Lyme disease is a systemic infection caused by the spirochete Borrelia burgdorferi. The bacterium enter the skin by a tick bite. The tick is almost always of the genus Ixodes.
The full spectrum was identified in 1975, when a cluster of statistically improbable cases of juvenile arthritis occurred in Connecticut. This outbreak stimulated intensive clinical and epidemiologic research that led to the discovery of the causative agent, the ecology, an expanding list of clinical manifestations, and the geographic range. Furthermore, the initial antibiotic responsiveness of the cutaneous manifestations was confirmed and extended.
The pathophysiology of Lyme disease is incompletely understood. While active infection by the spirochete causes many manifestations, others may be caused by immunopathogenic mechanisms. Although any body part can be involved, the organism shows a distinct propensity for the skin, CNS, heart, joints, and eyes.
The bacterium 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 (e.g.: 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.
Once in the skin, the spirochete can (1) be overwhelmed and eliminated by host defense mechanisms; (2) remain viable and localized in the skin where it produces the pathognomonic skin lesion, or erythema migrans (EM); or (3) disseminate through the lymphatics or blood. Hematogenous dissemination can occur within days to weeks of initial infection; the organism can travel to the skin, heart, joints, CNS, and other parts of the body.
The organism can also persist in skin (and possibly in the CNS) for years without causing symptoms. Experimentally, the spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone well above bacteriocidal levels for the spirochete. Clinically, organisms have been cultured from skin many years after primary infection. This mechanism may allow the spirochete to elude the normal host defense mechanisms directed against it.
As with syphilis, the disease classically is divided into stages: early localized, early disseminated, and late. However, distinct cutoff points between the stages are frequently unclear. Early localized Lyme disease refers to isolated EM and patients with an undifferentiated febrile illness. Early disseminated disease refers to the extracutaneous manifestations and secondary skin lesions that occur during the first weeks to months after infection. Late Lyme disease refers to later manifestations (usually in the nervous system and joints) that occur months to years later. Many patients initially have EM; however, in others, neurologic or rheumatologic complaints may be the initial symptoms, either because EM is not present or because it was unrecognized or misdiagnosed.
The incidence has been increasing over time. This is not simply a result of increased recognition, since in states that perform active surveillance, true incidence and geographic range have increased. The likely causes of this increase are expansion of deer herds and the expanded range of the vector. The CDC reported 17,029 cases in 2001 and, in 2002, that number rose to 23,763-a 40% increase. Year-to- year variation can be significant. More than 95% of cases come from 12 states (Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin). Even within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.
Overall in the United States, incidence is 6.0-8.2 cases per 100,000 population (2001 and 2002 data). However, in Connecticut in 2001, the rate was nearly 134 cases per 100,000 population, and, on the island of Nantucket, Massachusetts, the rate exceeded 1000 cases per 100,000 population. Epidemiologic data suggest that the actual incidence of Lyme disease could be as much as 10 times higher than the CDC data indicate. This probably is a result of a restrictive case definition from the CDC, inevitable misdiagnosis, and the fact that physicians tend to underreport reportable diseases of all kinds.
Rare fatalities are reported in patients with Lyme disease. Patients with neurologic disease that is not promptly diagnosed and treated can have neurologic damage that can be difficult to treat. These fixed neurologic deficits may not respond to antibiotics. Similarly, some genetically predisposed patients with arthritis may have ongoing joint inflammation that does not respond to further antibiotic therapy.
Because only about 25-30% of patients with Lyme disease recall the bite, history taking must be directed toward determining the epidemiologic probability of a tick bite. Because Lyme disease can affect many body parts, many presenting complaints can exist. Examples may include the following: Systemic manifestation; Fever is generally low grade. A high-grade fever or toxic appearance suggests co- infection, such as ehrlichiosis or babesiosis, or an alternative diagnosis; Fatigue is common; Myalgias and arthralgias occur early. Frank arthritis (i.e.: joint swelling, redness, pain) usually is a later manifestation but can occur in the early disseminated phase. Flulike illness (undifferentiated febrile illness) may occur. Although the frequency of this is unknown, the phenomenon of Lyme disease with typical flulike symptoms of fevers, chills, myalgias, arthralgias, and malaise (without rash) is well documented. The season of onset, epidemiologic likelihood of a tick bite, paucity of respiratory and GI symptoms, and prompt response to antiborrelial therapy are diagnostic clues.
The classic rash, erythema migrans (EM), is present in about 75% of patients. Because it is neither pruritic nor painful (although it can be either), some patients may have the rash but not notice it. EM can occur in the same patient more than once. About 20% of patients with Lyme disease have multiple lesions (from hematogenous dissemination). The higher figure is from earlier studies; current information suggests that the rate of multiple lesions is closer to 20%.
Headache can occur in early infection as a nonspecific finding and can herald CNS penetration and lymphocytic meningitis. 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. Patients notice facial weakness, which is similar to a typical Bell palsy and which can be the presenting symptom of Lyme disease. About 25% of patients with borrelial facial palsy have bilateral involvement, which may be sequential and is a point of differential diagnostic significance. Other than Lyme disease and Guillain- Barré syndrome, bilateral seventh nerve palsy is rare.
