma tends to occur in areas of previous (or concurrent) erythema migrans and may be up to a few centimeters in size. Regional lymphadenopathy may be present.

Other terms used to describe borrelial lymphocytoma include the following:

  • Lymphadenosis benigna cutis
  • Lymphocytoma cutis
  • Cutaneous lymphoid hyperplasia
  • Spiegler-Fendt lymphoid hyperplasia

Acrodermatitis chronica atrophicans

Acrodermatitis chronica atrophicans is a relatively uncommon physical manifestation of late Lyme disease that 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. The lesions also tend to become symmetric. The buttocks often become involved.

Later, atrophy supervenes and so-called cigarette-paper skin is seen, with an appearance similar to scleroderma. (See the image below.) 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. One third of patients with acrodermatitis chronicum have an associated sensory polyneuropathy.

Acrodermatitis chronica atrophicans is found almos Acrodermatitis chronica atrophicans is found almost exclusively in European patients and comprises an early inflammatory phase and a later atrophic phase. 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.

Other dermatologic manifestations

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.

Other European reports less commonly link the following with B burgdorferi infection:

  • Progressive facial hemiatrophy (Parry-Romberg syndrome)
  • Eosinophilic fasciitis

Musculoskeletal findings

Muscle tenderness can result from myositis. Tenderness of tendons and periarticular structures may be present.

Frank arthritis can occur after weeks, months, or years and may lead to erythema, edema, synovial effusion, and tenderness of the affected joints. Usually, this is a monoarthritis or oligoarthritis involving large joints, especially the knee. Swelling often is disproportional to the tenderness.

Lyme arthritis

Approximately 60% of all untreated patients develop symptoms of intermittent migratory monoarthritis. Episodes last a mean of 3 months and very often affect the knee or temporomandibular joints, although not universally. Migratory oligoarthritis involving the small or large joints can also occur. Joint symptoms develop in approximately 80% of all untreated patients within 2 years of infection.

The severity of joint involvement can range from intermittent episodes of subjective pain to frank arthritis to chronic erosive synovitis. During the attacks, the joints are swollen, hot, and painful, but they are not usually red or as severe as in a septic joint. Effusions may be large and generally recur following aspiration, as is often seen in spondyloarthropathies. Fewer than 10% of patients with arthritic sequelae develop pannus or erosion of cartilage and bone.

Neurologic involvement

Approximately 5-10% of untreated patients with Lyme disease have signs of cranial neuropathies, and up to 60% of patients with early neuroborreliosis develop cranial neuritis. Seventh nerve palsy is by far the most common. Bilateral facial palsy can be seen in 35% of patients and is a unique characteristic that is useful for distinguishing it from idiopathic Bell palsy and other disorders.

Typical associated findings depend on the nerve affected and can include visual or auditory disturbances, facial paresthesia, and/or vertigo. Other neurologic manifestations include diffuse or focal mononeuropathy multiplex (multifocal involvement of anatomically unrelated nerves), plexopathy, and/or radiculoneuropathy (more common in Europe). Less common presentations include myositis, pseudotumor cerebri, and cerebellitis.

Lyme meningitis is relatively common, occurring in as many as 15% of untreated patients bitten by the Ixodes tick and in 30% of Lyme disease cases, and does not manifest as the usual signs of bacterial meningitis (eg, boardlike rigidity, Kernig and Brudzinski signs). Meningitis may be accompanied by cranial or peripheral radiculoneuropathy. Neck stiffness can occur early, with or without frank meningitis.

Acute radiculoneuritis is reported in 50-85% of cases. Acute onset of motor deficits, severe radicular pain, and sensory loss are commonly seen after 2-4 weeks of infection. Multifocal asymmetric weakness is a common presentation. Although the presentation of inflammatory radiculoneuropathy is often indistinguishable from that of spinal-root compression, involvement of multiple dermatomes in the thorax and a lack of a precipitating injury can aid in diagnosis.

Chronic radicular paresthesias are usually not associated with motor or sensory deficits. The physical examination results are normal.

With peripheral neuropathy, patients usually report intermittent paresthesias. The most frequent finding upon examination is decreased vibratory sensation of the distal lower extremities. A stocking-glove distribution of epicritic sensory deficits is also a common finding. Sensory findings are more pronounced than motor findings.

With late axonal neuropathy, patients can report intermittent distal limb paresthesias months to years after infection. It is distinct from the neuropathy of early Lyme disease, because the symptoms are less severe. Acrodermatitis chronica atrophicans–associated neuropathy is common in Europe and manifests as neuropathic pain, paresthesias, and muscle cramps.

In Europe, common manifestations of Garin-Boujadoux-Bannwarth syndrome (Bannwarth syndrome) include neuritic pain, cranial neuritis without headache, and lymphocytic pleocytosis. Bannwarth syndrome has also been called tick-borne meningopolyneuritis, lymphocytic meningoradiculitis, and chronic lymphocytic meningitis. While this manifestation is typically associated with infection with B garinii, a recent cluster was reported from the Mayo Clinic in Rochester, MN.[35]

Neuropsychiatric findings in late-stage disease may include the following:

  • Depression
  • Anxiety
  • Schizophrenia-like psychosis
  • Bipolar disorder
  • Dementia

Cardiac involvement

Cardiac involvement ranges from atrial or ventricular arrhythmias to transient heart block or myopericarditis. Approximately 8% of untreated patients have acute-onset atrioventricular conduction abnormalities. Most cardiac episodes are isolated and transient, lasting less than a week. In rare instances, patients with heart block require electrical pacing.

In patients with complete heart block, cannon A waves may be observed in the neck. A slow or irregular pulse may be palpated. A cardiac rub, S3 and/or S4, may be auscultated in patients with myocarditis or pericarditis. Signs of tamponade very rarely can occur. In patients with chronic cardiac involvement with heart failure, typical signs of chronic heart failure may be present.

Ophthalmic involvement

Ophthalmic manifestations vary by disease stage. In stage 1 Lyme disease, the ocular manifestations are conjunctivitis and photophobia. These are mild and transient, and ophthalmologists usually need not be consulted.

Significant ophthalmic complications may appear during stage 2 Lyme disease.[36, 37, 38, 39] Blurred vision can be noted during stage 2, secondary to papilledema, optic atrophy, optic or retrobulbar neuritis, or pseudotumor cerebri. Optic nerve disease may be unilateral or bilateral, and solitary or associated with other neurologic or neuro-ophthalmologic manifestations. Some evidence exists that children are more predisposed to optic nerve disease than adults.[40]

In late stage 2 or stage 3 Lyme disease, most of the severe ocular manifestations of the disease are seen. These include the following:

  • Episcleritis
  • Symblepharon
  • Keratitis
  • Iritis
  • Posterior or intermediate uveitis
  • Pars planitis
  • Vitreitis
  • Chorioretinitis
  • Exudative retinal detachment
  • Retinal pigment epithelial detachment
  • Cystoid macular edema
  • Branch artery occlusion
  • Retinal vasculitis
  • Orbital myositis
  • Cranial nerve palsies

Of this group, keratitis, vitreitis, and pars planitis are the most common. The keratitis usually is a bilateral, patchy, nummular stromal keratitis. Posterior segment inflammatory disease generally presents as a bilateral pars planitis associated with granulomatous iritis and vitreitis. Many of these patients also have granulomatous keratic precipitates and posterior synechiae.[41]

 

DDx

Diagnostic Considerations

In most patients with erythema migrans, a carefully elicited history (including definitions of epidemiologic context) and a physical examination are all that is required to establish the diagnosis of Lyme disease. However, although many patients with Lyme disease present with erythema migrans, others first present with extracutaneous symptoms. In those cases, erythema migrans may never have occurred, may not have been recognized by the patient, or may not have been correctly diagnosed by the physician.

There can be a tendency to overdiagnose Lyme disease, especially in patients with a lifestyle that puts them in a high-risk category. Performing tests when the prior probability of disease is low increases the likelihood of false-positive results. The best way to avoid problems with diagnosis is to follow the Centers for Disease Control and Prevention (CDC) guidelines regarding diagnosis (see Workup), to use a reputable laboratory with experience in testing for Lyme disease, and to obtain the assistance of an infectious disease expert when any questions arise.

Because interpretation of testing is related to stage of disease and requires a two-stage test, laboratory results are often misinterpreted. Clinicians unfamiliar with Lyme disease or Lyme testing may falsely exclude the diagnosis by testing too early in the disease course, or falsely diagnose disease by following up negative enzyme immunoassay (EIA) results with Western blot testing (the latter is indicated only in patients with a positive or indeterminate EIA result).

