Lyme Disease

I. General description.

Lyme disease is the most common tick-borne illness in North America and Europe. In the United States, Lyme disease is caused by the spirochete Borrelia burgdorferi, transmitted mostly by Ixodes scapularis (deer ticks) in the eastern and northern mid-western states and by Ixodes pacificus ticks in the western states. In Europe and Asia, Borrelia afzelli and Borrelia garinii can also cause Lyme, transmitted by the tick species Ixodes persulatus and Ixodes ricinus.

Clinical presentation is divided into three phases:

  • Early disease (3-30 days after tick bite): The most common finding is erythema migrans (EM), a painless, round, expanding erythematous macule or papule. Seen in 80% of Lyme patients, it can reach 5-20 centimeters (cm) in size, and may have partial central clearing or necrotic areas. Intermittent arthralgia, myalgia, headache, fatigue, and less often fever can accompany the rash. Symptoms resolve in approximately 4 weeks without treatment. However, up to 60% of untreated patients proceed to develop late Lyme.
  • Early disseminated disease (weeks to months after tick bite): (a) Neurological disease manifests in 10% of untreated patients, most commonly as facial nerve palsy (may be bilateral), other cranial nerve palsies, meningitis with characteristics of aseptic meningitis, peripheral neuropathy, radiculopathy and encephalitis or encephalomyelitis; (b) Cardiac disease occurs in 5-8% of untreated patients, mostly as acute onset atrioventricular (AV) block of varying severity, sometimes with myocarditis. Complete heart block rarely ensues; (c) conjunctivitis; (d) Borrelia lymphocytoma in Europe, a red/ blue swelling near tick bite site that enlarges over days and resolves spontaneously.
  • Late disease (weeks to years after tick bite): A history of early Lyme is often lacking. Arthritis of one or more joints, or periarticular areas, usually including the knee, occurs in less than 10% of cases. It may occasionally be chronic and lead to cartilagenous erosion. Neurologic signs include peripheral neuropathy or encephalopathy, which may manifest as memory loss, mood changes or sleep disturbance. Most often seen in Europe, acrodermatitis chronica atrophicans is an insidious onset of bluish-red discoloration with doughy swelling, initially unilateral, and mostly on the extensor surface of the hands or feet. It enlarges slowly over months to years, eventually resolving and leaving atrophic skin.

A controversial phase of Lyme disease, called post-Lyme disease syndrome, posttreatment chronic Lyme disease, or chronic Lyme disease, refers to patients who have had documented Lyme disease who remain symptomatic for months to years after appropriate treatment, though “chronic Lyme disease” is also being incorrectly applied to patients who have never had documented Lyme disease. There is no standard definition or biologic marker for diagnosis, and according to the Infectious Disease Society of America guidelines, there is no quality evidence to suggest the existence of symptomatic chronic Borrelia burgderfori infection after appropriate treatment. Clinicians should be aware of this issue as there exists a patient and provider community that advocates for chronic Lyme disease and perceives that the medical community has failed to effectively explain or treat their illnesses.

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II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

  • Tick bite: non-deer tick bite, brown recluse spider bite, other arthropod bite.
  • Erythema migrans: tick hypersensitivity reaction (occurs less than 48 hours after a tick bite and resolves; EM occurs after 72 hours and expands slowly over several days), erythema multiforme (multiple lesions, central blistering, mucosal lesions and involves palms and soles, may have a clear cause like drugs/infections), cellulitis (rarely circular, may be painful), spider bite (often painful).
  • Fever, myalgia, arthralgia: co-infections (babesiosis, human granulocytic anaplasmosis), other viral infections. Prominent respiratory or gastrointestinal symptoms are atypical of Lyme disease.
  • Cranial nerve palsies: herpes simplex or varicella zoster-virus associated facial nerve palsy, idiopathic facial nerve palsy.
  • Myocarditis: rheumatic fever (cardiac Lyme usually has a milder course, and often results in fluctuating AV block, does not involve valves, and resolves after several weeks).
  • Meningitis/encephalomyelitis: syphilis, viral or bacterial infections.
  • Chronic Lyme disease: chronic fatigue syndrome or fibromyalgia, which tend to produce more generalized and disabling symptoms, and have been present for a longer period of time. These patients usually have a higher degree of anxiety and depression.
  • Arthritis: reactive arthritis (adults), juvenile rheumatoid arthritis (children), other inflammatory conditions.

