HISTORICAL BACKGROUND, DISTRIBUTION, AND PREVALENCE
In 1975, in the small Connecticut town of Old Lyme (population 5,000), an 8-year-old girl was diagnosed as having juvenile rheumatoid arthritis (JRA). Her mother became concerned when she discovered that two of her neighbors had had arthritis and that their children had been similarly diagnosed with JRA. Through her persistent efforts and those of another mother in Old Lyme, an epidemic focus of oligoarticular arthritis came to the attention of the Connecticut State Health Department and Dr. Allen Steere and colleagues at the Yale University School of Medicine.
The systematic investigations of the Yale group resulted in the identification of 39 children and 12 adults who had suffered from recurrent attacks of asymmetric arthritis of large joints. l Geographic and temporal case-clustering suggested that the illness was an arthropod-bome infection. In 25% of the original cases, joint symptoms were preceded by a distinctive skin eruption which was felt to be consistent with erythema chronicum migrans (ECM), first described in Europe in 1910. European ECM is associated with the bite of the sheep tick, Ixodes ricinus, and is associated with meningitis and polyneuritis, but not arthritis.2 A number of Steere's patients recalled having been bitten by ticks and the vector was soon identified as the deer tick Ixodes dammini. 3 With time a clinical syndrome of prodromal rash and subsequent neurologic, cardiac, and/or articular manifestations was clarified, and is now known as Lyme disease.
Success of empirical antibiotic therapy in European ECM prompted trials in Lyme disease with encouraging results, suggesting a bacterial etiology.4 In 1982, spirochetes were isolated from the midgut tissue of Ixodes ticks collected on Shelter Island, New York, a Lyme-endemic area. 5 Testing confirmed the presence of antibodies to this organism in the sera of Lyme disease patients. The etiology of Lyme disease was assured when spirochetes were isolated from the blood, cerebrospinal fluid, and skin lesions of affected patients.6,7 The organism has been officially named Borrelia burgdorferi.
Lyme disease has been reported in 24 continental states8 and has been recognized in at least 19 countries on three continents.9 Endemic foci have been well characterized in southern New England, the Middle Atlantic states, Wisconsin, and Minnesota. A few cases have been reported from the Pacific northwest and a focus may have been identified in Texas. In areas where the deer tick burden is high, attack rates during the summer and autumn months may reach four per 1,000.
Figure. Clinical manifestations of Lyme disease.
The most well-documented vector of Lyme disease is the deer tick Ixodes fammini, whose geographic distribution correlates with endemic foci of disease. The tick incriminated in the western United States is I. pacifiais. These ticks are quite small, an unengorged adult measuring only 2 mm in length, so it is not surprising that histories of tick bites are infrequently obtained.
The preferred hosts of I. damnum are the whitetailed deer and white-footed deer mouse, but virtually any feral or domestic mammal can act as intermediate hosts. Birds are frequent carriers as well and their migratory patterns may account for the unusual dispersal pattern of Lyme disease. 10 Recently, another tick, Amblyomma americanum (the "Lone Star tick") has been implicated as a secondary vector of Lyme disease in southern New Jersey. n The extensive range of this tick may be of importance in its potential to transmit Lyme disease outside known endemic areas (ie, Texas and the southeastern states).
Spirochetes probably enter the skin and blood stream through the saliva and feces of infected ticks. Organisms have been isolated from the periphery of ECM lesions, cerebrospinal fluid, and blood of affected patients and have been documented histologically in synovium12 and myocardium.13 Whether all disease manifestations are caused by persistence of the spirochete in involved organs or not is not clear.
Humoral immune responses to infection include elevation of serum IgM and IgM cryoglobulinemia14; immune complexes have been demonstrated in serum and synovial fluid.15 Cellular immune findings in active disease include lymphopenia and decreased sup' pressor cell activity. l6 Antigen-specific proliferative Tcells have been demonstrated in the CSF of patients with Lyme meningitis.17 These findings suggest a disease with an infectious origin and immunologic expression.
Steere has divided Lyme disease into three stages, as shown in the treatment plan above. 18 Stage 1 is associated with ECM, stage 2 with neurologic or cardiac complications, and stage 3 with arthritis. This is generally the order in which symptoms are noted, but the stages may overlap; eg, secondary ECM lesions are frequently present at the time of neurologic or cardiac disease. Virtually any clinical feature may occur in isolation or recur at intervals, greatly enlarging the clinical spectrum of disease and resulting in difficulties in diagnosis.
ERYTHEMA CHRONICUM MIGRANS AND EARLY SYMPTOMS
ECM is the hallmark of early Lyme disease. A tick bite (recalled by only 20% to 30% of adults) often leaves a small, erythematous papule or macule which is then followed by a gradual centrifugal expansion over a period of days to weeks. Most lesions clear centrally and take on an annular configuration, averaging 15 cm in diameter. The thigh, groin, and axilla are common sites of involvement. Up to half of patients report a burning sensation and the lesion is warm to the touch; it is occasionally pruritic. ECM may be mistaken for tinea corporis, erythema marginatum, or cellulitis in cases without central clearing. Occasionally, the initial lesion appears vesicular or ulcerates. The primary ECM lesion is frequently accompanied by influenzalike symptoms of malaise and fatigue, fever and chills, headache, and regional lymphadenopathy.