In addition, separating false-positive antibody tests from asymptomatic infection is impossible. Approximately 5-10% of patients in endemic areas have positive antibody results without a history of symptoms.

Unfortunately, antibodies induced by the infection are not protective against further exposures to Borrelia burgdorferi; therefore, reinfection easily could be confused with a recurrence. Because antibodies may persist for years following an infection, repeat infection is a difficult diagnosis without specific signs of Lyme disease (eg, erythema migrans). Increasing titers after adequate treatment certainly raises suspicion of an active infection, but this is not a reason to repeat posttreatment titers, as they may remain positive for many years.

Other problems to be considered include the following:

  • Ankylosing spondylitis and rheumatoid arthritis
  • Atrioventricular (AV) nodal block
  • Cellulitis (see image below)Contact dermatitis
  • Granuloma annulare
  • Confusional states and acute memory disorders
  • Gout and pseudogout
  • Prion-related diseases
  • The rash on the ankle seen in this photo is consis The rash on the ankle seen in this photo is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (presentation in July, in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin-clavulanate) is an effective strategy.

Co-infection

The pathogens responsible for babesiosis and ehrlichiosis share the same tick vector as B burgdorferi, making co-infection possible. Severe and even fatal acute infection caused by these pathogens is more common in asplenic individuals (babesiosis) or older adults (ehrlichiosis). Unlike B burgdorferi, however, these pathogens do not cause chronic infection. To add to the confusion, ehrlichial infection may cause a false-positive result for Lyme disease on immunoglobulin M (IgM) Western blot analysis.

In a prospective study from New York State, 52 adult patients with erythema migrans who had not received treatment for Lyme disease underwent testing for Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and the deer tick virus subtype of Powassan virus.  Nearly 90% of the  patients showed no evidence of co-infection. Polymerase chain reaction (PCR) tests for B microti DNA were positive in 3 patients, one of whom also had a positive blood smear; these patients also had clinical signs suspicious for babesiosis. And additional 3 patients had elevated convalescent-phase IgG titers for B microti.[42]  

The possibility of co-infection with another tick-borne pathogen should be considered if the patient’s condition does not respond to treatment as expected with ordinary early Lyme disease. Evidence suggests that co-infected patients have more symptoms of longer duration compared with other patients. In addition, these patients may be sicker than others on first observation.

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, as shown below.

Blood smear showing likely babesiosis. Babesiosis Blood smear showing likely babesiosis. Babesiosis can be difficult to distinguish from malaria on a blood smear.

Differential Diagnoses

 

Workup

Approach Considerations

In endemic areas, patients with probable erythema migrans and a recent source of tick exposure should be started on treatment without blood tests. At this early stage (the first several weeks of illness), the clinical probability of Lyme disease is high and the sensitivity of serologic tests is low. If the lesion is indeed erythema migrans, improvement should occur within a few days after initiation of empiric antibiotics, along with resolution of any constitutional symptoms.

Alternatively, observing the rash over several days is safe. In most patients with erythema migrans, some expansion of the rash is expected over 2-3 days without antibiotics. This is a reasonable alternative to immediate empiric therapy.

In contrast, laboratory tests are important for establishing the diagnosis in the many patients with suspected Lyme disease who do not recall a tick bite and did not notice or do not have erythema migrans. However, much confusion can occur in the interpretation of the tests used for Lyme disease.[41]

The most widely used tests for Lyme disease are antibody detection tests, which can demonstrate that a patient has been exposed to Borrelia burgdorferi but cannot confirm infection. In the presence of typical clinical manifestations and laboratory results suggestive of current disease activity (eg, elevated synovial and spinal fluid cell counts), they support the clinical diagnosis.

The US Centers for Disease Control and Prevention (CDC) recommends a two-step testing procedure. The first step typically consists of a screening enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA); if results are positive or equivocal, a Western immunoblot test is performed to confirm the results.[2]

In July 2019, the US Food & Drug Administration (FDA) approved the use of concurrent or sequential EIA testing for diagnosis of Lyme disease. The FDA approved the new indication on the basis of data from clinical studies showing that this alternative approach, referred to as a modified two-tier test, is as accurate as testing with EIA or IFA plus Western blot.[85]

Routine use of sequential serologic testing in individual patients with early Lyme disease should be discouraged. In addition, acute and convalescent-phase serologic testing has no role in Lyme disease. Because titers may remain elevated for extended periods (as can the positivity of Western blots), convalescent testing is not helpful.

Culturing B burgdorferi is impractical. Obtaining adequate samples requires an invasive procedure, such as biopsy or lumbar puncture, and the organism is difficult to grow.

Even if the tick that bit the patient is available, testing the tick for B burgdorferi is not recommended. The presence or absence of B burgdorferi in an Ixodes tick does not reliably predict the likelihood of Lyme disease.[6]

Biopsy of dermatologic lesions suggestive of borrelial lymphocytoma or acrodermatitis chronica atrophicans in patients without a clear history of other symptoms suggestive of Lyme disease may be helpful. Biopsy of other skin lesions should be restricted to research settings.

Most, but not all, patients with borrelial lymphocytoma are seropositive for antiborrelial antibodies. This is true for all early disseminated manifestations of Lyme disease. In addition, essentially all patients with acrodermatitis chronica atrophicans are seropositive for antiborrelial antibodies. Seriously question the diagnosis in seronegative patients.

In patients with clinical findings typical of Lyme disease, a complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), and liver function tests generally are unnecessary. However, leukopenia or thrombocytopenia suggests co-infection with Ehrlichia or Babesia species. Elevation of at least one liver enzyme level is reported to occur in 40% of patients with Lyme disease. This finding also is common in ehrlichiosis.

On urinalysis, microscopic hematuria and mild proteinuria have been described. Urine antigen testing has not been studied sufficiently. Because it has not been proven reliable or accurate, it should not be used as a diagnostic tool.

Joint aspiration for diagnostic reasons is unnecessary if only Lyme arthritis is suspected. However, arthrocentesis may be appropriate to exclude other causes of effusions, such as septic arthritis or, in adults, gout and pseudogout. In Lyme arthritis, joint fluid may have 25,000-125,000 white blood cells (WBCs)/µL, often with a polymorphonuclear predominance.

A retrospective study of children in areas where Lyme disease is endemic who presented with knee monoarthritis found that the presence of a peripheral blood absolute neutrophil count of 10 × 103 cells/mm3 or higher and an ESR of 40 mm/hour or higher predicted septic arthritis; no child with values below those cutoffs had septic arthritis. These researchers suggested that those criteria could be used to identify children with knee monoarthritis who are at low risk for septic arthritis and might not require diagnostic arthrocentesis.[43]

A draft guideline from the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR)  recommends testing for Lyme disease in patients with plausible exposure to high-risk ticks who present with meningitis, painful radiculoneuritis, mononeuropathy multiplex, or acute cranial neuropathies. The guideline recommends against routine Lyme disease testing for patients with other neurological syndromes or psychiatric illnesses.[6]

In patients with Lyme disease meningitis, cerebrospinal fluid (CSF) analysis often reveals a mild pleocytosis (< 1000 cells/µL) with lymphocyte predominance. CSF antibody is considered positive when the titer is higher than in serum.[44]

In children, the "Rule of 7's" can be used to identify those patients who are unlikely to have Lyme meningitis and can be managed in an outpatient setting while awaiting Lyme serology test results.[45] The Rule of 7’s classifies children as being at low risk when they meet the following three criteria:

  • < 7 days of headache
  • < 70% CSF mononuclear cells
  • Absence of seventh or other cranial nerve palsy

Electrocardiograms (ECGs) show fluctuating levels of atrioventricular block in patients with syncopal or near-syncopal symptoms secondary to Lyme carditis. In patients with possible exposure but without symptoms of myocardial ischemia, such changes should prompt further investigation for Lyme disease.

Imaging studies are almost never indicated in patients with Lyme disease who present with early syndromes. Patients with some clinical syndromes may require imaging studies to exclude other disorders, depending on the specifics of the case. For example, a patient with fever and severe back pain, with signs of radiculopathy, might require spine imaging.

Serologic Testing

Serologic testing for Lyme disease is complex. Rational ordering and interpretation of these test results requires some understanding of the basic underlying principles and performance characteristics of the tests. The test results do not rule in or rule out Lyme disease; however, the results make a clinical diagnosis of Lyme disease more (or less) likely.

The most frequently used test is the enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA). Much less often used for this purpose is the immunofluorescent assay (IFA).[2]

The principal limitation of these serologic tests has been the high frequency of both false-negative results and false-positive results. False-negative results occur during the acute phase of Lyme disease, when patients have not yet developed a sufficient antibody response to give a positive serologic test. Seroconversion can take as long as 6-8 weeks after a tick bite. The false-negative rate for ELISA is 32% in early disease.