B. Describe a diagnostic approach/method to the patient with this problem

  • The diagnosis is usually made clinically. Diagnostic tests are helpful only if well-validated and only for confirmation purposes, or in less typical cases.
  • Patients with a high likelihood of early disease are treated presumptively with antibiotics.
  • Co-infections with organisms transmitted by ticks, such as babesiosis or human granulocytic anaplasmosis, are not uncommon and must be sought in each case.

1. Historical information important in the diagnosis of this problem.

  • History of being in an environment that is likely a tick habitat, such as wooded grassy areas, in a Lyme-endemic area within 30 days of the onset of EM
  • Residence in the highest risk regions – coastal areas of Northeast, Northwest California and the Great Lakes region of the United States
  • Presentation between April and November
  • Black-legged tick (deer tick) engorged with blood found on patient, suggesting that it has been attached for at least 36 hours
  • Red relatively painless non-pruritic skin rash suggestive of EM

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  • A red macule or papule that expands over days to weeks, forming a red lesion at least 5cm in size, with partial central clearing. Secondary lesions may develop. EM is the best clinical marker for the disease.
  • Presence of an EM skin lesion accompanied by viral illness-like symptoms (intermittent myalgia, arthralgia, mild stiff neck, headache, chills, fatigue), without prominent respiratory or gastrointestinal symptoms such as cough, rhinorrhea, vomiting or diarrhea.
  • In early disseminated Lyme, EM lesions may be multiple.
  • Facial nerve palsy in spring and summer months, radiculopathy, headache, neck pain, stiffness, memory problems, insomnia and altered behavior.
  • Irregular pulse with missed beats.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  • Serologic testing for antibodies to Borrelia burgdorferi with enzyme-linked immunosorbent assay (ELISA), with confirmation of a positive test by Western blot. However, presence of IgM or IgG antibodies are an indication of previous exposure and not always active infection, thus should be correlated with history and physical exam.
  • Direct detection of the bacteria in patients with EM, such as biopsy or blood cultures are not available for weeks, and thus not recommended for clinical practice.
  • For Lyme meningitis, cerebrospinal fluid (CSF) with lymphocyte-predominant pleocytosis, elevated protein and normal to low glucose, and diagnostic titers of IgG or IgM in serum or CSF.
  • Four-fold interval increase in titers in convalescent compared to acute samples.
  • Exclusion of causes of biological false-positive tests, such as syphilis.
  • Electrocardiogram may demonstrate varying degrees of AV block, rarely with complete heart block.
  • White blood cell count may be normal or high. Hemoglobin, urinalysis and chemistry are usually normal.
  • For a patient with EM based on history and physical exam serologic testing is usually not helpful, as there is a high rate of false negative results.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

  • Lyme serology done outside the appropriate clinical context. False positive tests will mislead clinicians and patients and lead to inappropriate management of patients.
  • Lyme serology in a patient with a high pre-test probability of Lyme disease. In this situation, Lyme serology neither rules in nor rules out Lyme disease.

III. Management

For erythema migrans, first line treatment is with oral (PO) doxycycline, amoxicillin, or cefuroxime axetil, generally for 14-21 days. Children < 8 years of age, pregnant or lactating women should not receive doxycycline. If these cannot be used, second line agents include azithromycin, clarithromycin, or erythromycin.

Note that doxycycline can be used to treat co-infection with anaplasmosis, but will not treat babesiosis. Amoxicillin or cefuroxime axetil will not treat common co-infections.

Cranial nerve palsy without evidence of meningitis can be treated with PO doxycycline, amoxicillin, or cefuroxime axetil. Lyme meningitis should be treated with intravenous (IV) ceftriaxone or cefotaxime. For Lyme carditis or arthritis, the same PO or IV agents may be used for treatment.

Acrodermatitis chronica atrophicans is treated with PO doxycycline, amoxicillin, or cefuroxime axetil for 21 days.

First generation cephalosporins such as cephalexin are ineffective. If differentiating EM and bacterial cellulitis is uncertain, therapy should be amoxicillin-clavulanic acid or cefuroxime axetil.