Late Lyme disease can cause paresthesias or pain due to peripheral neuropathy and personality, cognitive, and sleep disturbances from chronic encephalopathy. All sorts of neurologic syndromes caused by Lyme disease involving nearly every part of the CNS and peripheral nervous system have been reported in numerous case reports; therefore, Lyme disease may produce numerous symptoms. Although the likelihood that these other symptoms result from Lyme disease in any particular patient may be small, the clinician must remain open minded to this possibility.
Cardiovascular involvement occurs in fewer than 10% of patients with untreated Lyme disease and is more common in male patients than in female patients. Palpitations, lightheadedness, and syncope may be a manifestation of varying degrees of heart block, including complete heart block, which occurs in 50% of patients with cardiac involvement. Lyme disease is an important reversible cause of heart block. Chest pain and dyspnea can occur in the setting of Lyme pericarditis, myocarditis, and myopericarditis. Tamponade has been reported.
Migratory pains in and around the joints and muscles are common late findings. These symptoms classically wax and wane over hours or days. Later, arthritis occurs generally with swelling, redness, and pain in one or a few large joints, typically the knees. Red, itchy eyes are the most common ocular symptom. Blurred vision and eye pain can occur from keratitis and iritis. Unilateral blindness from panophthalmitis has been reported as well.
The physical examination in patients with Lyme disease can reveal numerous findings, depending on the target organs involved and the phase of the disease at presentation. In addition to fever, findings may include the following:
Classic erythema migrans is an erythematous papule or macule that occurs at the site of the tick bite (1-33 d later; average, 7-10 d). Often, a central punctum is found at the site. The size varies enormously (as large as 70 cm; average, 16 cm) and depends on disease duration. EM usually is flat, round, or oval and monocyclic. Generally, neither itching nor pain is present. The rash enlarges a few centimeters per day and fades, even if untreated, after a few weeks. The rash can be triangular or linear and is sometimes fleeting in duration. Rash location is another important diagnostic clue. Approximately 20% of patients with EM have secondary lesions. These lesions generally are smaller than the primary one, lack the central punctum, and are not necrotic or vesicular.
Neck stiffness can occur early, with or without frank meningitis. Facial nerve palsy is a lower motor neuron lesion that causes facial weakness of both the lower face and forehead. It can be bilateral. Nearly every cranial nerve has been reported to be involved, although this is uncommon. Weakness and abnormal sensation can occur because of meningoradiculitis. Diminished reflexes can occur with this syndrome. Neuropsychiatric testing and mini-mental status testing may uncover cognitive, memory, and personality changes that occur in late Lyme encephalopathy.
In patients with complete heart block, Canon 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 congestive heart failure, typical signs of congestive heart failure may be present.
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.
Laboratory testing depends entirely on the presenting problem of the patients. Evaluation of the CBC, erythrocyte sedimentation rate, and liver function generally is unnecessary, and serologic tests can be misleading if performed in the wrong setting. The patient with solitary, typical EM requires no laboratory testing whatsoever. Expected results for the CBC and erythrocyte sedimentation rate are likely normal. At this stage of illness, serologic testing is unnecessary because the pretest probability of Lyme disease is high, and the sensitivity of the serologic test is low (during the first several weeks). Leukopenia or thrombocytopenia suggests co- infection with Ehrlichia or Babesia species. Elevation of at least one liver function test result is reported to occur in 40% of patients with Lyme disease. This finding also is common in ehrlichiosis.
Because of the organism’s fastidious growth requirements, culture has not been a useful test in the past; however, this situation is improving. Its usefulness depends on the specimen being cultured. Nevertheless, in routine practice, borrelial cultures are often unavailable.
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 test. Most importantly, the most commonly performed test measures antibodies to various proteins of the spirochete, some of which are very specific for the organism and others of which are nonspecific. 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 CDC recommends a 2-step procedure consisting of a screening enzyme-linked immunoassay (ELISA) (or immunofluorescent assay [IFA]) and a confirmatory Western blot for specimens that have positive or equivocal results with the ELISA. Furthermore, in patients with a high likelihood of having Lyme disease (e.g.: classic EM in an endemic area), no serologic test should be ordered. Conversely, in a patient with a low pretest likelihood of having Lyme disease (e.g.: someone with vague symptoms where the test is being used as a screening test), testing is also not recommended because in such a population, the number of false-positive results greatly outnumbers the true positive results. Numerous conditions (e.g.: viral and bacterial infections, inflammatory diseases, neoplasms) 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. Timing is extremely important. Seroconversion may take several weeks in patients infected with the spirochete, so early seronegativity is to be expected. The physician must remember 2 important concepts. First, a negative Lyme test result does not indicate the absence of disease, nor does a positive result indicate the presence of disease. Second, a positive result is not required for someone with clear-cut EM; these early-presenting patients frequently have negative results, and they should be treated for EM empirically.
