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Lyme Disease in Children
Infect Dis Clin N Am 22 (2008) 315–326
Lyme Disease in Children Henry M. Feder, Jr, MDa,b,* a
University of Connecticut Health Center, MC 2918, 263 Farmington Avenue, Farmington, CT 06030, USA b Connecticut Children’s Medical Center, 282 Washington Street, Hartford, CT 06106, USA
In 1977, Allen Steere and colleagues [1] reported a mysterious arthritis, proceeded by an annular rash, in 39 children and 12 adults. These patients came from three bordering rural Connecticut communities (Lyme, Old Lyme, and East Haddam). Steere termed this new affliction Lyme arthritis. Over the next 5 years, the mysteries of Lyme arthritis were solved. The rash was similar to erythema chronicum migrans, first described in Europe in 1909. Erythema chronicum migrans usually lasted for 2 to 6 weeks in Europe, whereas the American variant usually lasted for 1 to 3 weeks. Thus, the American rash was termed erythema migrans to emphasize its shorter duration. In 1982, the tick vector (deer tick, also called black-legged tick) and the spirochetal pathogen Borrelia burgdorferi were defined [2,3]; Lyme arthritis was part of a multisystem disease, Lyme disease or Lyme borreliosis. Lyme disease has been found to be endemic in 10 eastern states (New Hampshire, Massachusetts, Rhode Island, Connecticut, New York, Pennsylvania, New Jersey, Maryland, Delaware, and Virginia) and two midwestern states (Minnesota and Wisconsin). From 2003 to 2005, the US Centers for Disease Control and Prevention (CDC) received reports of 64,382 cases of Lyme disease from 46 states. Thirty percent of the Lyme disease cases occurred in children younger than 20 years old (Fig. 1). The highest-risk age groups were 5 to 14 years old and 45 and to 54 years old [4]. This article reviews pediatric Lyme disease in the United States. The agent of Lyme disease includes three pathogenic species (B burgdorferi, B afzelii, and B garinii), only B burgdorferi strains are found in the United States. The article’s discussion is limited to the single species B burgdorferi.
* Department of Family Medicine, University of Connecticut Health Center, MC 2918, 263 Farmington Avenue, Farmington, CT 06030-2918. E-mail address: [email protected] 0891-5520/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.12.007
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Fig. 1. Number of newly reported Lyme disease cases, by sex and age groupdUnited States, 2003–3005. (From CDC. Lyme diseasedUnited States, 2003–2005. MMWR Morbid Mortal Wkly Rep 2007;56:573–6.)
Erythema migrans in children Redness may occur immediately at the site of the deer tick bite. This early reaction is less than 5 cm in diameter and fades without therapy in 1 to 3 days. The erythema migrans rash itself begins as a red macule 2 to 30 days after the tick bite, expanding to an annular lesion from 5 to more than 60 cm within days or weeks. The sites of a single erythema migrans in children are the head and neck (26%), the arms and legs (25%), the back (24%), the abdomen (9%), the axilla (8%), the groin (5%), and the chest (3%) [5,6]. The most common sites for a single erythema migrans in adults are the head, neck, and back [7]. Erythema migrans lesions are usually flat; they are not scaly, and rarely warm. Although they may be pruritic, burning, or hyperesthetic, erythema migrans lesions are rarely painful. In the author’s experience, most single erythema migrans lesions in children are confluent erythema (Figs. 2 and 3). Children who have a single erythema migrans lesion have associated fever (24%), fatigue (58%), headache (42%), and arthralgias (33%) [6] Although no large studies describe the different
Fig. 2. Typical erythema migrans with confluent erythema.
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Fig. 3. Erythema migrans that has increased erythema centrally and thus could be described as a target lesion.
appearances of erythema migrans lesions in children, the author’s experience in children parallels that reported in a large adult study: homogenous erythema (59%), central erythema (30%), central clearing (9%), or central purpura (2%) [7]. In addition, 7% of the erythema migrans lesions in this adult study had central vesicles or ulcerations [7]. In a prospective study of children who had Lyme disease, 134 presented with a single erythema migrans lesion, and 34 children presented with multiple erythema migrans lesions [6]. In a prospective adult vaccine study, 112 adults had microbiologically confirmed erythema migrans (103 had a single erythema migrans lesion, and 9 had multiple erythema migrans lesions) [7,8]. Multiple erythema migrans lesions likely are caused by hematogenous spread of B burgdorferi from the primary site of infection. Compared with children who have a single erythema migrans lesion, children who have multiple erythema migrans lesions more commonly have fever (45% versus 24%), fatigue (80% versus 58%), and headache (70% versus 42%). Children may develop multiple erythema migrans lesions if the primary erythema migrans lesion was untreated, unnoticed, or never occurred. Multiple erythema migrans lesions frequently look like the primary but are smaller. If untreated, the secondary erythema migrans lesions usually resolve in about 1 month [5]. Because erythema migrans is a clinical diagnosis, serologic testing (ELISA and the Western blot) for children who have erythema migrans lesions usually is not recommended. In a Connecticut study of children who had Lyme disease, 31% of subjects who had a single erythema migrans lesion were IgM seropositive, compared with 89% of children who had multiple erythema migrans lesions were IgM seropositive [6]. All of the children in this study were treated with antibiotics, and follow-up serologies were performed at 8 weeks; there was infrequent seroconversion in those children who were initially seronegative. If follow-up serologies were performed at 2 to 4 weeks, an IgM response may have been identified. Seroconversion in initially seronegative adults with a treated erythema migrans
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lesion occurs in about 30% of patients (in these studies, follow-up serologies usually were done 2 to 4 weeks after presentation) [5].
Flu-like illness without erythema migrans in children Although erythema migrans is the classic sign of early Lyme disease, flulike illness without a rash may be its initial manifestation. In a 1991 longterm follow-up study of 146 children who had Lyme arthritis, seven children (15%) gave a history of a summer flu-like illness without erythema migrans preceding the arthritis [9]. In a 1993 study, 24 children, identified in a Lyme disease-endemic area, presented to their primary care physicians with fever, fatigue, and at least one of the following: arthralgias, myalgias, headaches, or neck pain [10]. Five of the 24 were IgM seropositive for B burgdorferi infection either acutely (one of five) or during follow-up (four of five). The presenting illnesses resolved spontaneously in 5 to 21 days. Two of these patients were treated when their fever recurred, which was associated with objective finding of Lyme disease (multiple erythema migrans, facial nerve palsy). The other three patients were treated when positive serology was reported. In the most comprehensive study of flu-like illness without erythema migrans, approximately 10,000 adults were followed for two tick seasons [8,11]; 24 subjects seroconverted with illnesses characterized by fever (15 of 24, 63%), fatigue (17 of 24, 71%), and/or arthralgias (17 of 24, 71%). Flu-like illness without erythema migrans presents a dilemma for physicians practicing in Lyme-endemic areas, because serology is usually negative at presentation. The decision between empiric therapy versus waiting and watching usually is made on a case-by-case basis.