A variety of diseases, including Rocky Mountain spotted fever, syphilis, systemic lupus erythematosus, and rheumatoid arthritis, can cause false-positive ELISA results. Also, a small percentage of the healthy population has positive test results with ELISA testing. For these reasons, confirmatory Western blot testing is recommended.

Patients with early Lyme disease who are treated with antibiotics may never develop positive titers. Of patients with early disseminated disease, 90% have a positive titer. Some patients with late disease are seronegative, but significant controversy exists regarding the frequency of late seronegativity. Most authorities suggest that this phenomenon is rare.

Two-tier testing

The US Centers for Disease Control and Prevention (CDC) recommends a two-step testing procedure. The first step typically consists of an EIA or ELISA.[2] The test for the first step may measure either a total Lyme titer or separate immunoglobulin G (IgG) and immunoglobulin M (IgM) titers.

If the results of the initial test are positive or equivocal, the second step is to confirm the results with a Western blot. If signs and symptoms have been present for 30 days or less, both IgM and IgG Western blot testing are performed; if signs and symptoms have been present for more than 30 days, only IgG Western blot testing is performed.

For IgM blots, the test is considered positive if any two of the following three bands are present, as they are the most commonly found in early disease:

  • 23 kd
  • 39 kd
  • 41 kd

For IgG blots, any five of the following bands are considered a positive test result:

  • 18 kd
  • 21 kd
  • 28 kd
  • 30 kd
  • 39 kd
  • 41 kd
  • 45 kd
  • 58 kd
  • 66 kd
  • 93 kd

A positive IgM titer is reliable only when measured 30 days or less from symptom onset. In patients with a high probability of having early Lyme disease, IgM testing is 96% specific and 93% predictive. In the absence of treatment, IgM titers usually peak 6-8 weeks after infection and disappear within 4-6 months, although levels sometimes remain elevated for several months or years.

IgG antibodies are typically detectable within 6-8 weeks after infection, peak within 4-6 months, and remain elevated indefinitely. In late-stage disease (>4-6 wk after infection), IgG results are more useful than IgM results.

Careful consideration of both IgG and IgM antibodies is essential because the IgG response may be negative in as many as 50% of patients (particularly those with early disease), whereas a persistence of IgM antibodies can lead to false-positive findings in patients infected for more than 1 month who subsequently receive effective treatment. Of note, serologic results can remain positive years after adequate treatment and cannot be used to distinguish active from inactive disease. Similarly, positive IgM titers with negative IgG more than 6-8 weeks after exposure in an untreated patient is thought to represent a false-positive test.

Two-step testing is not indicated for patients with erythema migrans, because the rash may develop before the antibodies. Nor is it recommended for patients who have not been in endemic areas, because of the high false-positive rates in that setting. In addition, inadequate antibiotic therapy for early Lyme disease may fail to control the infection yet still suppress the antibody response, potentially yielding a false-negative result.

Western blot testing should be performed only in conjunction with antibody titer testing, and only as followup of a recent positive or equivocal ELISA titer. Ordering a “Lyme titer with reflex testing” ensures that two-step testing is performed properly.

In the United States, patients with extracutaneous involvement in the absence of treatment almost universally have positive titers.[46] In Europe, negative serum titers have been reported in patients with neurologic Lyme disease that was confirmed by intrathecal antibody production.

The results of one study noted that differing sensitivity and specificity were found between various assays used to detect anti-Borrelia antibodies in patients suspected of having Lyme disease. False-positive results occurred in 7% of healthy controls in two of the eight ELISA assays tested. This variability makes it very difficult to compare results from different laboratories, both among different patients and in individual patients.[47]

C6 peptide testing

A newer serologic test that measures IgG to a peptide from the sixth invariant region (C6) of the variable major proteinlike sequence-expressed (VlsE) lipoprotein of B burgdorferi may be more sensitive in patients with erythema migrans.[46] However, because the recommendation in patients with erythema migrans is to treat without obtaining laboratory tests,[4] there is no clear reason to perform this assay in clinical practice. The C6 peptide test may be effective in differentiating southern tick-associated rash illness (STARI) from Lyme disease, as well as confirming infection in patients who may have been infected in Europe.

Polymerase Chain Reaction Testing

Polymerase chain reaction (PCR) testing is growing in uses and availability, but is not readily available to most clinicians in routine practice. PCR remains a research technique in part because laboratories performing PCR tests must be meticulous in technique to minimize the likelihood of false-positive results. In addition, no large clinical series have been reported that assess the performance of Lyme disease PCR in the nonresearch setting.

PCR can be used to detect B burgdorferi DNA in the blood, CSF, urine, or synovial fluid within weeks of infection. The result is positive in approximately 30% of patients with active Lyme disease.

A notable disadvantage of PCR testing is the likelihood of false-negative results because of a sparsity of spirochetes in infected tissues. Likewise, inexperience with the PCR technique can yield false-positive findings when care is not taken to prevent contamination and when incorrect primers are used in preparing the specimen.

Although most PCR results become negative within 2 weeks of antimicrobial therapy, results can remain positive for years after apparent cure. One of the most compelling uses of PCR may be in confirming persistent or recurrent disease, because a positive result is highly specific for exposure to B burgdorferi.

With the exception of synovial fluid, PCR testing is not recommended because of unacceptable low sensitivity, especially from the CSF (though it does have high specificity if the result is positive). CSF titers to B burgdorferi should not be used for diagnosis of Lyme meningitis but may have value in patients who have recurrent infection or for following serial markers in patients with persistent symptoms. CSF titers should be performed and interpreted at a reference laboratory.

Blood Studies

In patients with Lyme disease, the white blood cell count (WBC) can be normal or elevated. The erythrocyte sedimentation rate (ESR) is usually elevated. The serum aspartate transaminase (AST) may be elevated. On complement testing, C3 and C4 levels are generally normal or slightly elevated. Antinuclear antibody (ANA) and rheumatoid factor test results are negative.

Synovial Fluid Analysis

In patients with Lyme arthritis, synovial fluid is usually inflammatory, with cell counts ranging from 500-98,000/µL reported. In adult patients, the fluid should also be examined for crystals to rule out gout and pseudogout.

One study that included 63 patients with Lyme arthritis found that although the majority had positive polymerase chain reaction (PCR) results for B burgdorferi DNA in synovial fluid, none of the samples tested were positive for B burgdorferi messenger RNA (a marker of spirochetal viability), even when the specimen was obtained before initiation of antibiotic treatment. These results suggest that detection of B burgdorferi DNA in synovial fluid is not a reliable test for active joint infection in Lyme disease.[48]

Cerebrospinal Fluid Evaluation

A lumbar puncture should be performed if Lyme meningitis is in the differential diagnosis. Whether all patients with cranioneuropathy require lumbar puncture before treatment is controversial. Occasionally Lyme disease presents as pseudotumor cerebri, and in such cases an opening pressure is essential for diagnosis. In most patients with isolated Bell palsy and no associated signs of aseptic meningitis, most physicians do not perform a lumbar puncture.

For most other patients with cranioneuropathies and suspected Lyme disease, a lumbar puncture should be performed, particularly in patients who live in an endemic area and present during peak Lyme disease season. Computed tomography (CT) scan or magnetic resonance imaging (MRI) should be performed before the lumbar puncture if increased intracranial pressure or mass lesion is suspected.

Unlike most bacterial infections in the spinal fluid, Lyme disease produces a pleocytosis characterized by mononuclear cells. In addition, spinal fluid levels of IgM and IgG antibodies to B burgdorferi should be measured, and an index of cerebrospinal fluid (CSF) to serum antibody (immunoglobulin-to-albumin ratio) should be calculated.[49] This is particularly true in patients who have no other signs of Lyme disease.

Although CSF cultures are positive in fewer than 10% of Lyme disease patients with apparent meningitis, intrathecal antibodies and a lymphocytic pleocytosis (approximately 100 cells/µL) are present in more than 80%. Patients with meningitis typically have elevated protein concentrations (>50 mg/dL) but normal glucose levels (45-80 mg/dL). Oligoclonal bands specific for B burgdorferi may be present.

Ongoing controversy surrounds the diagnosis of neurologic Lyme disease. One of the most important concepts to understand is that a positive Lyme disease serology in CSF does not mean that the patient has neuroborreliosis. It could represent evidence of a previous infection or simply reflect potential leakage of serum antibodies across the blood-brain barrier.[50] IgG and IgM antibodies may persist in CSF long after adequate treatment and in the absence of evidence of active neurologic disease.

