OVERVIEW: What every practitioner needs to know

Are you sure your patient has Lyme disease? What are the typical findings for this disease?

The most common manifestation is the rash, termed erythema migrans (early localized Lyme disease).

Single erythema migrans (66% of cases) occurs 7–21 days after tick bite (bite may not be recognized). It is an expanding erythematous macular rash that without treatment persists for weeks (Figure 1 and Figure 2). Although central clearing (the “bull’s eye” appearance) may occur, nearly two thirds of erythema migrans rashes are uniformly erythematous only. Erythema migrans often is asymptomatic but it may be pruritic or, rarely, painful, and can have central vesicles on occasion.

Figure 1.

Erythema migrans rash

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Figure 2.

Erythema migrans rash.

Early disseminated disease occurs when there is dissemination from the skin to other sites through spirochetemia (3–8 weeks after bite). This early disease is manifested as the following:

Multiple erythema migrans (15%–20%; Figure 3)

Figure 3.

Multiple erythema migrans.

Facial nerve palsy (3%)

Meningitis (2%): presents like aseptic meningitis but is typically of longer duration and may be associated with papilledema and increased intracranial pressure

Carditis (<1%): usually manifests as heart block, most often not serious but rarely can present with syncope from transient complete heart block

Late Lyme disease (6 weeks-months after the bite)

Arthritis (7%, usually of the knee): Typically subacute with mild to moderate pain associated with frank arthritis; sometimes may mimic acute bacterial (septic) arthritis

Less Common Manifestations of Lyme Disease

Bannwarth syndrome (meningoradiculitis)

Optic neuritis; palsy of other cranial nerves

Lymphocytoma (benign)

Acrodermatitis chronic atrophica

Accompanying Symptoms

Nonspecific symptoms such as headache, myalgia, fever, fatigue, arthralgia may (or may not) accompany any of the above-cited objective signs. Nonspecific symptoms alone without objective signs are unlikely to be due to Lyme disease. Fever and other systemic symptoms are most common with early disseminated disease.

What other disease/condition shares some of these symptoms?

For single erythema migrans:

  • Nummular eczema

  • Ringworm

  • Cellulitis

  • Insect or spider bites

  • Erythema granulare

For multiple erythema migrans:

  • Erythema multiforme

  • Multiple insect bites

For facial palsy:

  • Idiopathic (Bell’s palsy)

Tumors (e.g., acoustic neuroma, lymphoma)

For meningitis:

Aseptic (viral) meningitis (e.g., enterovirus)

For arthritis:

  • Juvenile inflammatory arthritis

  • HLA-B27 arthritis

  • Septic arthritis

  • Arthritis associated with other diseases (e.g., lupus erythematosus, inflammatory bowel disease, psoriasis)

What caused this disease to develop at this time?

Lyme disease is caused by infection with Borrelia burgdorferi, a spirochetal bacterium. It is a zoonosis. The vectors for Lyme disease are ixodid (hard) ticks, primarily Ixodes scapularis in New England, the mid-Atlantic states, and the Upper Midwest. Ixodes pacificus is the vector on the West Coast of the United States. Lyme disease has a limited geographic distribution, with the vast majority of cases occurring in southern New England and the eastern mid-Atlantic states. It also occurs with some frequency in areas of Wisconsin and Minnesota, and in some neighboring areas. Lyme disease occurs less commonly along the central and northern Pacific coast. Persons most often acquire Lyme disease in suburban areas that border on woodlands. The ticks thrive in leaf litter and in vegetation.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?


Diagnosis of early Lyme disease is based on the characteristic rash, erythema migrans (Figure 1, Figure 2, Figure 3).

Serologic tests (antibody tests) can be useful to make the diagnosis in patients without the rash who have other objective signs of Lyme disease.

Two-stage testing is performed (a quantitative test—usually an enzyme-linked immunosorbent assay [ELISA] and if that is positive or equivocal, a Western immunoblot to confirm the specificity of the positive ELISA. There are specific criteria for the number of bands necessary, in combination with a positive or equivocal ELISA, to be considered positive (2 of 3 bands for IgM; 5 of 10 bands for IgG). A positive blot result with a negative ELISA result should be considered a negative result.

Antibody tests are not specific enough to be used for screening: use of these tests in patients with a low probability of having Lyme disease will result in a high proportion of false-positive results, even when performed by excellent laboratories.

Antibody testing should be done only in patients with objective signs of extracutaneous Lyme disease (e.g., arthritis, facial nerve palsy). These tests are not appropriate to use for screening patients with nonspecific symptoms without specific signs of Lyme disease.