Rheumatologic manifestations of Lyme disease in children Approximately 60% of untreated children who have erythema migrans or other early manifestations of Lyme disease will develop arthritis between 2 weeks and 2 years (mean six months) after the initial infection. Most children today who have Lyme arthritis have a negative history for erythema migrans; therefore, children who have Lyme arthritis either had unseen erythema migrans, or they never had it at all. The inflammation of Lyme arthritis is usually brief and involves a single large joint. Lyme arthritis involves the knee (Fig. 4) in more than 90% of children [12,13]. After the knee, other joints most commonly affected are the hip, the ankle, the wrist, and the elbow [13]; occasionally, multiple joints may be affected. Recurrent episodes can involve the same joint or different joints. Fever is noted in 25% to 50% of children who have Lyme arthritis, whereas fever occurs in less than 25% of adults who have Lyme arthritis [12,13]. Children who have Lyme arthritis usually have normal peripheral leukocyte counts and slightly to moderately elevated erythrocyte sedimentation rates (25% have less than
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Fig. 4. Lyme arthritis manifested as left knee swelling without redness and very little pain.
20 mm/h; 48% have 20 to 60 mm/h; 25% have greater than 60 mm/h). The joint fluid in children who have Lyme arthritis averages 38,000 cells/mm3 (range between 180 and 99,000 cells/mm3) with a preponderance (greater than 75%) of neutrophils. In the last few years, the author has seen two children with Lyme arthritis who had 100,000 to 120,000 cells/mm3 in their synovial fluid. Like adults, children who have Lyme arthritis almost invariably have markedly positive B burgdorferi serology [12,13]. Lyme arthritis is usually less severe in children than in adults, and the prognosis for children who have Lyme arthritis is excellent. Szer and colleagues [9] reviewed the outcomes of 46 children with Lyme arthritis who went untreated during the first 4 years of their illnesses; spontaneous recovery occurred in 80% of children during the first 4 years following the onset of arthritis, in 90% of children by 6 years, and in 100% of children by 9 years. Inflammatory eye lesions, including panophthalmitis, ischemic optic atrophy, or interstitial keratitis, occurred alone or in association with Lyme arthritis in some of these children [9]. In a review of 85 children treated for Lyme arthritis, 42 received a single course of oral antibiotics, two received a single course of intravenous antibiotics, and 41 received two to five courses of oral and/or intravenous antibiotics. Two children who had persistent Lyme arthritis had undergone synovectomy. A telephone follow-up was performed an average of 7 years after the initial onset of arthritis, and in all patients, the Lyme arthritis had resolved. Four children had ongoing nonspecific musculoskeletal complaints [13]. Chronic arthritis (arthritis persisting more than 6 months despite antibiotic therapy) is associated with the HLA-DR4 and HLA-DR2 alleles [14]. Although culturing B burgdorferi from the joint fluid of children or adults who have Lyme arthritis is very difficult, polymerase chain reaction (PCR) for B burgdorferi is frequently positive. In patients who have
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persistent effusion, the initially positive PCR changes to negative following antibiotic treatment [15,16]. Therefore, persistent effusion does not mean persistent infection. Children and adults who have Lyme arthritis and persistent effusions have two options. They can be treated symptomatically and over many months the effusion will probably resolve, or they can have a surgical synovectomy. A synovectomy was performed in 2 of 90 (2%) children who had Lyme arthritis [13] versus in 6 of 54 (11%) adults who had Lyme arthritis [17]. Some children who have Lyme disease develop arthralgias rather than arthritis; arthralgias and/or myalgias may precede the development of objective findings, including Lyme arthritis. Antibiotic treatment of children who have arthralgias and/or myalgias usually should be reserved for those who have positive B burgdorferi serology.
Neurological manifestations of Lyme disease in children Approximately 15% to 20% of untreated children or adults who have early Lyme disease develop neurologic symptoms within months of initial infection. Neurological manifestations occur in the central and peripheral nervous systems [3]. The pathogenesis of neurologic Lyme disease includes direct invasion by B burgdorferi and/or vascular inflammation [3,18]. Most children today who have neurologic Lyme disease have not had recognized erythema migrans or other manifestations of Lyme disease. The most common manifestations of neurologic Lyme disease in children are facial nerve palsy (Fig. 5), sixth nerve palsy, and lymphocytic meningitis. Although peripheral neuropathies, radiculopathies, and Bannwarth’s syndrome (lymphocytic meningitis, radicular pain, and peripheral and cranial neuropathy) occur in adults, they are unusual in children [3]. Cerebrospinal fluid findings in children who have Lyme meningitis reveal an increased number of leukocytes (10 to 316 cells/mm3, with more than 67%
Fig. 5. Left-sided peripheral facial nerve palsy. This individual cannot wrinkle her left forehead, she cannot close left eye, and she cannot lift the left angle of her mouth.
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lymphocytes and monocytes), elevated protein concentration (averaging 68 mg/dL), and a normal or slightly decreased glucose concentration [19,20]. Dayan and colleagues [21] reported an unusual case of a 11-year-old child with Lyme meningitis with CSF findings of 733cells/mm3 (98% lymphocytes and 2% monocytes), a protein concentration of 267 mg/dL, and a glucose concentration of 1 mg/dL. In addition to meningitis, she had sixth nerve palsy and elevated intracranial pressure [21]. Most children who have Lyme meningitis have additional findings associated with Lyme disease, including facial nerve palsy, sixth nerve palsy, papilledema, increased intracranial pressure, or erythema migrans. Patients who have neurologic manifestations of Lyme disease usually have demonstrable serum antibodies to B burgdorferi either acutely or in convalescence [19–21]. Unusual manifestations of neurologic Lyme disease in children include ataxia, chorea, myelitis, pseudotumor cerebri, meningoencephalitis, and encephalopathy [22–24]. The prognosis of neurologic Lyme disease is excellent [25–28]. Facial nerve palsy caused by Lyme disease resolves irrespective of antibiotics in more than 95% of children. Treating facial nerve palsy with antibiotics does not influence the outcome of the palsy; however, it does prevent further manifestations of Lyme disease. If children who have facial nerve palsy from Lyme disease have nuchal signs (positive Bruzinski and/or Kernig signs), they need a lumbar puncture. Many children who have Lyme-related facial nerve palsy are playful and otherwise well; a lumbar puncture for these children usually is not recommended [26]. Some pediatric neurologists disagree, because they have found lymphocytic meningitis in well-appearing children [29]. Most children with Lyme-related facial nerve palsy who are not seen by neurologists do not receive lumbar punctures, and they are treated with oral antibiotics with excellent outcomes [28]. If meningitis is defined, then the patient should be treated with 2 to 4 weeks of intravenous ceftriaxone.