Intrathecal anti-Borrelia antibody production is typically seen within 3-6 weeks of infection. Anti-Borrelia antibody CSF-to-serum index has been reported to show a 97% specificity and 75% sensitivity for the diagnosis of neuroborreliosis.[5] A CSF-to-serum index greater than 1.0 suggests synthesis of antibody in the central nervous system (CNS).

It has been proposed that four of the following five criteria should be present in order to diagnose neuroborreliosis[51] :

  • No past history of neuroborreliosis

  • CSF anti-B burgdorferiantibodies

  • Positive anti-B burgdorferi antibody index

  • Favorable clinical outcome after proper antibiotic therapy

  • Absence of alternative diagnosis

Brain Imaging

Magnetic resonance imaging (MRI) shows abnormalities in approximately 15-20% of patients in the United States who have neurologic manifestations of Lyme disease. In European patients with CSF-confirmed Lyme disease, imaging findings have suggested that microvasculitis and macrovasculitis in the central nervous system may be responsible for neurologic sequelae and the MRI changes seen in patients with neuroborreliosis.

Punctate lesions of the periventricular white matter are common and resemble changes seen in demyelinating or inflammatory disorders. In an attempt to differentiate radiologic manifestations of neuroborreliosis and multiple sclerosis, one study proposed that occult brain tissue damage (seen by brain magnetization transfer and diffusion tensor magnetic resonance) are not common in neuroborreliosis, as opposed to multiple sclerosis.[52] Space-occupying lesions have also been reported as a rare manifestation.

Functional brain imaging, such as single-photon emission computed tomography (SPECT) scanning, may contribute to the diagnosis of chronic neurologic Lyme disease. In a study of SPECT scanning in 183 patients who met the clinical definition of chronic Lyme disease, 75% showed abnormalities in perfusion to various areas of the brain. By comparison, MRI demonstrated brain abnormalities in only 14% of study patients. In 70% of patients, the abnormalities resolved or improved over 1-2 years with antibiotic treatment.[53]

Culture

Because of the fastidious growth requirements for B burgdorferi, culture has not been a useful test in the past. In routine practice, borrelial cultures are often unavailable.[54]

In the skin, where findings are most likely to be positive, culturing is least likely to be clinically useful, except in cases of atypical rash. In other body fluids (eg, blood, synovial fluid, CSF), the yield is lower. Although one study from an endemic area reported positive blood culture results in 43.7% of untreated adult patients with erythema migrans, this required culturing specifically for Lyme disease. In addition, all but two of the 213 patients met CDC criteria for Lyme disease and warranted treatment, regardless of culture results.[8]

Biopsy

Approximately 60-80% of specimens isolated from the leading edge of a suspected erythema migrans lesion by means of saline-lavage needle aspiration or 2-mm punch biopsy reveal B burgdorferi. However, because the presence of a lesion along with a compatible history and clinical presentation are sufficient to initiate treatment, these skin biopsy procedures are seldom performed.

Histologic Findings

Histologic findings in erythema migrans 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 infiltrates 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.

Borrelial lymphocytoma

Histologic examination is recommended in patients with suspected borrelial lymphocytoma, when the location of the lesion or the clinical history is not clear enough to support a diagnosis. Borrelial lymphocytoma biopsy specimens show a dense dermal lymphocytic infiltrate with lymphoid follicles and pseudogerminal centers. Lymphocytes with both B- and T-cell markers, occasional macrophages, plasma cells, and eosinophils are seen.

Acrodermatitis chronica atrophicans

In acrodermatitis chronica atrophicans, 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 acrodermatitis chronica atrophicans 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 one patient, cultivation was successful more than 10 years after the lesion's first appearance.

 

Treatment

Approach Considerations

Antibiotic selection, route of administration, and duration of therapy for Lyme disease are guided by the patient’s clinical manifestations and stage of disease, as well as the presence of any concomitant medical conditions or allergies. Prompt treatment increases the likelihood of therapeutic success. With prompt and appropriate antibiotic treatment, most patients with early-stage Lyme disease recover rapidly and completely.

A draft guideline from the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR) recommends administering a single dose of oral doxycycline for prophylaxis within 72 hours of removing a tick after a high-risk bite. For a bite to be considered high risk, it must be from an Ixodes tick, in a highly endemic area, and from a tick engorged and attached for 36 hours or more. The dose is 200 mg for adults and 4.4 mg/kg, up to a maximum of 200 mg, for children. Antibiotic prophylaxis should not be given for tick bites that are equivocal or low risk.[6]

Doxycycline has traditionally been considered contraindicated in patients younger than 8 years and in pregnant and breastfeeding women. Although more recent research suggests that doxycycline for at least up to 14 days is safe in young children, amoxicillin remains the usual first choice for pediatric patients.[6] See the tables below.

Table 1. Clinical presentation and therapy for the stages of Lyme disease (Open Table in a new window)

Disease

Stage

Clinical

Manifestations

 

Treatment

 

Duration

Early localized

Erythema migrans

Oral

10-14 days

(azithromycin, 7 days)

Early disseminated

Multiple erythema migrans

Oral

14 days

Isolated cranial nerve palsy

Oral

14-21 days

Meningoradiculoneuritis

Oral

14-28 days

Meningitis

Intravenous or oral

14-21 days

Carditis

 

 

-Ambulatory

Oral

14-21 days

-Hospitalized

Intravenous followed by oral

14-21 days

Borrelial lymphocytoma

Oral

14 days

Late

Arthritis

Oral

28 days

Recurrent arthritis after oral therapy

Oral or intravenous

28 days or 14-28 days

Encephalitis

Intravenous

14-28 days

Acrodermatitis chronica atrophicans

Oral

21-28 days

Table 2. Adult and pediatric treatment options, dosages, and routes of administration (Open Table in a new window)

 

Treatment

Adult Dose

Pediatric Dose

Oral Therapy

Doxycycline

(patients =8 y)

100 mg twice a day

4 mg/kg (up to 100 mg)

twice a day

Amoxicillin

500 mg three times a day

50 mg/kg (up to 500 mg)

three times a day

Cefuroxime axetil

500 mg twice a day

30 mg/kg (up to 500 mg)

twice a day

Phenoxymethylpenicillin

500 mg four times a day,

or 1 gm three times a day

50-100 mg/kg/day in three divided doses;

maximum 1 g/dose

Azithromycin

(for patients unable to take doxycycline or beta-lactams)

500 mg once a day

 

50-100 mg/kg/day in three divided doses;

maximum 1 g/dose

Intravenous therapy

Ceftriaxone

2 g once a day

10 mg/kg/day 

(maximum, 500 mg/day)

Cefotaxime

2 g every 8 h

150-200 mg/kg (up to 2 g) every 8 h

Penicillin G

18-24 million U/d divided

every 4 h

200,000-400,000 mg/kg

(up to 2 g) every 8 h

In most patients with carditis, prompt institution of appropriate antibiotics is the only treatment needed. However, occasional patients with Lyme disease–related atrioventricular (AV) block may require hospitalization for temporary cardiac pacing. The indications for cardiac pacing are the same as for any other patient with varying degrees of heart block. Permanent pacing is very rarely needed.

Symptoms of arthritis may persist for a few weeks beyond adequate therapy. Repeat treatment usually is not necessary unless symptoms worsen or persist beyond 2 months.

Persistent arthritis after clearance of the infection is most likely related to autoimmunity and is more prevalent among individuals with HLA-DR2, HLA-DR3, or HLA-DR4 allotypes. These patients should be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), plus hydroxychloroquine if necessary. As a last resort, such patients may need a synovectomy to eradicate the inflammatory arthritis in the involved joint.

Neurologic manifestations of Lyme disease in both adults and children respond well to penicillin, ceftriaxone, cefotaxime, and doxycycline. Although most studies of neuroborreliosis have used intravenous antibiotics, European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, or radiculitis, with intravenous regimens reserved for patients with parenchymal central nervous system (CNS) involvement, other severe neurologic symptomatology, or failure to respond to oral treatment.[5]

Borrelial lymphocytoma is sufficiently uncommon that no comparative trials address the ideal duration of treatment, route of administration of the antibiotic, or the choice of medication. Treatment is usually with 14-21 days of oral antibiotics. When symptoms of dissemination are noted, however, parenteral therapy sometimes is used.

Physicians should observe patients closely for possible Jarisch-Herxheimer reactions after the institution of therapy. This allergic/inflammatory response may manifest in the skin, mucous membranes, viscera, or nervous system.

In endemic areas, antibiotic prophylaxis may be appropriate for selected patients with a recognized tick bite (see Prevention). Prophylactic antibiotics are not routinely recommended, however, as tick bites rarely result in Lyme disease, and if infection does develop, early antibiotic treatment has excellent efficacy.