Nearly half of patients develop multiple, smaller secondary annular lesions which lack indurated centers and are less migratory. Secondary lesions may occur anywhere, but spare the palms and soles. Malar rashes, urticaria, and photosensitive macules may be seen as well. Patients with multiple skin lesions can develop more severe constitutional symptoms and may exhibit severe headache and signs of meningeal irritation, mild encephalopathy, migratory arthralgia and myalgia, generalized lymphadenopathy, splenomegaly, conjunctivitis, sore throat, abdominal pain, and cough. These signs and symptoms are generally intermittent and create a rapidly changing clinical picture which may be confused with a number of viral illnesses or hypersensitivity reactions. 19
Headache is the most frequent neurologic symptom of Lyme disease and can be excruciatingly painful. In the early stages of disease, headache is not associated with objective neurologic abnormalities. After an average of 4 weeks, however, between 10% and 15% of patients will develop meningitis, cranial nerve palsies, and/or peripheral radiculoneuropathy, the triad of neurologic Lyme disease. 20
Meningitis is characterized by headache and stiff neck, but Kernig's and Brudzinski's signs are invariably absent and a viral etiology is frequently presumed. Subtle encephalitic symptoms can occur, manifested as sleep disturbances, difficulty in concentration, memory loss, and emotional lability.21
The VII cranial nerve is the most frequently involved in Lyme disease with facial palsies occurring in up to 11% of patients. Although seen in 50% of patients with meningitis, isolated Bell's palsy may be the sole neurologic manifestation and is frequently bilateral.22 Peripheral and sensory radiculoneuropathy is associated with severe neuritic pain, dysesthesias, focal weakness, and arreflexia. Other less common neurologic manifestations include chorea, cerebellar ataxia, Guillain-Barré syndrome, pseudotumor cerebri and demyelinating encephalopathy.
This is an uncommon complication occurring in less than 10% of patients an average of 4 to 5 weeks after ECM. The most common abnormality is a fluctuating atrioventricular block which can become complete. Patients may be asymptomatic, but can develop syncope, palpitations, dyspnea, chest pain, and severe bradycardia. Less commonly, there is evidence of myopericarditis or ventricular dysfunction. Unlike rheumatic heart involvement, the valves are spared.23
Approximately 50% of patients with ECM develop arthritis, typically 4 to 6 weeks after the rash, but occasionally months to years later. Lyme arthritis is characterized by recurrent attacks of asymmetric pain and swelling of large joints, which may go on for months to years. The knee is most frequently affected (75% of cases), followed by the shoulder, temporomandibular joint, elbow, ankle, and wrist. Arthritis is self-limiting, lasting 7 to 14 days. Children are generally asymptomatic between attacks; recurrences do not always involve the same joint. The clinical picture may be confused with reactive arthritis, viral synovitis, culture-negative septic arthritis, or pauciarticular JRA. Occasionally, there is a migratory polyarthritis which resembles acute rheumatic fever. In up to 10% of cases, chronic, erosive arthritis develops which may be difficult to distinguish from JRA.24 The risk of developing chronic arthritis appears to be related to the presence of the B cell alloantigen DR2.25
LYME DISEASE AND PREGNANCY
Transplacental transmission of B. bwrgdor/êri has been documented in a pregnant woman with Lyme disease in the first trimester who did not receive antibiotic therapy. She delivered at 35 weeks gestation a 3,000 g male with valvular aortic stenosis, coarctation of the aorta, and a poorly contractile left ventricle. The child succumbed despite balloon catheter dilatation of the coarctation and aortic valvulotomy. At post-mortem examination, spirochetes were demonstrated in the spleen, renal tubules, and bone marrow. 26 Nineteen other pregnancies have been reported with 14 normal outcomes. There were no other incidences of congenital heart disease, but intrauterine deaths, premature births, and developmental delay have occurred.27
Routine laboratory testing in Lyme disease can be frustratingly unrewarding. Hemoglobin, white blood cell, and platelet counts are usually normal. The sedimentation rate is elevated at times of disease activity.
The only other clue to diagnosis may be an elevation of serum IgM, while IgG and IgA remain normal. IgM cryoglobulins may be present and appear to correlate with more severe disease manifestations.14 Fluorescent tests for antinuclear antibodies may be transiently positive in some children; tests for rheumatoid factor are occasionally positive as well. Complement levels are variable. Circulating immune complexes have been demonstrated in serum and synovial fluid.15
The CSF in Lyme meningitis reveals a normal opening pressure, lymphocytic pleocytosis of from 15 to 700 cells/mm3, and elevated protein.21 Tests for myelin basic protein and VDRL are negative. In patients with encephalitic symptoms, electroencephalograms may show mild slowing and excess sharp wave activity; CT scans are normal.