Cardiac manifestations of Lyme disease in children Lyme carditis occurs rarely in children: one study reported only 1 of 20 (5%) patients who had Lyme carditis were in the pediatric age group [30]. The patient in this study was an asymptomatic 6-year-old who was found to have heart block on electrocardiogram. In untreated adults with early Lyme disease, approximately 4% to 8% will develop Lyme carditis within 3 months of initial infection. The pathogenesis of Lyme carditis involves either circulating immune complexes that damage the atrioventricular conduction system or direct invasion of the myocardium by B burgdorferi [30]. The most common manifestations of Lyme carditis are high-grade secondor third-degree atrioventricular heart block; less frequent are myopericarditis, left ventricular dysfunction, and cardiomegaly. Symptoms in adults who have Lyme carditis include syncopy, shortness of breath, and chest pain.
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The author’s limited experience in children includes two teenagers who had Lyme carditis; both developed syncope while exercising and were taken to emergency departments, where they had heart rates under 50 beats per minute because of third-degree heart block (Fig. 6). Lyme carditis should not be confused with rheumatic fever. The fever with rheumatic fever is hectic, while the fever with Lyme carditis is lowgrade or normal. Complete heart block is relatively common in Lyme carditis, but rare in rheumatic fever. Valvular involvement, first-degree heart block, and myocardial involvement are rare in Lyme carditis, but common in rheumatic fever. Patients who have Lyme carditis usually have positive B burgdorferi serology, either acutely or at follow-up [30]. Second- or third-degree heart block secondary to Lyme disease can be treated with intravenous antibiotics, and a permanent pacemaker rarely is needed [30].
Treatment of Lyme disease in children The treatment of Lyme disease is similar in children and in adults; an exception is the usage of doxycycline, which should not be used in children younger than 8 years [31]. Erythema migrans can be treated with doxycycline (in children 8 and above) for 10 to 21 days, amoxicillin for 14 to 21 days, or cefuroxime axetil for 14 to 21 days. Facial nerve palsy can be treated with doxycycline (in children 8 and above) or amoxicillin for 14 to 21 days. Lymphocytic meningitis caused by Lyme disease can be treated with intravenous ceftriaxone for 14 to 28 days. (The author treats most children who have lymphocytic meningitis intravenously for 14 days.) Lyme arthritis can be treated with oral doxycycline (children 8 and above) or amoxicillin for 28 days [31]. A small percentage of children will have persistent subjective symptoms, including headache, fatigue, neck pain, arthralgias, and/or myalgias following treatment and resolution of the objective sings of Lyme disease. These persistent symptoms are termed post-Lyme disease symptoms. The cause is unknown, and in the author’s experience, they resolve spontaneously in weeks to months without additional antibiotic therapy.
Fig. 6. Complete heart block with a rate 40 beats/min in a 13-year-old boy who fainted at a camp dance and had Lyme carditis.
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Lyme disease in pregnancy Maternal-to-fetal transmission of B burgdorferi has been documented in only three cases [32–34]. Two women had erythema migrans in their first trimester that was not treated [32,33]; a third women was given inadequate antibiotic treatment for erythema migrans [34]. The infants born to these three mothers died of respiratory, cardiac, or hepatic failure in the first 48 hours of life. B burgdorferi was found in multiple organs by means of immunofluorescent, immunochromogenic, and/or silver staining, or by means of culture. There was no evidence of inflammation or granuloma formation in any of the three infants, raising questions as to the pathogenesis of the B burgdorferi infection in these newborns [35]. In the one large serologic study of Lyme disease in pregnancy conducted in the United States [36], B burgdorferi was not implicated directly in any neonatal adverse outcome. Chronic congenital Lyme disease has been reported on the Internet but never scientifically documented. In a study searching for infants who had congenital Lyme disease, none of 162 pediatric neurologists from Lymeendemic states reported having cared for a child who had congenital Lyme disease [35]. Mothers who develop Lyme disease in pregnancy can be reassured that fetal B burgdorferi infection never has occurred if the mother is treated adequately [37].
Deer tick bites and Lyme disease prevention in children There have been two large controlled trials of antibiotic prophylaxis for deer tick bites [38,39]. One involved children and adults and used amoxicillin (250 mg three times daily for 10 days) versus placebo. Infection occurred in zero of 205 antibiotic recipients versus 2 of 182 placebo recipients. In the second trial [39] of only adults, subjects received doxycycline (one dose of 200 mg) or placebo. Infection occurred in 1 of 235 antibiotic recipients versus 8 of 247 placebo recipients. In these two prophylaxis trials, all the patients who became infected developed erythema migrans, and they were easily treated with 2 to 4 weeks of antibiotics. Antibiotic prophylaxis is not recommended routinely [37] for deer tick bites; however, the ultimate decision for or against prophylaxis is made on a case-by-case basis. In a survey of Connecticut physicians [40], 26% of all physicians routinely prescribed antibiotic prophylaxis for high-risk tick bites. Pediatricians (11%) were the least likely to prescribe antibiotic prophylaxis, and dermatologists (46%) were the most likely [40]. Other than tick-bite possible prophylaxis, recommendations for preventing Lyme disease include: Daily tick checks and tick removal before the tick is engorged (deer ticks usually have to be attached for greater 24 hours to cause infection) Wearing long sleeves and long pants tucked into shoes when outside in deer tick-infested areas (easier said than done for children)
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Treating exposed skin with 30% DEET, which repels ticks for 8 hours (DEET can applied safely to the skin in infants 2 months of age and older) [37,41] The Internet and chronic Lyme disease in children The concept that B burgdorferi can cause chronic infection unresponsive to standard courses of antibiotics has been advanced on the Internet and in anecdotal publications [42]. Children who have subjective complaints such as headaches, fatigue, trouble concentrating, and arthralgias may get diagnosed with chronic Lyme disease, whether or not they have ever had symptomatic Lyme disease, and whether or not they have positive B burgdorferi serology. Many physicians who regularly diagnose chronic Lyme disease belong to the International Lyme and Associated Diseases Society (ILADS). Members of ILADS believe that chronic Lyme disease is common; they promote their theories on the Internet, in lay publications, and in the political arena [42,43]. Steere and colleagues [44] emphasized the overdiagnosis of Lyme disease in adults in a 1993 study; they reported that 452 of 788 (57%) subjects referred to their Lyme disease clinic with nonspecific symptoms that were blamed on Lyme disease, never really had Lyme disease. Feder and Hunt reported the overdiagnosis of Lyme disease in children in a 1995 study [45]. Fifty-six of 156 (38%) children referred to the author’s clinic came with the diagnosis of Lyme disease that could not be confirmed. The author has seen children and adults who have presumed chronic Lyme disease. Many of these misdiagnosed children and adults are told they have chronic Lyme disease to explain their many subjective complaints [46]. In the author’s experience, debating patients or parents who believe in the diagnosis of chronic Lyme disease leads nowhere. Instead, symptoms should be defined, and a plan to treat these symptoms without antibiotics should be physician’s goal. Summary Lyme disease in children is defined by erythema migrans, or rheumatologic symptoms (usually knee arthritis), neurologic symptoms (usually facial nerve palsy and/or lymphocytic meningitis), and rarely carditis (usually second- or third-degree heart block). With rheumatologic, neurologic, or cardiac manifestations of Lyme disease, B burgdorferi serology should be positive. Arthritis and meningitis are more common in children than adults who have Lyme disease [6,13]. With 2 to 4 weeks of antibiotic therapy, the objective manifestations of Lyme disease resolve, and sequelae are unusual. Acknowledgment I wish to thank Alex Butensky for reviewing this manuscript.