Several groups have published Lyme disease guidelines. The Infectious Diseases Society of America (IDSA) has released clinical practice guidelines for the assessment, treatment, and prevention of Lyme disease.[4] The American Academy of Neurology has established guidelines for the treatment of nervous system Lyme disease.[5]

The International Lyme and Associated Diseases Society (ILADS) issued updated recommendations for the management of Lyme disease in 2014.[55] The recommendations are all based on "very low quality evidence" and use patient preference as major portion of the support for the recommendations. In addition, the recommendations are limited to three specific aspects of Lyme disease. The differences between the IDSA and ILADS recommendations are outlined in the table below.

Table 3. Comparison of Infectious Diseases Society of America (IDSA) and International Lyme and Associated Diseases Society (ILADS) recommendations for Lyme disease treatment (Open Table in a new window)

Treatment Focus

IDSA

ILADS

Treatment of a tick bite without symptoms of Lyme disease

Doxycycline, 200 mg as a single dose

Doxycycline, 100 mg bid for 20 days

Erythema migrans

Doxycycline, amoxicillin, or cefuroxime for 14-21 days

Doxycycline, amoxicillin, or cefuroxime for 28-42 days or azithromycin for at least 21 days

“Persisting symptoms of Lyme disease”

No antibiotic therapy

Multiple agents (individually or in combination) are mentioned without specific doses or duration recommended

Controversy regarding the treatment of Lyme disease abounds, including an antitrust investigation initiated in 2008 by the Connecticut Attorney General (CAG) into the development process for the 2006 IDSA Lyme disease treatment guidelines. The CAG claimed the process was tainted by suppression of scientific evidence and conflicts of interest.[56]

In April 2008, the CAG and the IDSA reached an agreement to end the investigation. In 2010, a review panel convened as part of that agreement concluded that “the IDSA’s 2006 Lyme disease guidelines were based on the highest-quality medical and scientific evidence available at the time and are supported by evidence that has been published in more recent years.”[57]

Treatment of Early Lyme Disease

Early localized Lyme disease refers to isolated erythema migrans and to an undifferentiated febrile illness. This stage occurs 1-30 days after the tick bite. In endemic areas, patients with erythema migrans and a recent history of possible or proven tick exposure can be treated empirically, without laboratory confirmation of the diagnosis. Serologic testing is appropriate for patients who present more than 3 weeks after tick exposure.

Doxycycline, amoxicillin, cefuroxime axetil, or phenoxymethylpenicillin is recommended for the treatment of adult patients with early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of specific neurologic manifestations or third-degree heart block. Antibiotics recommended for children include amoxicillin, cefuroxime axetil, and  phenoxymethylpenicillin; in children 8 years and older, doxycycline may be used. Because of its cost, cefuroxime axetil is reserved for patients unable to take amoxicillin or doxycycline

Treatment for 10 to 14 days is recommended (10 d for doxycycline and 14 d for amoxicillin, cefuroxime axetil, or phenoxymethylpenicillin).[6]  Longer treatment was previously recommended.[58, 59] Erythema migrans typically shows improvement within a few days after the institution of appropriate antibiotic therapy.

The macrolide antibiotic azithromycin is an alternative agent that can be used when the first-line agents are not tolerated or are contraindicated. Although one study found amoxicillin significantly superior to azithromycin for atients with erythema migrans, other studies have found that azithromycin has clinical efficacy comparable to that of other antimicrobials.[6, 60]  

Neurologic Lyme disease is effectively treated with a 2-week course of parenteral penicillin, ceftriaxone, or cefotaxime.[5, 61] Oral doxycycline is as efficacious as parenteral antibiotics in patients who have Lyme-associated meningitis, facial nerve palsy, or radiculitis.[5]

Pregnancy

For pregnant women with erythema migrans, 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 erythema migrans.[62]

Pregnant women who develop Lyme disease should not be treated with doxycycline or another tetracycline. Risks to the fetus include permanent discoloration of the teeth, enamel hypoplasia, and retardation of skeletal development.

Lyme Arthritis

In patients without neurologic disease, Lyme arthritis can usually be treated successfully with oral antibiotics, with an extended treatment time of 28 days. Recommended regimens for adult patients are as follows[4] :

  • Doxycycline, 100 mg twice daily
  • Amoxicillin, 500 mg three times daily
  • Cefuroxime axetil, 500 mg twice daily per day

Recommended regimens for pediatric patients are as follows[4] :

  • Amoxicillin, 50 mg/kg/day in three divided doses (maximum of 500 mg/dose)
  • Cefuroxime axetil, 30 mg/kg/day in two divided doses (maximum of 500 mg/dose)
  • Doxycycline, 4 mg/kg/day in two divided doses (maximum of 100 mg/dose), if the patient is 8 years of age or older

Patients with mild residual joint swelling after a recommended course of oral antibiotic therapy can be re-treated with another 4-week course of oral antibiotics. Patients whose arthritis fails to improve or worsens can be re-treated with a 2- to 4-week course of intravenous ceftriaxone. IDSA guidelines suggest that clinicians consider waiting several months before starting a second round of antibiotics, as joint inflammation tends to resolve slowly even when the infection has been eliminated.[4]

In patients with persistent arthritis despite intravenous therapy, polymerase chain reaction (PCR) of synovial fluid (and synovial tissue, if available) can be done. PCR results may remain positive for several weeks after the eradication of Borrelia burgdorferi; nevertheless, if PCR is positive for B burgdorferi DNA, the patient can be treated with oral antibiotic therapy for another month.[23]

If PCR is negative, the patient should be given symptomatic treatment with nonsteroidal anti-inflammatory drugs NSAIDs). If necessary, NSAID treatment can be supplemented with oral hydroxychloroquine, 20 mg twice daily.[23, 4] Consultation with a rheumatologist is recommended in these cases.

Eventual resolution of chronic Lyme arthritis can be expected in all patients. However, patients who continue to have significant pain or limitation of function after 3-6 months of symptomatic therapy can be considered for arthroscopic synovectomy.[23, 4]

Intra-articular corticosteroids should not be given before antibiotic treatment, as they may promote persistent Lyme arthritis. Intra-articular corticosteroids are rarely indicated after antibiotic treatment.[61]

Lyme Carditis

The patient with myocarditis generally is not very ill, and significant muscle dysfunction is unusual. Pericarditis with tamponade, while rare, has been reported.

Patients with atrioventricular (AV) heart block and/or myopericarditis associated with early Lyme disease may be treated with either oral or parenteral antibiotic therapy for 14 days (range, 14-21 days). Hospitalization and continuous monitoring are advisable for patients with any of the following[63] :

  • Associated symptoms (eg, syncope, dyspnea, or chest pain)

  • Second-degree or third-degree AV block

  • First-degree heart block with prolongation of the PR interval to more than 30 milliseconds (the degree of block may fluctuate and worsen very rapidly in such patients)

For patients with advanced heart block, a temporary pacemaker may be required; consultation with a cardiologist is recommended. Use of the pacemaker may be discontinued when the advanced heart block has resolved. An oral antibiotic treatment regimen should be used for completion of therapy and for outpatients, as is used for patients with erythema migrans without carditis.

Neurologic Manifestations

Although facial palsies may resolve without treatment, oral antibiotic therapy may prevent further sequelae. Encephalitis/encephalopathy should be treated with intravenous antibiotic therapy for 28 days.

The use of ceftriaxone in early Lyme disease has been recommended for adult patients with acute meningitis or radiculopathy. Possible satisfactory alternatives include parenteral therapy with cefotaxime or penicillin G. For patients who are intolerant of β-lactam antibiotics, increasing evidence indicates that oral doxycycline (200-400 mg/d in two divided doses orally for 10-28 d) may be adequate.[64, 65, 66] For all patients, except those with encephalitis, oral agents may be satisfactory.[67] With any regimen, neurologic symptoms may take 6 months to reach maximum improvement.

Patients with Lyme meningitis may need to be admitted not only for pain control but also for administration of intravenous antibiotics. If diagnostic uncertainty exists regarding the etiology of the meningitis, the antibiotic coverage may need to be extended for other more serious bacterial pathogens until the precise etiology is clarified.

Adult patients with late neurologic disease affecting the central or peripheral nervous system should be treated with intravenous medication. Response to treatment is usually slow and may be incomplete. Retreatment is not recommended unless relapse is shown by reliable objective measures.

Ocular Manifestations

Conjunctivitis and photophobia in stage 1 Lyme disease require no therapy. Bell palsy in stage 2 Lyme disease is self-limited, but patients require supportive therapy to prevent the complications of exposure keratitis. Keratitis and episcleritis benefit from topical corticosteroids, usually a short course of prednisolone acetate 1% or fluorometholone 0.1%.