False-positive IgM results are common and are even less specific than IgG results; anyone with symptoms for 4 weeks or longer should not have a positive IgM result without a concomitant positive IgG result. Sometimes a positive IgM result can persist for long periods (years) even after treatment and cure of infection; a positive IgM test result does not necessarily indicate either early or active infection.

As with other antibodies, IgG antibody also may persist for many years despite cure of the infection. It is not a measure of activity of disease.

Because single erythema migrans usually develops 1–3 weeks after the bite, but antibodies usually are not detectable until 3–4 weeks after infection, antibody tests are not indicated for patients with early Lyme disease (a negative antibody test result is common early in infection and if patients receive early treatment, a positive result may never develop because bacteria are killed).

Index for specific antibody in cerebrospinal fluid (CSF) is one method of confirming infection of the central nervous system. This is performed by taking the ratio of concentration of IgG antibody against B. burgdorferi in CSF divided by total IgG in CSF and dividing that result by the ratio of the same antibodies in serum. If the result is greater than 1 (some say >2 to correct for possible error), it suggests production of specific antibody in the central nervous system.

Assay for antibodies to B. burgdorferi in joint fluid is not useful (many false-positive results). PCR of joint fluid may be useful, but a positive result can persist for a prolonged time after treatment and does not mean viable bacteria are present.

There are a number of “Lyme specialty laboratories” that conduct tests for Lyme disease that are unconventional and have not been shown to be associated with or useful for the diagnosis of Lyme disease or that perform conventional tests but have unconventional interpretations of the results of these tests (see references). Beware of using these laboratories or the results of their tests to diagnose Lyme disease.

Would imaging studies be helpful? If so, which ones?

Imaging studies rarely are useful for Lyme disease unless facial palsy persists for longer than expected (no improvement after 4–6 weeks) and magnetic resonance imaging (MRI) of the brain is needed to rule out a tumor as the cause of the palsy.

Radiographs may be useful to document joint effusion if there is any uncertainty and computed tomography or MRI of the brain may document enlargement of ventricles if there is increased intracranial pressure associated with Lyme meningitis.

If you are able to confirm that the patient has Lyme disease, what treatment should be initiated?

Treatment options for Lyme disease can be seen in Table I.

Route of Administration Treatment Dose* Advantages and Disadvantages
Oral Doxycycline (Patients ≥8 y)Amoxicillin Cefuroxime Paxetil 4-8 mg/kg(up to 100 mg/dose)Twice a day50 mg/kg (up to 500 mg)Three times/day30 mg/kg (up to 500 mg)Twice a day Well absorbedExcellent penetration into CNSAlternative for patients allergic to beta-lactam antimicrobialsInexpensiveTwice daily administrationMay cause nausea, especially when administered without foodNot recommended for children <8 y because of small risk of staining of permanent teethWell tolerated with small risk of minor diarrheaCan administer to young childrenThree times daily administrationCan be given to young childrenTwice daily administrationMore expensive than amoxicillin or doxycyclineBroad spectrum of antimicrobial activity not necessary
Intravenous CeftriaxoneCefotaximePenicillin G 50-75 mg/kg (up to 2 g)Once daily 150-200 mg/kg (up to 2 g/dose)every 8 h200,000-400,000 U/kg divided every 4 h(up to 18-24 million U/day) Good CNS penetrationOnce daily administrationMust be administered parenterallyGood CNS penetrationExpensiveMust be administered parenterally three times daily  Few side effectsMust be administered very frequently because of short half-life

*Total and maximum daily dosages and frequency of administration/day (divide daily dose by frequency)

Up to 200 mg/dose for neuroborreliosis

CNS = central nervous system

The bacterium is highly susceptible to antimicrobial agents and there are no reports of resistance to such recommended agents.

Prolonged treatment with antimicrobial agents for persistent nonspecific symptoms without objective signs is not indicated; it is associated with substantial risk and no benefit.

Occasionally, Lyme arthritis persists or recurs, in which case a second course of orally-administered antimicrobial treatment for 4 weeks is recommended.

Adjunctive therapy, such as nonsteroidal antiinflammatory drugs to decrease inflammation in patients with arthritis, or drugs to manage increased intracranial pressure in patients with meningitis and papilledema, may be indicated.

What are the adverse effects associated with each treatment option?

Adverse effects from treatment are presented in Table I. In addition, rarely a Jarisch-Herxheimer reaction may occur after treatment is begun. This manifests as an increase in fever and/or myalgia and arthralgia 24–48 hours after antimicrobial treatment is begun. The reaction is self-limited and usually resolves in 24–48 hours. Antimicrobial treatment should be continued; use of nonsteroidal antiinflammatory drugs may provide symptomatic relief.