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References [1] Steere AC, Malawista SE, Syndmam DR, et al. Lyme arthritisdan epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 1977; 20:7–17. [2] Burgdorfer W, Barbour AG, Hayes SR, et al. Lyme diseaseda tick-borne spirochetosis? Science 1982;216:1317–9. [3] Steere AC. Lyme disease. N Engl J Med 2001;345:115–24. [4] CDC. Lyme diseasedUnited States, 2003–2005. MMWR Morb Mortal Wkly Rep 2007;56: 573–6. [5] Malane MS, Grant-Kels JM, Feder HM Jr, et al. Diagnosis of Lyme disease based on dermatologic manifestations. Ann Intern Med 1991;114:490–8. [6] Gerber MA, Shapiro ED, Burke GS, et al. Lyme disease in children in southeastern Connecticut. N Engl J Med 1996;335:1270–4. [7] Smith RP, Schoem RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med 2002;136:421–8. [8] Steere AC, Sikand VJ, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209–15. [9] Szer IS, Taylor E, Steere AC. The long-term course of Lyme arthritis in children. N Engl J Med 1991;325:159–63. [10] Feder HM Jr, Gerber MA, Krause PJ, et al. Early Lyme disease: a flu-like illness without erythema migrans. Pediatrics 1993;91:456–9. [11] Steere AC, Dhar A, Hernandez J, et al. Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Am J Med 2003;114:58–62. [12] Eichenfield AH, Goldsmith DP, Benach JL, et al. Childhood Lyme arthritis: experience in an endemic area. J Pediatr 1986;109:753–8. [13] Gerber MA, Zemel LS, Shapiro ED. Lyme arthritis in children: clinical epidemiology and long-term outcomes. Pediatrics 1998;102:905–8. [14] Steere AC, Dwyer E, Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med 1990;323:219–23. [15] Nocton JJ, Dressler F, Rutledge BJ, et al. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med 1994;330:229–34. [16] Carlson D, Hernandez J, Bloom BJ, et al. Lack of Borrelia burgdorferi DNA in synovial samples from patients with antibiotic treatment-resistant Lyme arthritis. Arthritis Rheum 1999; 42:2705–9. [17] Steere AC, Levin RE, Molloy PJ, et al. Treatment of Lyme arthritis. Arthritis Rheum 1994; 37:878–88. [18] Belmam AL. Neurologic complications of Lyme disease in children. International Pediatrics 1992;7:136–43. [19] Eppes SC, Nelson DK, Lewis LL, et al. Characterization of Lyme meningitis and comparison with viral meningitis in children. Pediatrics 1999;103:957–60. [20] Shah SS, Zaoutis TE, Turnquist J, et al. Early differentiation of Lyme from enteroviral meningitis. Pediatr Infect Dis J 2005;24:542–5. [21] Dayan NE, Rubin LG, John DD, et al. Hypoglycorrhachia in Lyme meningitis. Pediatr Infect Dis J 2004;23:370–1. [22] Feder HM Jr, Zalneraitis EL, Reik L Jr. Lyme disease: acute focal meningoencephalitis in a child. Pediatrics 1988;82:931–4. [23] Belman AL, Iyer M, Coyle PK, et al. Neurologic manifestations in children with North American Lyme disease. Neurology 1993;43:2609–14. [24] Steenhoff AP, Smith MJ, Shah SS, et al. Neuroborreliosis with progression from pseudotumor cerebri to aseptic meningitis. Pediatr Infect Dis J 2006;25:91–2.