Patients with carditis have electrocardiographic findings of atrioventricular block and, less frequently, T-wave changes or intraventricular conduction defects.23 Small pericardial effusions may be documented by echocardiography. Lyme myocarditis diagnosed by gallium scan has been reported in a child with normal EKG and echocardiogram.28
Synovial fluid analyses reveal elevated leukocyte counts, ranging from 2,000 to over 100,000 cells/mm3 with a polymorphonuclear predominance. Joint fluid proteins range from 3 to 6.4 g/dl. Synovial biopsies reveal villous hypertrophy, vascular proliferation, and a heavy infiltration of mononuclear cells.24
DIAGNOSIS AND SEROLOGIC TESTING
Identification of Lyme disease is best made on clinical recognition of signs and symptoms and history of exposure in an endemic area. Difficulties may arise in diagnosis, given the infrequent history of tick bite, variability in cutaneous manifestations, and incidence of incomplete clinical presentations. Isolation of B. burgdorferi is a low-yield procedure even in the most specialized research facilities. Diagnosis of Lyme disease can be confirmed through serologic testing, either by indirect immunofluorescence (IFA) or enzymelinked immunosorbent (ELISA) assays. The availability of such tests in state health departments, the Centers for Disease Control, and proprietary laboratories has made confirmation of clinically suspected cases possible.
However, such testing is not without its problems. Although IFA and ELISA have been repeatedly shown to be both sensitive and specific, false-positive results can be encountered in patients with other spirochetal illnesses. AU positive sera should also be tested for antibodies to T. pallidum, although syphilis can usually be ruled out on clinical grounds. Patients with early ECM lesions may have negative IFA results; ELISA seems to be more sensitive in such cases. Furthermore, very early antibiotic treatment may abrogate the immune response altogether. Later findings, such as meningitis and arthritis, are associated with IFA titers ≥1:256. Thus, the finding of an elevated antispirochetal antibody titer in conjunction with compatible symptoms is considered diagnostic.29 Caution should be taken to interpret results in the context of illness; epidemiologic investigations have revealed that individuals may become seropositive in the absence of clinical Lyme disease30 and elevated titers tend to persist for years.
Early empiric trials of oral antibiotics resulted in shortening of the duration of ECM and prevention or amelioration of further complications. Tetracycline appeared to be somewhat more effective than penicillin; either is more effective than erythromycin. This has led to the recommendation that adults with ECM be treated with tetracycline 250 mg four times daily for 10 to 20 days (Table). Children over 8 years of age can receive tetracycline 40 to 50 mg/kg/day, up to 1,000 mg. Children under 8 years with ECM should receive phenoxymethyl penicillin 50 mg/kg/day for the same period of time. In cases of penicillin allergy, erythromycin 30 mg/kg/day can be substituted. Patients may experience a Jarisch-Herxheimer-like reaction in the first days of therapy.4
Adults with Lyme meningitis have been successfully treated with high-dose intravenous penicillin G (20,000,000 units/day for 10 days).31 Children should receive between 200,000 and 300,000 U/kg/day up to 20,000,000 units. In a recent retrospective study of 101 patients with VIl nerve palsies, there appeared to be no significant effect of antibiotic therapy, but treatment regimens were not assigned randomly.22 Antibiotics should be given to such patients to prevent further complications, orally if the palsy is an isolated finding and intravenously if associated with meningitis.
Recommended treatment of Lyme carditis includes anti-inflammatory therapy as either aspirin (80 to 100 mg/kg/day up to 3.6 g) or prednisone (1 to 2 mg/kg/day up to 60 mg), depending on clinical severity. Placement of a temporary pacemaker may be necessary in patients with complete heart block.23 Consideration should also be given to treatment with high-dose intravenous penicillin G.
Treatment of Lyme arthritis includes the symptomatic use of aspirin and nonsteroidal anti-inflammatory drugs. Patients with arthritis have been successfully treated with high-dose intravenous penicillin (as for meningitis).32 Our own experience33 indicates that oral antibiotic therapy as outlined for ECM may be effective for Lyme arthritis when given for 3 to 4 weeks.
DIRECTIONS FOR FUTURE STUDY
With the more general availability of serologic testing it should be possible to further define the clinical spectrum of Lyme disease, especially as regards "incomplete" presentations without history of ECM. Our own experience suggests that in endemic areas, Lyme disease may be as common a cause of oligoarticular arthritis in childhood as pauciarticular JRA and that a history of rash may be absent in up to half of cases.33 Surveillance for Lyme disease should be extended to areas outside those generally regarded as endemic, given the recent identification of a potential focus in Texas and the emergence of new vectors. Lyme disease remains a unique model for study of the pathogenesis of rheumatic diseases in general, especially as the relative roles of infection, inflammation, and immunoregulation become clarified.
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3. Sceere AC, Malawista AC: Cases of Lyme disease in die United States: Locations correlated with distribution of Ixodes damnum. Ann Intern Med 1979; 91:730-734.
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22. dark JR, Carlson RD, Sasaki CT, et al: Facial paralysis in Lyme disease. Laryngoscope 1985; 95:1341-1345.
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33. Eichenfield AH, Goldsmith DP, Benach JL, et al: Childhood Lyme arthritis: Experience in an endemic area. J Pt&atr (in press).