What are the possible outcomes of this disease?

The outcomes of treatment of patients with Lyme disease are excellent, with virtually all patients making a full recovery. The most common reason for failure of treatment is misdiagnosis: the patient did not have Lyme disease. Treatment is generally safe and highly effective. Families should be cautioned about the large amount of inaccurate information about Lyme disease, which can be frightening, on the Internet.

What causes this disease and how frequent is it?

Detailed epidemiology:

Approximately 20,000–30,000 cases of Lyme disease are reported each year in the United States (likely a relatively small proportion of all cases). Nearly three quarters of these cases occur in fewer than 70 counties in the United States.

The great majority of cases of Lyme disease in the United States occur in southern New England and the eastern mid-Atlantic states, with a smaller number of cases in the northern midwestern states and even fewer cases on the Pacific Coast. In the most highly endemic areas of the United States, such as Connecticut, the incidence is about 1 cases/1000 persons but can be substantially higher in local areas.

The incidence is highest in children 5–10 years of age, nearly twice as high as the incidence among adults.

Lyme disease is transmitted by the bite of Ixodid (hard) ticks. B. burgdorferi live in the gut of infected ticks; the tick needs to feed for a substantial length of time (36–48 hours or longer) and become engorged with blood for the bacteria to migrate to the salivary glands of the tick and then be inoculated into the human host.

The tick has a three-stage (larva, nymph, adult), 2-year life cycle and feeds once at each stage of the cycle.

Lyme disease is a zoonosis. The major reservoirs for the bacteria are a variety of small mammals (e.g., white-footed mice) and birds. Larval ticks are uninfected when they hatch but become infected by feeding on infected animal reservoirs, such as the mice.

The larvae (which hatch in the summer) overwinter and emerge the following spring as nymphal-stage ticks. Nymphal ticks are most likely to transmit Lyme disease because they may be infected with the bacteria and are small and difficult to see (and therefore are more likely to remain attached long enough to transmit infection).

Nymphs molt to adults in the fall. They spend the winter on large mammals such as deer (hence the common name for Ixodes scapularis—the deer tick). They are not a competent reservoir for B. burgdorferi but they are important for the life cycle of the tick.

Risk factors for Lyme disease in endemic areas include residing near woodlands or near fields adjacent to woodlands (where vector ticks are abundant) and outdoor activity (either recreational or occupational) in such environments.

No genetic susceptibility to infection has been identified. In very rare cases of persistent inflammation after Lyme arthritis in adults, there may be an association with HLA types that are associated with rheumatoid diseases.

How do these pathogens/genes/exposures cause the disease?

The tick injects the spirochete into the skin, which results in local inflammation and the typical erythema migrans rash. Subsequent dissemination through the bloodstream can lead to invasion of multiple different tissues by the organism, including, heart, synovium, and the central nervous system. The bacteria do not produce exotoxins. The inflammatory response results in disease.

Congenital Lyme disease has not been documented. Person-to-person transmission does not occur. Lyme disease cannot be transmitted through breast-feeding.

What complications might you expect from the disease or treatment of the disease?

Complications are extremely rare in children. Complete heart block can cause syncope and sudden death. There have been extremely rare reports of serious optic neuritis or blindness that resulted from persistent increased intracranial pressure that was not managed adequately. Slow resolution of arthritis is relatively common (likely due to slow clearance of fragments of dead bacteria), but “treatment-resistant” arthritis (not due to antimicrobial resistance but rather due either to autoimmune inflammation or to extremely slow clearance of antigen) is very rare in children.

Although not a complication of Lyme disease itself, the vector tick can also transmit human granulocytic anaplasmosis and Babesiainfections, which can cause coinfections and concommitant illness. Borrelia miyamotoi, a newly recognized bacteria from the relapsing fever group of Borrelia, has been shown to be transmitted by Ixodes ticks.

Are additional laboratory studies available; even some that are not widely available?

The C6 ELISA is sometimes suggested as a substitute for two-stage testing with ELISA and Western immunoblot. C6 is a peptide antigen, a conserved immunodominant portion of surface protein VisE. Although it has been shown to have reasonably good sensitivity, its specificity is worse than that of two-stage testing. Since the major issue with antibody testing for Lyme disease is specificity, the C6 test generally should not be used as a substitute for two-stage testing.

Polymerase chain reaction (PCR) assays may be available. However, there are a number of potential drawbacks to this test. Sensitivity is generally poor (except in joint fluid) because the organism usually presents only in low concentrations. Also, invasive procedures (lumbar puncture, skin biopsy; synovial biopsy) are often necessary to obtain suitable material for the assay. In addition, especially in commercial laboratories, there is a risk of false-positive results because of contamination of the sample in the laboratory.