Because the spirochete can enter the CSF early in the course of infection and because the finding of meningitis (defined here as abnormal CSF in the setting of active Lyme disease) changes the treatment, many physicians have a low threshold for performing a lumbar puncture in patients with EM and any CNS symptoms or in patients with isolated seventh nerve palsy due to Lyme disease. The finding of elevated protein levels or pleocytosis mandates parenteral therapy. Definitive data to either support or refute this practice are lacking. In addition, a lumbar puncture ought to be performed if Lyme meningitis is in the differential diagnosis.
Animal studies have shown that transmission of infection is unlikely if the duration of tick attachment is less than 24 hours, and transmission is very likely for ticks attached for longer than 72 hours. This finding presumes that the tick is infected in the first place and the percentage of Ixodes ticks that are infected varies with geography. Several randomized placebo- controlled studies have been conducted to investigate prophylactic treatment of tick bites. All revealed that the rate of symptomatic infection and asymptomatic seroconversion is about 2% in placebo groups. This study occurred in areas in which about 15-30% of ticks were infected; this finding indicates that many bites from infected ticks do not result in transmission of the spirochete. These studies form the basis of the often-cited recommendation to withhold tick bite prophylaxis.
Although most patients do not require treatment, consider tick bite prophylaxis on a case-by-case basis. Base the decision on the species of the tick, duration of attachment (degree of engorgement of the tick is a surrogate marker), geography (percentage of ticks infected where the bite took place), method of tick removal, anxiety level of patient, and pregnancy (lower threshold to treat pregnant women). After performing this exercise in clinical decision-making, one may decide to treat a given patient with prophylactic antibiotics. In the studies mentioned previously, no patient in the treatment group (which received 10 d of antibiotic treatment) had the disease. Historically, if one were to choose to treat, 10 days of oral amoxicillin, doxycycline, or cefuroxime axetil would seem prudent, depending on patient factors such as age, allergy, and pregnancy.
In one of the most recent studies (2001), a single 200- mg dose of doxycycline was used for prophylaxis with excellent results.
For Solitary EM: Oral antibiotics (e.g.: amoxicillin, doxycycline, cefuroxime axetil, erythromycin, azithromycin, amoxicillin-clavulanate) should be administered for 10-30 days. The average therapy is 3 weeks duration. Recent data show that 21 days of oral doxycycline is as effective as 14 days of intravenous ceftriaxone for disease in this stage. Early disseminated disease with meningitis or a high- degree heart block may be treated with intravenous ceftriaxone for 2-4 weeks. In the case of heart block, a permanent pacemaker rarely is necessary, but close monitoring in a telemetry unit is warranted. Once patients are no longer dependent on the pacemaker, their intravenous antibiotics may be switched to oral antibiotics. Occasionally, prednisone may hasten resolution of the conduction defect. Arthritis may be treated with oral antibiotics for 30-60 days, and intravenous ceftriaxone may be administered for coexistent neurologic disease.
Lyme disease initially misdiagnosed or treated late may progress to harder-to-treat disease with some symptoms, especially neurologic, that can be debilitating. Thus, the physician must be aware of Lyme disease and must promptly initiate treatment or refer patients to their primary care physician or other physician for appropriate antibiotic therapy; specific care depends on specific details of the situation. Third-degree heart blocks often require a temporary pacemaker insertion and, on rare occasions, a permanent pacemaker insertion. Doxycycline can cause severe cutaneous photosensitivity. Caution patients to use sunblock with an SPF of at least 30 and to wear wide-brimmed hats for further protection. A primary care physician should follow-up patients receiving long-term intravenous ceftriaxone, because biliary colic can develop from the sludge that forms secondary to this therapy.
Several studies report an excellent prognosis for patients who are promptly treated for early Lyme disease. As in most diseases, the earlier treatment begins, the better the results. Patients with late disease may have symptoms that are hard to eradicate. Also, these symptoms tend to disappear more slowly than do early symptoms. Controversy exists regarding the best therapy for these patients. The types of syndromes that emergency physicians generally treat, which is to say the early ones, respond well.
Failure to diagnose several tick-borne diseases, including Lyme disease, is a pitfall. A related pitfall is a failure to consider Lyme disease because of the absence of a known tick bite. Only about 25-30% of patients with Lyme disease recall the bite. Far more importantly, inquire about activities that may increase the patient’s risk for tick bites.
Another pitfall is a failure to consider Lyme disease because of the absence of central clearing in a patient with EM. This classic finding of clearing occurs in only a minority of patients and is not needed for making the diagnosis.
Patients with Lyme disease may be co-infected with other organisms, especially Ehrlichia and Babesia species. Patients with definite Lyme disease and symptoms such as higher fever or atypical manifestations (e.g.: leukopenia) may have such co- infections and require different therapies. Co- infections occur in roughly 10-15% of patients with Lyme disease.
Serologic tests for Lyme disease can be highly insensitive and non-specific. Results can be false positive or false negative. Misinterpretation of results can lead to serious problems. This is especially true in early presenting patients and in those with asymptomatic tick bites. Those with EM often have negative serologic test results. If EM is the likely diagnosis, empiric treatment, not serologic testing, is the appropriate action.
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