In patients with syncope, chest pain, shortness of breath, PR interval greater than 300 milliseconds or second or third degree heart blocks, immediate admission and telemetry monitoring should be instituted, along with intravenous antibiotic therapy. Close consultation with a cardiologist is warranted. A temporary pacemaker may be required.

Post-Lyme disease syndromes: These are not well-defined. There is no evidence of symptomatic chronic Lyme disease after recommended therapy, and antibiotic therapy has not been proven to be useful in patients with symptoms lasting more than 6 months after appropriate therapy. As such, further antibiotic therapy is NOT recommended and is likely to be harmful.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

  • A rash that develops while the tick is attached, or in less than 48 hours after the tick is removed, is more likely a hypersensitivity reaction to the tick bite and not EM. In case of doubt, mark the edges with ink and observe for up to 2 days without antibiotics. Tick-bite hypersensitivity usually resolves, while EM expands during this period.
  • Palpitations, bundle branch block, bradycardia or myocarditis alone are not sufficient for the diagnosis of cardiac Lyme.
  • Headache, paresthesia, fatigue or a stiff neck alone are not sufficient for diagnosis of neurologic Lyme disease.
  • The same vector for Borrelia burgdorferi can transmit Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis, and Babesia microti, the etiology for babesiosis. Up to 75% of patients with tick-borne illnesses have more than one infection. Suspect co-infection if:

    Patient is in a geographic area where these pathogens are endemic.

    There are more severe symptoms than would be expected from Lyme disease alone.

    There is resolution of EM without resolution of viral illness-like symptoms.

    High grade fever persists for greater 48 hours despite recommended antibiotic therapy.

    There is accompanying leukopenia, thrombocytopenia, and anemia that has no obvious etiology.

  • The best way to prevent Lyme disease is to avoid exposure to the vector ticks. If exposure to the ticks is unavoidable, then use of protective clothing, tick repellents, inspecting the body daily for ticks and promptly removing them may reduce the risk of infection.

IV. What’s the evidence?

Wormser, GP, Dattwyler, RJ, Shapiro, ED, Halperin, JJ, Steere, AC, Klempner, MS, Karuse, PH, Baken, JS, Strle, F, Stanek, G, Bockenstedt, L, Fish, D, Dumler, JS, Nadelman, RB. “The Clinical Assessment, Treatment, and Prevention f Lyme Disease, Human Granulocytic Anaplasmosis and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America”. Clinics in Infectious Diseases. vol. 43. 2006. pp. 1089-1134.

Patterson, FC, Winn, WC. “Practical Identification of Hard Ticks in the Parasitology Laboratory”. Pathology Case Reviews. vol. 8. 2003. pp. 187-198.

Bratton, RL, Whiteside, JW, Hovan, MJ, Engle, RL, Edwards, FD. “Diagnosis and Treatment of Lyme Disease”. Mayo Clinic Proceedings. vol. 83. 2008. pp. 566-571.

Wormser, GP, McKeena, D, Carlin, J, Nadelman, RB, Cavalier, LF, Holmgren, D, Byrne, DW, Nowakowski, J. “Brief communication: hematogenous dissemination in early Lyme disease”. Annals of Internal Medicine. vol. 142. 2005. pp. 751

Halprein, JJ, Luft, BJ, Anand, AK, Roque, CT, Alvarez, O, Volkman, DJ, Dattwyler, RJ. “Lyme neuroborreliosis: central nervous system manifestations”. Neurology. vol. 39. pp. 753

Krause, PJ, McKay, K, Thompson, CA, Sikand, VK, Lentz, R, Lepore, T, Closter, L, Christianson, D, Telford, SR, Persing, D, Radolf, JD, Spielman, A. “Deer-Associated Infection Study Group: Disease-specific diagnosis of co-infecting tick-borne zoonoses: babesiosi, human granulocytic ehrlichiosis, and Lyme disease”. Clinical Infectious Diseases. vol. 34. 2002. pp. 1184

Hayes, EB, Piesman, J. “How Can We Prevent Lyme Disease”. New England Journal of Medicine. vol. 348. 2003. pp. 2424-2430

Shapiro, ED. “Lyme disease”. New England Journal of Medicine. vol. 370. 1. pp. 1724-31.

Lantos, PM. “Chronic Lyme Disease”. Infect Dis Clin North Am. vol. 29. 2015. pp. 325-40.