The bacteria can be cultured on special media (Barbour-Stoner-Kelly media). However, although false-positive results are less likely than with PCR assays, sensitivity is poor and invasive procedures are necessary to obtain material to culture. In addition, bacterial growth is slow, so it may take 2–4 weeks for a culture to have positive results.

How can Lyme disease be prevented?

Antimicrobial prophylaxis to prevent Lyme disease for persons who are bitten by Ixodes ticks is not indicated routinely. However, there is evidence that a single dose of doxycycline (4 mg/kg to a maximum dose of 200 mg) may be indicated for persons 8 years of age or older who discover an engorged or at least partially engorged nymphal or adult-stage deer tick on them. Doxycycline should be given with food to minimize nausea.

Risk of Lyme disease from a recognized bite of Ixodes scapularis is low; nearly three quarters of ticks that are recognized are removed in less than 48 hours (before transmission of the spirochete is likely to occur even if the tick is infected). Most physicians are unable to identify species of tick (indeed, in one study nearly one third of ticks submitted for identification by physicians were not even ticks).

There is no evidence that use of amoxicillin for chemoprophylaxis for tick bites in younger children is effective; the pharmacokinetics of amoxicillin make it likely that one dose may not be effective.

No vaccine is available.

Avoiding tick infested areas and, if one does walk through fields and woodlands in endemic areas wearing light-colored (to facilitate recognition of ticks) long pants tucked into socks and long-sleeved shirts, if possible, will minimize exposure. Insect repellants that contain 30% DEET may be effective, as may spraying of outer clothing with permethrin. After being in tick-infested areas check your body for and remove any ticks.

What is the evidence?

Seltzer, EG, Shapiro, ED. “Misdiagnosis of Lyme disease: When not to order serologic tests”. Pediatr Infect Dis J. vol. 15. 1996. pp. 762-3.

Gerber, MA, Shapiro, ED, Burke, GS. “Pediatric Lyme Disease Study Group. Lyme disease in children in southeastern Connecticut”. N Engl J Med. vol. 335. 1996. pp. 1270-4.

Gerber, MA, Zemel, LS, Shapiro, ED. “Lyme arthritis in children: clinical epidemiology and long-term outcomes”. Pediatrics. vol. 102. 1998. pp. 905-8.

Shapiro, ED. “Clinical practice: Lyme disease”. N Engl J Med. vol. 370. 2014. pp. 1724-31.

Vázquez, M, Sparrow, SS, Shapiro, ED. “Long-term neuropsychologic and health outcomes of children with facial nerve palsy due to Lyme disease”. Pediatrics. vol. 112. 2003. pp. e93-7.

Wormser, GP, Dattwyler, RJ, Shapiro, ED. “The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 43. 2006. pp. 1089-1134.

“Surveillance for Lyme disease—United States, 1992–2006”. MMWR Surveill Summ. vol. 57. 2008. pp. 1-9.

Feder, HM, Johnson, BJB, O’Connell, S. “A critical appraisal of “chronic Lyme disease.””. N Engl J Med. vol. 357. 2007. pp. 1422-30.

Shapiro, ED. “Doxycycline for tick bites: not for everyone”. N Engl J Med. vol. 345. 2001. pp. 133-4.

Warshafsky, S, Lee, DH, Francois, LK. “Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis”. J Antimicrob Chemother. vol. 65. 2010. pp. 1137-44.

Ongoing controversies regarding etiology, diagnosis, treatment

There continues to be a great deal of controversy about the long-term effects of Lyme disease, despite overwhelming scientific evidence that bacteria are uniformly killed by standard antimicrobial treatment.

There is controversy about persons with chronic subjective nonspecific symptoms and whether these symptoms alone can be a manifestation of “chronic Lyme disease.” There is no evidence that such an entity exists. The majority of patients with “chronic Lyme disease” have no clinical or laboratory evidence of ever having had Lyme disease. Numerous randomized double-blind clinical trials of long-term antibiotic therapy for “chronic Lyme disease” have demonstrated no benefit and substantial risks of long-term antibiotic administration for patients with chronic symptoms without objective signs after Lyme disease.

There is a cadre of “Lyme-literate” doctors who diagnose and treat (with antibiotics for long periods) patients with chronic nonspecific symptoms (now often referred to in the adult literature as “medically unexplained symptoms”) for chronic Lyme disease despite no valid evidence that Lyme disease is the cause of their symptoms or that antimicrobial treatment will have a beneficial effect.