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[25] Adams WV, Rose CD, Eppes SC, et al. Cognitive effects of Lyme disease in children. Pediatrics 1994;94:185–9. [26] Shapiro ED, Gerber MA. Lyme disease and facial nerve palsydmore questions than answers. Arch Pediatr Adolesc Med 1997;151:1183–4. [27] Bingham PM, Galetta SL, Athreya B, et al. Neurologic manifestations in children with Lyme disease. Pediatrics 1995;96:1053–6. [28] Vazquez M, Sparrow SS, Shapiro ED. Long-term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics 2003;112:e93–7. [29] Belman AL, Reynolds L, Preston T, et al. Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy. Arch Pediatr Adolesc Med 1997;151:1224–8. [30] Steere AC, Batsford WP, Weinberg M, et al. Lyme carditis: cardiac abnormalities in Lyme disease. Ann Intern Med 1980;93:8–11. [31] Treatment of Lyme disease. The Medical Letter 2007;49:49–51. [32] Schlesinger PA, Duray PH, Burke BA, et al. Maternal–fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:67–8. [33] MacDonald AB, Benach JL, Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med 1987;87:615–6. [34] Weber K, Bratzke H, Neubert U, et al. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988;7:286–9. [35] Gerber MA, Zalneraitis EL. Childhood neurologic disorders and Lyme disease during pregnancy. Pediatr Neurol 1994;11:41–3. [36] Markowitz LE, Steere AC, Benach JL, et al. Lyme disease during pregnancy. JAMA 1986; 255:3394–6. [37] American Academy of Pediatrics, Committee on Infectious Diseases. Lyme disease. In: Pickering LK, editor. Red book. 27th edition. Elk Grove Village (IL): American Academy of Pediatrics; 2006. p. 428–33. [38] Shapiro ED, Gerber MA, Holibird NB, et al. A controlled trial of antibiotic prophylaxis for Lyme disease after deer tick bites. N Engl J Med 1992;327:1769–73. [39] Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001;345: 79–84. [40] Murray T, Feder HM Jr. Management of tick bites and early Lyme disease: a survey of Connecticut physicians. Pediatr Infect Dis J 2001;108:1367–70. [41] Hayes EB, Piesman J. How can we prevent Lyme disease? N Engl J Med 2003;348:2424–30. [42] Cooper JD, Feder HM Jr. Inaccurate information about Lyme disease on the Internet. Pediatr Infect Dis J 2004;23:1105–8 and 24:577–9. [43] Feder HM Jr, Johnson BJB, O’Connell S, et al. A critical appraisal of chronic Lyme disease. N Engl J Med 2007;357:50–8. [44] Steere AC, Taylor E, McHugh GL, et al. The overdiagnosis of Lyme disease. JAMA 1993; 269:1812–6. [45] Feder HM Jr, Hunt MS. Pitfalls in the diagnosis and treatment of Lyme disease in children. JAMA 1995;274:66–8. [46] Feder HM Jr. Differences are voiced by two Lyme camps at a Connecticut public hearing on insurance coverage of Lyme disease. Pediatrics 2000;105:855–7.
Lyme Disease in Children Henry M. Feder, Jr, MDa,b,* a
University of Connecticut Health Center, MC 2918, 263 Farmington Avenue, Farmington, CT 06030, USA b Connecticut Children’s Medical Center, 282 Washington Street, Hartford, CT 06106, USA
In 1977, Allen Steere and colleagues [1] reported a mysterious arthritis, proceeded by an annular rash, in 39 children and 12 adults. These patients came from three bordering rural Connecticut communities (Lyme, Old Lyme, and East Haddam). Steere termed this new affliction Lyme arthritis. Over the next 5 years, the mysteries of Lyme arthritis were solved. The rash was similar to erythema chronicum migrans, first described in Europe in 1909. Erythema chronicum migrans usually lasted for 2 to 6 weeks in Europe, whereas the American variant usually lasted for 1 to 3 weeks. Thus, the American rash was termed erythema migrans to emphasize its shorter duration. In 1982, the tick vector (deer tick, also called black-legged tick) and the spirochetal pathogen Borrelia burgdorferi were defined [2,3]; Lyme arthritis was part of a multisystem disease, Lyme disease or Lyme borreliosis. Lyme disease has been found to be endemic in 10 eastern states (New Hampshire, Massachusetts, Rhode Island, Connecticut, New York, Pennsylvania, New Jersey, Maryland, Delaware, and Virginia) and two midwestern states (Minnesota and Wisconsin). From 2003 to 2005, the US Centers for Disease Control and Prevention (CDC) received reports of 64,382 cases of Lyme disease from 46 states. Thirty percent of the Lyme disease cases occurred in children younger than 20 years old (Fig. 1). The highest-risk age groups were 5 to 14 years old and 45 and to 54 years old [4]. This article reviews pediatric Lyme disease in the United States. The agent of Lyme disease includes three pathogenic species (B burgdorferi, B afzelii, and B garinii), only B burgdorferi strains are found in the United States. The article’s discussion is limited to the single species B burgdorferi.
* Department of Family Medicine, University of Connecticut Health Center, MC 2918, 263 Farmington Avenue, Farmington, CT 06030-2918. E-mail address: [email protected] 0891-5520/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.12.007
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Fig. 1. Number of newly reported Lyme disease cases, by sex and age groupdUnited States, 2003–3005. (From CDC. Lyme diseasedUnited States, 2003–2005. MMWR Morbid Mortal Wkly Rep 2007;56:573–6.)
Erythema migrans in children Redness may occur immediately at the site of the deer tick bite. This early reaction is less than 5 cm in diameter and fades without therapy in 1 to 3 days. The erythema migrans rash itself begins as a red macule 2 to 30 days after the tick bite, expanding to an annular lesion from 5 to more than 60 cm within days or weeks. The sites of a single erythema migrans in children are the head and neck (26%), the arms and legs (25%), the back (24%), the abdomen (9%), the axilla (8%), the groin (5%), and the chest (3%) [5,6]. The most common sites for a single erythema migrans in adults are the head, neck, and back [7]. Erythema migrans lesions are usually flat; they are not scaly, and rarely warm. Although they may be pruritic, burning, or hyperesthetic, erythema migrans lesions are rarely painful. In the author’s experience, most single erythema migrans lesions in children are confluent erythema (Figs. 2 and 3). Children who have a single erythema migrans lesion have associated fever (24%), fatigue (58%), headache (42%), and arthralgias (33%) [6] Although no large studies describe the different
Fig. 2. Typical erythema migrans with confluent erythema.
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Fig. 3. Erythema migrans that has increased erythema centrally and thus could be described as a target lesion.
appearances of erythema migrans lesions in children, the author’s experience in children parallels that reported in a large adult study: homogenous erythema (59%), central erythema (30%), central clearing (9%), or central purpura (2%) [7]. In addition, 7% of the erythema migrans lesions in this adult study had central vesicles or ulcerations [7]. In a prospective study of children who had Lyme disease, 134 presented with a single erythema migrans lesion, and 34 children presented with multiple erythema migrans lesions [6]. In a prospective adult vaccine study, 112 adults had microbiologically confirmed erythema migrans (103 had a single erythema migrans lesion, and 9 had multiple erythema migrans lesions) [7,8]. Multiple erythema migrans lesions likely are caused by hematogenous spread of B burgdorferi from the primary site of infection. Compared with children who have a single erythema migrans lesion, children who have multiple erythema migrans lesions more commonly have fever (45% versus 24%), fatigue (80% versus 58%), and headache (70% versus 42%). Children may develop multiple erythema migrans lesions if the primary erythema migrans lesion was untreated, unnoticed, or never occurred. Multiple erythema migrans lesions frequently look like the primary but are smaller. If untreated, the secondary erythema migrans lesions usually resolve in about 1 month [5]. Because erythema migrans is a clinical diagnosis, serologic testing (ELISA and the Western blot) for children who have erythema migrans lesions usually is not recommended. In a Connecticut study of children who had Lyme disease, 31% of subjects who had a single erythema migrans lesion were IgM seropositive, compared with 89% of children who had multiple erythema migrans lesions were IgM seropositive [6]. All of the children in this study were treated with antibiotics, and follow-up serologies were performed at 8 weeks; there was infrequent seroconversion in those children who were initially seronegative. If follow-up serologies were performed at 2 to 4 weeks, an IgM response may have been identified. Seroconversion in initially seronegative adults with a treated erythema migrans
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lesion occurs in about 30% of patients (in these studies, follow-up serologies usually were done 2 to 4 weeks after presentation) [5].