A treatment regimen for severe neuro-ophthalmic disease (involving the optic nerve) or posterior segment disease (eg, pars planitis, vitreitis) has not been established. Oral corticosteroids without concomitant antibiotics should not be used.

The best approach for these patients might be a trial of antibiotic therapy, in which patients receive 2-3 weeks of intravenous penicillin or ceftriaxone. If patients respond to treatment, the trial is successful, ocular Lyme disease is diagnosed, and no further therapy is needed. Recurrences of Lyme uveitis, once adequate intravenous therapy has been given, can be treated with judicious corticosteroids.

Acrodermatitis Chronica Atrophicans

Acrodermatitis chronica atrophicans is usually treated with 1-month course of oral antibiotics, usually a beta-lactam or doxycycline. One study showed fewer relapses with 30 days compared with 20 or fewer days of therapy. In the same study, 30 days of oral antibiotics were more effective than 15 days of intravenous ceftriaxone (2 g/d).[68] It is important to ensure that no neurologic manifestations are present before embarking on oral therapy.

Post-Treatment Lyme Disease Syndrome

Despite appropriate antibiotic treatment, patients with Lyme disease may experience lingering symptoms similar to fibromyalgia (eg, fatigue, pain, joint and muscle aches). This condition has been termed chronic Lyme disease or, more precisely, post-treatment Lyme disease syndrome (PTLDS).[69]

These symptoms have not been shown in any controlled trials to be responsive to antibiotic therapy.[61]  The IDSA/AAN/ACR draft guideline recommends against additional antibiotic therapy for patients who have persistent or recurrent nonspecific symptoms (eg, fatigue, pain, cognitive impairment) after treatment for appropriately diagnosed Lyme disease but who have no objective evidence of reinfection or treatment failure (eg, arthritis, meningitis, neuropathy).[6]  

A study by Klempner et al failed to show a benefit of treatment with 2 g of intravenous ceftriaxone daily for 30 days, followed by oral doxycycline at 200 mg/d for 60 days.[70] Long-term IV ceftriaxone therapy can result in the formation of biliary sludge, which can lead to biliary colic.

Similarly, the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) study, a double-blind, randomized, placebo-controlled trial in 280 patients, found that longer-term use of antibiotics does not improve health-related quality of life in patients with PTLDS. In PLEASE, patients received open-label ceftriaxone for 2 weeks and were then randomized to a 12-week oral regimen of doxycycline (n = 86), clarithromycin combined with hydroxychloroquine (n = 96), or placebo (n = 98). At the end of the treatment period, the three groups showed no significant difference in health-related quality of life, which was the study's primary outcome, or in secondary outcomes, including physical and mental aspects of health-related quality of life and fatigue.[71, 72]

Extended antibiotic therapy, sometimes for longer than 6 months, has been advocated for PTLDS. This not only can cause great harm to patients but also has resulted in one or more deaths.[73] The Centers for Disease Control and Prevention has reported five cases of serious bacterial infections in patients receiving intravenous antibiotic treatment for chronic Lyme disease, including septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess.[74, 75]

The existence of PTLDS has been called into question as a result of a lack of direct evidence of persistent infection.[76, 77] Hassett and colleagues reported that rates of psychiatric comorbidity and other psychological factors (eg, depression, anxiety, tendency to catastrophize pain) were higher in patients with “chronic Lyme disease” (defined as symptomatic patients with previously treated Lyme disease and patients whose symptoms were attributed to Lyme disease without good evidence for Lyme disease) than in other patients commonly seen in Lyme disease referral centers, and that those factors were related to poor functional outcomes.[78]

The IDSA/AAN/ACR draft guideline notes that patients labeled as having chronic Lyme disease may in fact have other specific disorders that are diagnosable and potentially treatable, and in such cases, management should be directed accordingly. However, many of these patients have medically unexplained illness, and management of these symptoms complexes remains poorly understood.[6]

Jutras et al found evidence linking Lyme arthritis with a chemically atypical peptidoglycan (PGBb) that is a major component of the Borrelia burgdorferi cell envelope. B burgdorferi sheds fragments of PGBb into its environment during growth, and PGBb is released but not degraded when the spirochete dies. These researchers detected PGBb in 94% of synovial fluid samples (32 of 34) from patients with Lyme arthritis, many of whom had undergone oral and intravenous antibiotic treatment. Synovial fluid analysis demonstrated an ongoing immune response (ie, anti-PGBb immunoglobulins and proinflammatory cytokines, particularly tumor necrosis factor α). Systemic administration of PGBb in mice elicited acute arthritis.[79]

These researchers propose that persistence of this antigen in the joint may contribute to synovitis after antibiotics have eradicated B burgdorferi, by provoking a chronic innate and adaptive immune response. They speculate that this mechanism may expain other post-Lyme complications, such as skin lesions, carditis, and meningitis.[79]

Co-infection

Co-infection with other tick-borne illnesses occur in roughly 10-15% of patients with Lyme disease and should be considered in patients with a poor response to conventional antimicrobial therapy or atypical clinical presentations (eg, high fever, leukopenia). Co-transmitted infective organisms can include the following:

  • Babesia microti, the primary cause of babesiosis
  • Anaplasma phagocytophilum and Ehrlichia chaffeensis, which cause ehrlichiosis
  • Flavivirus, the cause of tick-borne encephalitis
  • Powassan or tick-borne encephalitis-like virus

Prevention

Prevention of tick-borne disease can be divided into personal and environmental measures. Clinicians in endemic areas should provide patient education on personal measures for tick avoidance and management of tick exposure (see Patient Education).

Environmental prevention involves clearing underbrush and spraying acaricides in the spring around property sites. These measures prevent both mice and ticks from encroaching on properties. Studies involving the treatment of wild deer and mice have not been conclusive in reducing tick-borne diseases in humans.

Tick removal

In patients in endemic areas who present with an attached tick, prompt removal can reduce the likelihood of contracting Lyme disease. Transmission of infection is unlikely if the duration of tick attachment is less than 24 hours, but is very likely for ticks attached for longer than 72 hours.

Removal of a tick is ideally accomplished using fine-tipped forceps and wearing gloves. Grasp the tick as close to the skin surface as possible, including the mouth parts, and pull upward with steady, even traction. (See the image below). Do not twist or jerk the tick because this may cause the mouth parts to break off and remain in the skin; however, note that the mouth parts themselves are not infectious. Wear gloves to avoid possible infection.

To remove a tick, use fine-tipped forceps and wear To remove a tick, use fine-tipped forceps and wear gloves. Grasp the tick as close to the skin surface as possible, including the mouth parts, and pull upward with steady, even traction. Do not twist or jerk the tick because this may cause the mouth parts to break off and remain in the skin; however, note that the mouth parts themselves are not infectious. When removing, wear gloves to avoid possible infection.

The use of forceps and gloves represents an optimal method of removal. However, removal of the tick should not be delayed in order to obtain forceps and it is extremely unlikely that one can become infected by touching an engorged tick even if the tick is carrying Borrelia (which most of them are not, even in endemic areas).

Using lidocaine (subcutaneously or topically) may actually irritate the tick and prompt it to regurgitate its stomach contents. Once the tick is removed, wash the bite area with soap and water or with an antiseptic to destroy any contaminating microorganisms.

For more information, see Tick Removal.

Antibiotic prophylaxis

Routine prophylaxis after a recognized tick bite is not recommended. A guideline from the Infectious Disease Society of America recommends prophylactic antibiotic therapy for adults and children older than 8 years, using a single 200-mg dose of doxycycline (in children, 4 mg/kg up to a maximum dose of 200 mg) only if all of the following criteria are met[4] :

  • The attached tick can be reliably recognized as a nymphal or adult Ixodes scapularis

  • The tick has been attached for at least 36 hours, as determined by the degree of engorgement of the tick or certainty about the time of exposure to the tick

  • Prophylaxis can be started within 72 hours of the time the tick was removed

  • The local rate of infection of these ticks with Borrelia burgdorferi is at least 20% (unlikely outside of select areas in New England, the mid-Atlantic States, Minnesota, and Wisconsin)

  • Doxycycline treatment is not contraindicated

The species of tick is important because non-Ixodes ticks (and other insects), although they can contain the organism, are highly unlikely to cause disease. The one clinically relevant exception may be bites by Amblyomma americanum in the central and southern midwestern United States, but few data exist on treating these tick bites prophylactically.