Flu-like illness without erythema migrans in children Although erythema migrans is the classic sign of early Lyme disease, flulike illness without a rash may be its initial manifestation. In a 1991 longterm follow-up study of 146 children who had Lyme arthritis, seven children (15%) gave a history of a summer flu-like illness without erythema migrans preceding the arthritis [9]. In a 1993 study, 24 children, identified in a Lyme disease-endemic area, presented to their primary care physicians with fever, fatigue, and at least one of the following: arthralgias, myalgias, headaches, or neck pain [10]. Five of the 24 were IgM seropositive for B burgdorferi infection either acutely (one of five) or during follow-up (four of five). The presenting illnesses resolved spontaneously in 5 to 21 days. Two of these patients were treated when their fever recurred, which was associated with objective finding of Lyme disease (multiple erythema migrans, facial nerve palsy). The other three patients were treated when positive serology was reported. In the most comprehensive study of flu-like illness without erythema migrans, approximately 10,000 adults were followed for two tick seasons [8,11]; 24 subjects seroconverted with illnesses characterized by fever (15 of 24, 63%), fatigue (17 of 24, 71%), and/or arthralgias (17 of 24, 71%). Flu-like illness without erythema migrans presents a dilemma for physicians practicing in Lyme-endemic areas, because serology is usually negative at presentation. The decision between empiric therapy versus waiting and watching usually is made on a case-by-case basis.
Rheumatologic manifestations of Lyme disease in children Approximately 60% of untreated children who have erythema migrans or other early manifestations of Lyme disease will develop arthritis between 2 weeks and 2 years (mean six months) after the initial infection. Most children today who have Lyme arthritis have a negative history for erythema migrans; therefore, children who have Lyme arthritis either had unseen erythema migrans, or they never had it at all. The inflammation of Lyme arthritis is usually brief and involves a single large joint. Lyme arthritis involves the knee (Fig. 4) in more than 90% of children [12,13]. After the knee, other joints most commonly affected are the hip, the ankle, the wrist, and the elbow [13]; occasionally, multiple joints may be affected. Recurrent episodes can involve the same joint or different joints. Fever is noted in 25% to 50% of children who have Lyme arthritis, whereas fever occurs in less than 25% of adults who have Lyme arthritis [12,13]. Children who have Lyme arthritis usually have normal peripheral leukocyte counts and slightly to moderately elevated erythrocyte sedimentation rates (25% have less than
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Fig. 4. Lyme arthritis manifested as left knee swelling without redness and very little pain.
20 mm/h; 48% have 20 to 60 mm/h; 25% have greater than 60 mm/h). The joint fluid in children who have Lyme arthritis averages 38,000 cells/mm3 (range between 180 and 99,000 cells/mm3) with a preponderance (greater than 75%) of neutrophils. In the last few years, the author has seen two children with Lyme arthritis who had 100,000 to 120,000 cells/mm3 in their synovial fluid. Like adults, children who have Lyme arthritis almost invariably have markedly positive B burgdorferi serology [12,13]. Lyme arthritis is usually less severe in children than in adults, and the prognosis for children who have Lyme arthritis is excellent. Szer and colleagues [9] reviewed the outcomes of 46 children with Lyme arthritis who went untreated during the first 4 years of their illnesses; spontaneous recovery occurred in 80% of children during the first 4 years following the onset of arthritis, in 90% of children by 6 years, and in 100% of children by 9 years. Inflammatory eye lesions, including panophthalmitis, ischemic optic atrophy, or interstitial keratitis, occurred alone or in association with Lyme arthritis in some of these children [9]. In a review of 85 children treated for Lyme arthritis, 42 received a single course of oral antibiotics, two received a single course of intravenous antibiotics, and 41 received two to five courses of oral and/or intravenous antibiotics. Two children who had persistent Lyme arthritis had undergone synovectomy. A telephone follow-up was performed an average of 7 years after the initial onset of arthritis, and in all patients, the Lyme arthritis had resolved. Four children had ongoing nonspecific musculoskeletal complaints [13]. Chronic arthritis (arthritis persisting more than 6 months despite antibiotic therapy) is associated with the HLA-DR4 and HLA-DR2 alleles [14]. Although culturing B burgdorferi from the joint fluid of children or adults who have Lyme arthritis is very difficult, polymerase chain reaction (PCR) for B burgdorferi is frequently positive. In patients who have
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persistent effusion, the initially positive PCR changes to negative following antibiotic treatment [15,16]. Therefore, persistent effusion does not mean persistent infection. Children and adults who have Lyme arthritis and persistent effusions have two options. They can be treated symptomatically and over many months the effusion will probably resolve, or they can have a surgical synovectomy. A synovectomy was performed in 2 of 90 (2%) children who had Lyme arthritis [13] versus in 6 of 54 (11%) adults who had Lyme arthritis [17]. Some children who have Lyme disease develop arthralgias rather than arthritis; arthralgias and/or myalgias may precede the development of objective findings, including Lyme arthritis. Antibiotic treatment of children who have arthralgias and/or myalgias usually should be reserved for those who have positive B burgdorferi serology.
Neurological manifestations of Lyme disease in children Approximately 15% to 20% of untreated children or adults who have early Lyme disease develop neurologic symptoms within months of initial infection. Neurological manifestations occur in the central and peripheral nervous systems [3]. The pathogenesis of neurologic Lyme disease includes direct invasion by B burgdorferi and/or vascular inflammation [3,18]. Most children today who have neurologic Lyme disease have not had recognized erythema migrans or other manifestations of Lyme disease. The most common manifestations of neurologic Lyme disease in children are facial nerve palsy (Fig. 5), sixth nerve palsy, and lymphocytic meningitis. Although peripheral neuropathies, radiculopathies, and Bannwarth’s syndrome (lymphocytic meningitis, radicular pain, and peripheral and cranial neuropathy) occur in adults, they are unusual in children [3]. Cerebrospinal fluid findings in children who have Lyme meningitis reveal an increased number of leukocytes (10 to 316 cells/mm3, with more than 67%
Fig. 5. Left-sided peripheral facial nerve palsy. This individual cannot wrinkle her left forehead, she cannot close left eye, and she cannot lift the left angle of her mouth.