Doxycycline is relatively contraindicated in children younger than 8 years and in pregnant women. Amoxicillin should not be substituted for doxycycline in persons for whom doxycycline prophylaxis is contraindicated, for the following reasons[80] :

  • The absence of data on an effective short-course regimen for prophylaxis

  • The likely need for a multiday regimen (and its associated adverse effects)

  • The excellent efficacy of antibiotic treatment of Lyme disease if infection develops

  • The extremely low risk that a person with a recognized bite will develop a serious complication of Lyme disease

Even in areas where about 15-30% of ticks are infected with Borrelia burgdorferi, tick bites rarely result in Lyme disease. Nevertheless, appropriate prophylaxis can significantly reduce that risk.[81] In a 2010 meta-analysis of trials in which patients with no clinical evidence of Lyme disease were randomly allocated to treatment or placebo groups within 72 hours after an Ixodes tick bite, the risk of Lyme disease in the control group was 2.2% compared with 0.2% in the antibiotic-treated group.[82]

Vaccination

In December 1998, the FDA approved a vaccine (LYMErix Lyme disease vaccine [recombinant OspA]) 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 because of poor demand.[83] Patients who received this vaccine are no longer protected against Lyme disease, because the vaccine’s effect was not long lasting.

Consultations

In most patients with erythema migrans, no consultation is needed. However, consultation with appropriate specialists (eg, rheumatologist, neurologist, cardiologist) may be indicated to ensure that other diseases are not the cause of unusual presenting symptoms in a patient with a positive Lyme titer.

Difficulties can arise in choosing the appropriate antibiotic treatment regimen, especially in children or potentially pregnant women. An infectious disease consult is helpful in these situations.[84]

Consultation with a rheumatologist may be helpful in the evaluation and treatment of patients with persistent arthritis despite conventional antimicrobial therapy and those who present with fibromyalgia occurring after treated Lyme disease.

Consultation with a neurologist is recommended in patients with persistent or chronic manifestations of Lyme disease, such as chronic fatigue syndrome. In addition, in patients with acrodermatitis chronica atrophicans, neurologic disease is not uncommon and its presence alters the treatment plan; therefore, consultation is appropriate if neurologic signs or symptoms are present.

Consultation with a cardiologist may be indicated in patients with coexisting cardiac disease.

Long-Term Monitoring

Follow-up monitoring until all signs and symptoms have completely resolved is indicated for all patients with Lyme disease. In early Lyme disease, lack of prompt resolution should lead the physician to question the original diagnosis. Later manifestations tend to resolve much more slowly than early ones. Follow-up monitoring by the primary care physician or an appropriate specialist is indicated for patients with extracutaneous manifestations.

Patients with Lyme disease whose specific symptoms of Lyme disease (not symptoms of fibromyalgia or chronic fatigue) do not improve may need retreatment. Patients who plateau in their improvement may also need retreatment. Given the cost and convenience, a 30-day course of oral antibiotic therapy may be indicated before repeating intravenous therapy.

Repeat serologic testing is not indicated, because IgM titers may persist with treatment, and changes in IgG titers do not reflect the efficacy of treatment. That is, the standard serologic tests, with initial positive results, may remain positive for long periods and should not be used as a test of cure. Data suggest that C6-peptide may return negative results after treatment with antibiotics.

Follow-up may be of particular importance in patients with the chronic sequelae of the controversial post-Lyme disease syndrome. These patients’ condition may be refractory to conventional therapies.

 

Medication

Medication Summary

The antibiotic regimen for Lyme disease depends on the stage and manifestations of the disease, as well as on patient factors. Antimicrobial therapy typically focuses on Borrelia burgdorferi sensu lato, but should cover all likely pathogens in the context of the clinical setting. Coverage for co-infecting organisms, such as Ehrlichia species, should be considered, especially in patients with atypical clinical presentations.

Tetracyclines

Class Summary

Doxycycline is the preferred drug for oral treatment of Lyme disease in all patients except for pregnant and nursing women and children younger than 8 years of age.

Doxycycline (Vibramycin, Avidoxy, Monodox, Doxy 100, Doryx, Oracea, Adoxa)

Doxycycline is the drug of choice for early localized and early disseminated disease without evidence of central nervous system (CNS) involvement. It can be used for arthritis that is not persistent or recurrent. It has also been promoted for single-dose postexposure prophylaxis. Doxycycline has the key advantage of covering other tick-borne pathogens that may have been co-transmitted (eg, Ehrlichia species, Rickettsia species).

Doxycycline inhibits protein synthesis and thus bacterial growth by binding to the 30S and possibly the 50S ribosomal subunits of susceptible bacteria. This agent interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria.

Tetracycline

Tetracycline is used to treat gram-positive and gram-negative organisms, as well as mycoplasmal, chlamydial, and rickettsial infections. This agent inhibits bacterial protein synthesis by binding with the 30S and possibly 50S ribosomal subunits of susceptible bacteria. Tetracycline is an alternative drug to doxycycline. Because of its dosing schedule, doxycycline is preferred for compliance reasons; however, tetracycline may be less expensive.

Penicillins

Class Summary

Penicillins provide effective treatment of Lyme disease. These agents are used in patients who are intolerant of doxycycline and in pregnant women and children under the age of 8 years, in whom doxycycline is contraindicated. Intravenous formulations are used in patients who require parenteral therapy.

Penicillin VK

Penicillin VK inhibits the biosynthesis of cell wall mucopeptide. This agent is bactericidal against sensitive organisms when adequate concentrations are reached, and penicillin VK is most effective during the stage of active multiplication. Inadequate concentrations of this drug may produce a bacteriostatic effect only. In addition, penicillin VK can be used to treat erythema migrans, as it is safe in both pregnant and pediatric patients, although amoxicillin is used more commonly these patients.

Penicillin G aqueous (Pfizerpen-G)

Penicillin G is a penicillin antibiotic that inhibits cell-wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria. This agent is an alternative drug to ceftriaxone in patients requiring parenteral therapy for CNS infection, persistent or recurrent arthritis, and/or carditis. The usefulness of penicillin G is limited by the need to administer it six times a day.

Amoxicillin

Amoxicillin is the drug of choice for oral treatment for pregnant or nursing women and children younger than 8 years. It is used for early localized and early disseminated disease without evidence of central nervous system (CNS) involvement. It can be used for arthritis that is not persistent or recurrent. This agent interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Macrolides

Class Summary

Macrolides are second-line agents for treatment of Lyme disease. They are appropriate only for patients with intolerance or contraindications to the use of tetracycline and beta-lactam antibiotics.

Erythromycin ethylsuccinate (E.E.S., EryPed, PCE, Erythrocin)

Use of erythromycin should be limited to patients who cannot take tetracyclines or beta-lactam antibiotics, as erythromycin is inferior to those agents for treatment of Lyme disease. Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

In children, age, weight, and severity of infection determine the proper dosage. When twice-daily dosing is desired, half the total daily dose may be taken every 12 hours. For more severe infections, double the dose.

Azithromycin (Zithromax, Zmax)

Azithromycin is a second-line drug. Like erythromycin, this agent has excellent in vitro sensitivities, but mixed data exist regarding its clinical efficacy in early Lyme disease. Because of its once-daily dosing, azithromycin can be considered in pregnant patients who are allergic to beta-lactams and in patients in whom compliance is a major issue.

Clarithromycin (Biaxin, Biaxin XL)

Clarithromycin is a macrolide antibiotic that inhibits protein synthesis by binding to the 50S ribosomal subunit. This drug is not first-line therapy but is an alternative agent for patients intolerant of doxycycline, amoxicillin, and cephalosporins.

Cephalosporins, 3rd Generation

Class Summary

Intravenously administered cephalosporins are drugs of choice for more severe manifestations of Lyme disease.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin that is the preferred drug for intravenous therapy, as it has excellent activity against Borrelia burgdorferi and has favorable pharmacokinetics. It is the drug of choice for CNS infections (eg, meningitis, multiple cranioneuropathies), persistent (ie, minimal improvement within 7 d of initiating oral therapy) or recurrent arthritis, and carditis.

Ceftriaxone inhibits bacterial cell wall synthesis by binding to one or more penicillin-binding proteins. Bacteria eventually lyse because of ongoing activity of cell wall autolytic enzymes, while cell wall assembly is inhibited.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin that inhibits bacterial cell-wall synthesis. This agent is an alternative drug to ceftriaxone in patients requiring parenteral therapy.

Cephalosporins, 2nd Generation

Class Summary

Orally administered cefuroxime is an alternative to doxycycline, for patients with intolerance or contraindications to the use of tetracycline antibiotics.

Cefuroxime axetil (Ceftin, Zinacef)

Cefuroxime is a second-generation cephalosporin that is the only drug approved by the Food and Drug Administration (FDA) for use in Lyme disease. Cefuroxime is approved for use in adults. Its principal limitation is its expense. Cefuroxime binds to penicillin-binding proteins and inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death.