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lymphocytes and monocytes), elevated protein concentration (averaging 68 mg/dL), and a normal or slightly decreased glucose concentration [19,20]. Dayan and colleagues [21] reported an unusual case of a 11-year-old child with Lyme meningitis with CSF findings of 733cells/mm3 (98% lymphocytes and 2% monocytes), a protein concentration of 267 mg/dL, and a glucose concentration of 1 mg/dL. In addition to meningitis, she had sixth nerve palsy and elevated intracranial pressure [21]. Most children who have Lyme meningitis have additional findings associated with Lyme disease, including facial nerve palsy, sixth nerve palsy, papilledema, increased intracranial pressure, or erythema migrans. Patients who have neurologic manifestations of Lyme disease usually have demonstrable serum antibodies to B burgdorferi either acutely or in convalescence [19–21]. Unusual manifestations of neurologic Lyme disease in children include ataxia, chorea, myelitis, pseudotumor cerebri, meningoencephalitis, and encephalopathy [22–24]. The prognosis of neurologic Lyme disease is excellent [25–28]. Facial nerve palsy caused by Lyme disease resolves irrespective of antibiotics in more than 95% of children. Treating facial nerve palsy with antibiotics does not influence the outcome of the palsy; however, it does prevent further manifestations of Lyme disease. If children who have facial nerve palsy from Lyme disease have nuchal signs (positive Bruzinski and/or Kernig signs), they need a lumbar puncture. Many children who have Lyme-related facial nerve palsy are playful and otherwise well; a lumbar puncture for these children usually is not recommended [26]. Some pediatric neurologists disagree, because they have found lymphocytic meningitis in well-appearing children [29]. Most children with Lyme-related facial nerve palsy who are not seen by neurologists do not receive lumbar punctures, and they are treated with oral antibiotics with excellent outcomes [28]. If meningitis is defined, then the patient should be treated with 2 to 4 weeks of intravenous ceftriaxone.
Cardiac manifestations of Lyme disease in children Lyme carditis occurs rarely in children: one study reported only 1 of 20 (5%) patients who had Lyme carditis were in the pediatric age group [30]. The patient in this study was an asymptomatic 6-year-old who was found to have heart block on electrocardiogram. In untreated adults with early Lyme disease, approximately 4% to 8% will develop Lyme carditis within 3 months of initial infection. The pathogenesis of Lyme carditis involves either circulating immune complexes that damage the atrioventricular conduction system or direct invasion of the myocardium by B burgdorferi [30]. The most common manifestations of Lyme carditis are high-grade secondor third-degree atrioventricular heart block; less frequent are myopericarditis, left ventricular dysfunction, and cardiomegaly. Symptoms in adults who have Lyme carditis include syncopy, shortness of breath, and chest pain.
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The author’s limited experience in children includes two teenagers who had Lyme carditis; both developed syncope while exercising and were taken to emergency departments, where they had heart rates under 50 beats per minute because of third-degree heart block (Fig. 6). Lyme carditis should not be confused with rheumatic fever. The fever with rheumatic fever is hectic, while the fever with Lyme carditis is lowgrade or normal. Complete heart block is relatively common in Lyme carditis, but rare in rheumatic fever. Valvular involvement, first-degree heart block, and myocardial involvement are rare in Lyme carditis, but common in rheumatic fever. Patients who have Lyme carditis usually have positive B burgdorferi serology, either acutely or at follow-up [30]. Second- or third-degree heart block secondary to Lyme disease can be treated with intravenous antibiotics, and a permanent pacemaker rarely is needed [30].
Treatment of Lyme disease in children The treatment of Lyme disease is similar in children and in adults; an exception is the usage of doxycycline, which should not be used in children younger than 8 years [31]. Erythema migrans can be treated with doxycycline (in children 8 and above) for 10 to 21 days, amoxicillin for 14 to 21 days, or cefuroxime axetil for 14 to 21 days. Facial nerve palsy can be treated with doxycycline (in children 8 and above) or amoxicillin for 14 to 21 days. Lymphocytic meningitis caused by Lyme disease can be treated with intravenous ceftriaxone for 14 to 28 days. (The author treats most children who have lymphocytic meningitis intravenously for 14 days.) Lyme arthritis can be treated with oral doxycycline (children 8 and above) or amoxicillin for 28 days [31]. A small percentage of children will have persistent subjective symptoms, including headache, fatigue, neck pain, arthralgias, and/or myalgias following treatment and resolution of the objective sings of Lyme disease. These persistent symptoms are termed post-Lyme disease symptoms. The cause is unknown, and in the author’s experience, they resolve spontaneously in weeks to months without additional antibiotic therapy.
Fig. 6. Complete heart block with a rate 40 beats/min in a 13-year-old boy who fainted at a camp dance and had Lyme carditis.
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Lyme disease in pregnancy Maternal-to-fetal transmission of B burgdorferi has been documented in only three cases [32–34]. Two women had erythema migrans in their first trimester that was not treated [32,33]; a third women was given inadequate antibiotic treatment for erythema migrans [34]. The infants born to these three mothers died of respiratory, cardiac, or hepatic failure in the first 48 hours of life. B burgdorferi was found in multiple organs by means of immunofluorescent, immunochromogenic, and/or silver staining, or by means of culture. There was no evidence of inflammation or granuloma formation in any of the three infants, raising questions as to the pathogenesis of the B burgdorferi infection in these newborns [35]. In the one large serologic study of Lyme disease in pregnancy conducted in the United States [36], B burgdorferi was not implicated directly in any neonatal adverse outcome. Chronic congenital Lyme disease has been reported on the Internet but never scientifically documented. In a study searching for infants who had congenital Lyme disease, none of 162 pediatric neurologists from Lymeendemic states reported having cared for a child who had congenital Lyme disease [35]. Mothers who develop Lyme disease in pregnancy can be reassured that fetal B burgdorferi infection never has occurred if the mother is treated adequately [37].
Deer tick bites and Lyme disease prevention in children There have been two large controlled trials of antibiotic prophylaxis for deer tick bites [38,39]. One involved children and adults and used amoxicillin (250 mg three times daily for 10 days) versus placebo. Infection occurred in zero of 205 antibiotic recipients versus 2 of 182 placebo recipients. In the second trial [39] of only adults, subjects received doxycycline (one dose of 200 mg) or placebo. Infection occurred in 1 of 235 antibiotic recipients versus 8 of 247 placebo recipients. In these two prophylaxis trials, all the patients who became infected developed erythema migrans, and they were easily treated with 2 to 4 weeks of antibiotics. Antibiotic prophylaxis is not recommended routinely [37] for deer tick bites; however, the ultimate decision for or against prophylaxis is made on a case-by-case basis. In a survey of Connecticut physicians [40], 26% of all physicians routinely prescribed antibiotic prophylaxis for high-risk tick bites. Pediatricians (11%) were the least likely to prescribe antibiotic prophylaxis, and dermatologists (46%) were the most likely [40]. Other than tick-bite possible prophylaxis, recommendations for preventing Lyme disease include: Daily tick checks and tick removal before the tick is engorged (deer ticks usually have to be attached for greater 24 hours to cause infection) Wearing long sleeves and long pants tucked into shoes when outside in deer tick-infested areas (easier said than done for children)
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Treating exposed skin with 30% DEET, which repels ticks for 8 hours (DEET can applied safely to the skin in infants 2 months of age and older) [37,41] The Internet and chronic Lyme disease in children The concept that B burgdorferi can cause chronic infection unresponsive to standard courses of antibiotics has been advanced on the Internet and in anecdotal publications [42]. Children who have subjective complaints such as headaches, fatigue, trouble concentrating, and arthralgias may get diagnosed with chronic Lyme disease, whether or not they have ever had symptomatic Lyme disease, and whether or not they have positive B burgdorferi serology. Many physicians who regularly diagnose chronic Lyme disease belong to the International Lyme and Associated Diseases Society (ILADS). Members of ILADS believe that chronic Lyme disease is common; they promote their theories on the Internet, in lay publications, and in the political arena [42,43]. Steere and colleagues [44] emphasized the overdiagnosis of Lyme disease in adults in a 1993 study; they reported that 452 of 788 (57%) subjects referred to their Lyme disease clinic with nonspecific symptoms that were blamed on Lyme disease, never really had Lyme disease. Feder and Hunt reported the overdiagnosis of Lyme disease in children in a 1995 study [45]. Fifty-six of 156 (38%) children referred to the author’s clinic came with the diagnosis of Lyme disease that could not be confirmed. The author has seen children and adults who have presumed chronic Lyme disease. Many of these misdiagnosed children and adults are told they have chronic Lyme disease to explain their many subjective complaints [46]. In the author’s experience, debating patients or parents who believe in the diagnosis of chronic Lyme disease leads nowhere. Instead, symptoms should be defined, and a plan to treat these symptoms without antibiotics should be physician’s goal. Summary Lyme disease in children is defined by erythema migrans, or rheumatologic symptoms (usually knee arthritis), neurologic symptoms (usually facial nerve palsy and/or lymphocytic meningitis), and rarely carditis (usually second- or third-degree heart block). With rheumatologic, neurologic, or cardiac manifestations of Lyme disease, B burgdorferi serology should be positive. Arthritis and meningitis are more common in children than adults who have Lyme disease [6,13]. With 2 to 4 weeks of antibiotic therapy, the objective manifestations of Lyme disease resolve, and sequelae are unusual. Acknowledgment I wish to thank Alex Butensky for reviewing this manuscript.
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[25] Adams WV, Rose CD, Eppes SC, et al. Cognitive effects of Lyme disease in children. Pediatrics 1994;94:185–9. [26] Shapiro ED, Gerber MA. Lyme disease and facial nerve palsydmore questions than answers. Arch Pediatr Adolesc Med 1997;151:1183–4. [27] Bingham PM, Galetta SL, Athreya B, et al. Neurologic manifestations in children with Lyme disease. Pediatrics 1995;96:1053–6. [28] Vazquez M, Sparrow SS, Shapiro ED. Long-term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics 2003;112:e93–7. [29] Belman AL, Reynolds L, Preston T, et al. Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy. Arch Pediatr Adolesc Med 1997;151:1224–8. [30] Steere AC, Batsford WP, Weinberg M, et al. Lyme carditis: cardiac abnormalities in Lyme disease. Ann Intern Med 1980;93:8–11. [31] Treatment of Lyme disease. The Medical Letter 2007;49:49–51. [32] Schlesinger PA, Duray PH, Burke BA, et al. Maternal–fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:67–8. [33] MacDonald AB, Benach JL, Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med 1987;87:615–6. [34] Weber K, Bratzke H, Neubert U, et al. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988;7:286–9. [35] Gerber MA, Zalneraitis EL. Childhood neurologic disorders and Lyme disease during pregnancy. Pediatr Neurol 1994;11:41–3. [36] Markowitz LE, Steere AC, Benach JL, et al. Lyme disease during pregnancy. JAMA 1986; 255:3394–6. [37] American Academy of Pediatrics, Committee on Infectious Diseases. Lyme disease. In: Pickering LK, editor. Red book. 27th edition. Elk Grove Village (IL): American Academy of Pediatrics; 2006. p. 428–33. [38] Shapiro ED, Gerber MA, Holibird NB, et al. A controlled trial of antibiotic prophylaxis for Lyme disease after deer tick bites. N Engl J Med 1992;327:1769–73. [39] Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001;345: 79–84. [40] Murray T, Feder HM Jr. Management of tick bites and early Lyme disease: a survey of Connecticut physicians. Pediatr Infect Dis J 2001;108:1367–70. [41] Hayes EB, Piesman J. How can we prevent Lyme disease? N Engl J Med 2003;348:2424–30. [42] Cooper JD, Feder HM Jr. Inaccurate information about Lyme disease on the Internet. Pediatr Infect Dis J 2004;23:1105–8 and 24:577–9. [43] Feder HM Jr, Johnson BJB, O’Connell S, et al. A critical appraisal of chronic Lyme disease. N Engl J Med 2007;357:50–8. [44] Steere AC, Taylor E, McHugh GL, et al. The overdiagnosis of Lyme disease. JAMA 1993; 269:1812–6. [45] Feder HM Jr, Hunt MS. Pitfalls in the diagnosis and treatment of Lyme disease in children. JAMA 1995;274:66–8. [46] Feder HM Jr. Differences are voiced by two Lyme camps at a Connecticut public hearing on insurance coverage of Lyme disease. Pediatrics 2000;105:855–7.