Aminoquinolines

Class Summary

Some agents in this class can be used to supplement nonsteroidal anti-inflammatory drugs in patients with Lyme arthritis that is unresponsive to antibiotic therapy, as the synovial inflammation in these patients may represent an autoimmune response.[23] Aminoquinolines may impair complement-dependent antigen-antibody reactions.

Hydroxychloroquine sulfate (Plaquenil)

The mechanism of action of hydroxychloroquine is unknown. This agent may impair complement-dependent antigen-antibody reactions; it inhibits locomotion of neutrophils and chemotaxis of eosinophils. Patients with rheumatic disease may take 4-6 months to show response to hydroxychloroquine; peak response takes several months.

 

Questions & Answers

Overview

What is Lyme disease?

What are the signs and symptoms of Lyme disease?

Which physical findings are characteristic of early disseminated Lyme disease?

What is the CDC recommended serologic testing for Lyme disease?

What is the role of Western blot testing in the diagnosis of Lyme disease?

Which tests may be performed in the evaluation of Lyme disease?

What is the focus for the treatment of Lyme disease?

What are the treatment options for Lyme disease?

What are the treatment options for Lyme arthritis?

What are the treatment options for Lyme carditis?

What is Lyme disease?

What is the clinical presentations of Lyme disease?

How is Lyme disease diagnosed and treated?

What is the historical background of Lyme disease?

Which areas in the US are commonly affected by Lyme disease?

What is the infectious cycle of Borrelia burgdorferi?

What is the mode of transmission of Lyme disease?

What is the pathogenesis of Lyme disease?

What is the clinical progression of Lyme disease?

What are the signs and symptoms of Stage 1 (early localized) Lyme disease?

What is Stage 2 (early disseminated) Lyme disease?

What is Stage 3 (chronic) Lyme disease?

What causes Lyme disease?

Which species of Borrelia burgdorferi sensu lato that causes Lyme disease?

How does the clinical presentation of Lyme disease differ by causative agent?

Where is of Lyme disease endemic?

What is the incidence of Lyme disease in the US?

Which US states have the highest rates of Lyme disease?

What is the incidence of Lyme disease when does peak incidence occur?

What is the global prevalence of Lyme disease?

What are racial predilections of Lyme disease?

How does the incidence of Lyme disease vary by sex?

How does the incidence of Lyme disease vary by age?

What is the prognosis of Lyme disease?

What is the prognosis of post-treatment Lyme disease syndrome (PTLDS)?

What is included in patient education about Lyme disease?

How should inspection and tick removal be performed for the prevention of Lyme disease?

What is the role of repellents in the prevention of Lyme disease?

What is the role of prophylactic antibiotics in the prevention of Lyme disease?

What is the role of pets in the prevention of Lyme disease?

Presentation

Which clinical history findings are characteristic of Lyme disease?

What is the frequency of reinfection and recurrence of Lyme disease?

How does the clinical presentation of Lyme disease vary based on species of Borrelia?

What are the stages of Lyme disease progression?

How is erythema migrans (EM) characterized in Lyme disease?

What are the non-cutaneous signs and symptoms of Stage 1 (early) Lyme disease?

What is the prevalence of co-infection in Lyme disease?

What is the clinical presentation of Stage 2 (early disseminated) Lyme disease?

How does arthritis present in Lyme disease?

What are neurologic manifestations of Lyme disease?

What are cutaneous manifestations in Stage 2 (local disseminated) Lyme disease?

What are the signs and symptoms of Stage 3 (chronic) Lyme disease?

What are the signs and symptoms of acrodermatitis chronica atrophicans in patients with Lyme disease?

Which physical findings are characteristic of Lyme disease?

What are the physical characteristics of erythema migrans (EM) in patients with Lyme disease?

What are atypical presentations of erythema migrans (EM) in patients with Lyme disease?

Where are erythema migrans (EM) located in Lyme disease?

What is southern tick-associated rash illness (STARI) and how is it differentiated from Lyme disease?

How are hypersensitivity reactions differentiated from the erythema migrans (EM) of Lyme disease?

What is borrelial lymphocytoma in Lyme disease?

Which dermatologic manifestations of Lyme disease have been reported in European patients?

Which musculoskeletal findings suggest Lyme disease?

Which physical findings indicate arthritis in patients with Lyme disease?

Which neurologic findings suggest Lyme disease?

Which neuropsychiatric findings are characteristic of late-stage Lyme disease?

Which cardiac findings suggest Lyme disease?

Which ophthalmic findings suggest Lyme disease?

Which ocular findings are characteristic of Lyme disease?

DDX

How is Lyme disease diagnosed?

Which conditions should be included in the differential diagnosis of Lyme disease?

How are co-infections diagnosed in patients with Lyme disease?

What are the differential diagnoses for Lyme Disease?

Workup

What is the initial approach to evaluation of suspected Lyme disease?

What is the CDC recommended testing procedure for the diagnosis of Lyme disease?

What is the role of lab testing in patients with clinical findings of Lyme disease?

When is joint aspiration indicated in the evaluation of Lyme disease?

What is the role of cerebrospinal fluid (CSF) analysis in the evaluation of Lyme disease?

What is the Rule of 7&#39;s and how is it used to determine risk for Lyme disease?

What is the role of electrocardiograms (ECGs) in the workup of Lyme disease?

When are imaging studies indicated in the workup of Lyme disease?

What is the role of serologic testing in the evaluation of Lyme disease?

What are tiers of serologic testing in the evaluation of Lyme disease?

Which serologic findings confirm a diagnosis of Lyme disease?

What is the accuracy of serologic testing for the diagnosis of Lyme disease?

When is serologic testing indicated in the workup of Lyme disease?

What is the role of C6 peptide testing in the diagnosis of Lyme disease?

What is the role of polymerase chain reaction (PCR) testing in the diagnosis of Lyme disease?

What are role of blood studies in the workup of Lyme disease?

What is the role of synovial fluid analysis in the workup of Lyme disease?

What is the role of lumbar puncture in the workup of Lyme disease?

What are the diagnostic criteria for neuroborreliosis in patients with Lyme disease?

What is the role of imaging studies in the workup of Lyme disease?

What is the role of culture in the workup of Lyme disease?

What is the role of biopsy in the workup of Lyme disease?

Which histologic findings of erythema migrans are characteristic of Lyme disease?

Which histologic findings of borrelial lymphocytoma are characteristic of Lyme disease?

Which histologic findings of acrodermatitis chronica atrophicans are characteristic of Lyme disease?

Treatment

What guides the selection of treatment for Lyme disease?

How is cardiac involvement managed in Lyme disease?

How is persistent arthritis managed in Lyme disease?

How is neuroborreliosis managed in Lyme disease?

How is borrelial lymphocytoma managed in Lyme disease?

When is antibiotic prophylaxis indicated for the prevention of Lyme disease?

What are the treatment guidelines for Lyme disease?

What is the controversy surrounding the IDSA treatment guidelines for Lyme disease?

What are the treatment options for early localized Lyme disease?

How is early Lyme disease managed in pregnant women?

What are the regimens for treatment of Lyme arthritis in adults?

What are the regimens for Lyme arthritis in pediatric patients?

What are the treatment options for Lyme arthritis following an initial antibiotic regimen?

What are the treatment options for Lyme carditis?

What are treatment options for neurologic manifestations of Lyme disease?

What are treatments options for ocular manifestations of Lyme disease?

How is acrodermatitis chronica atrophicans managed in patients with Lyme disease?

What are the treatments options for post-treatment Lyme disease syndrome (PTLDS)?

When should co-transmitted infective organisms be considered in patients with Lyme disease?

How is Lyme disease prevented?

How is tick removal performed to reduce the likelihood of contracting Lyme disease?

When is antibiotic prophylaxis indicated in the prevention of Lyme disease?

What are contraindications for doxycycline prophylaxis against Lyme disease?

What is the role of vaccination in the prevention of Lyme disease?

Which medical personnel provide consultations to patients with Lyme disease?

What is included in the long-term monitoring of patients with Lyme disease?

Medications

What is the role of antibiotic therapy in the treatment of Lyme disease?

Which medications in the drug class Aminoquinolines are used in the treatment of Lyme Disease?

Which medications in the drug class Cephalosporins, 2nd Generation are used in the treatment of Lyme Disease?

Which medications in the drug class Cephalosporins, 3rd Generation are used in the treatment of Lyme Disease?

Which medications in the drug class Macrolides are used in the treatment of Lyme Disease?

Which medications in the drug class Penicillins are used in the treatment of Lyme Disease?

Which medications in the drug class Tetracyclines are used in the treatment of Lyme Disease?