Br J Ophthalmol 1999;83:1149–1152 1149 Ocular manifestations in children and adolescents with Lyme arthritis

Hans-Iko Huppertz, Doris Münchmeier, Wolfgang Lieb

Abstract lead to blindness.56 Ocular involvement has Background—Lyme arthritis is the most also been found in an animal model of Lyme frequent late manifestation of Lyme bor- borreliosis.7 reliosis and has been associated with ocu- Ocular Lyme borreliosis has also been lar inflammation. reported in children.8–14 For example, two cases Methods—A group of 153 children and of late have been described in a group adolescents with arthritis, 84 of whom had of 46 American children with Lyme arthritis.9 Lyme arthritis and 69 other causes of In view of these reports we have investigated arthritis, were followed prospectively for the occurrence of inflammatory in a 22–73 (median 44) months in the course of large cohort of European children with Lyme a national study. arthritis. Specifically we wanted to know if Results—Three of 84 patients with Lyme regular screening for eye involvement in arthritis had ocular inflammation (4%), patients with Lyme arthritis is warranted. including keratitis, anterior , and uveitis intermedia. All three had symp- toms of decreased visual acuity. Whereas Patients and methods anterior uveitis disappeared without se- In 1991 we started a prospective multicentre quelae, a corneal scar and a permanent study to investigate the late manifestations of loss of visual acuity in the patients with Lyme borreliosis in European children and keratitis and intermediate uveitis re- adolescents. Physicians were encouraged to mained. Systematic examination of all enter patients when they suspected Lyme 15 16 patients revealed no further ocular in- arthritis. Patients in whom arthritis had volvement. Of 69 patients with other started before their 16th birthday, were in- causes of arthritis who were followed in cluded if the attending physician considered parallel as a control group, four of 15 that they might have Lyme arthritis. patients with early onset pauciarticular Clinical data were recorded and all patients juvenile rheumatoid arthritis had chronic were tested for IgG and IgM antibodies to B anterior uveitis and two of 12 patients with burgdorferi in our laboratory using in-house 15 juvenile spondyloarthropathy had acute ELISA and immunoblot methods. Lyme anterior uveitis. arthritis was diagnosed on the basis of a Conclusions—Ocular involvement with positive ELISA and immunoblot analysis (>6 keratitis, anterior uveitis, and intermedi- specific bands) for IgG antibodies to B ate uveitis may occur in children and ado- burgdorferi. These criteria for interpretation of lescents with Lyme arthritis. Visual loss immunoblot analysis are considered equivalent appears to be symptomatic, making regu- to the Dearborn criteria published after the 17 18 lar ocular screening of such patients initiation of this study. unnecessary. In some patients, serum was also tested for (Br J Ophthalmol 1999;83:1149–1152) antibodies to B burgdorferi using the haemag- glutination assay (HAT) (Biologische Arbeits- gemeinschaft, Lich, Germany). Peripheral Children’s Hospital, Lyme borreliosis, which has an incidence of blood lymphocytes were tested for reactivity to University of 100/100 000, is the most frequent vector borrelial antigens19 and urine was examined Würzburg, Würzburg, borne disease in Germany.1 Early symptoms of using the polymerase chain reaction for the Germany the tick borne Borrelia burgdorferi infection presence of a B burgdorferi specific segment of a H-I Huppertz 20 D Münchmeier include erythema migrans, the most frequent gene encoding for the 41 kD flagellin. manifestation, and inflammatory disorders of Patients not fulfilling the criteria for Lyme 2 Department of the meninges, cranial nerves, and heart. The arthritis who had other causes of arthritis were , most frequent late manifestation is Lyme also followed: University of arthritis presenting as episodic arthritis which + Reactive arthritis associated with a Salmo- Würzburg, Würzburg, may become chronic. The eye may be aVected nella, Yersinia, Chlamydia, Mycoplasma,or Germany W Lieb in the course of neuroborreliosis involving the parvovirus B19 infection and with diar- 2nd, 3rd, 4th, 6th, and 7th cranial nerves or as rhoea, urethritis, or the typical rash preced- Correspondence to: ocular borreliosis that may occur during the ing arthritis. Diagnosis was confirmed by Professor Dr med Hans-Iko early and late stages of Lyme borreliosis. Dur- culture, polymerase chain reaction, or serol- Huppertz, Zentralkrankenhaus ing early Lyme borreliosis, 11% of patients ogy. 3 Sankt-Jürgen-Strasse, have transient follicular . In- + Juvenile spondyloarthropathy, where the Professor-Hess-Kinderklinik, flammatory lesions of all sites of the eye, onset of arthritis occurred before the age of 28205 Bremen, Germany. including anterior uveitis, intermediate uvei- 16 years, was diagnosed according to the Accepted for publication tis, and keratitis have been described during European Spondyloarthropathy Study 25 July 1999 late stages of the disease.34 Severe cases may Group (ESSG) criteria.21 1150 Huppertz, Münchmeier, Lieb

Table 1 Diagnosis of 69 paediatric control patients with last ophthalmological assessment was per- causes of arthritis other than Lyme borreliosis formed after a period of 44 months (median, range 22–73 months) after entering the study. No of Diagnosis patients Lyme arthritis was diagnosed in 84 patients of which 49 (58%) were male with a median Early onset pauciarticular JRA 15 Rheumatoid factor negative polyarticular JRA 1 age at the time of entry to the study of 11 years Oligoarticular JRA without subclassification 16 7 months (range 2 years 8 months–16 years 8 Acute transient arthritis 12 months). The remaining 69 patients had other Reactive arthritis 11 Juvenile spondyloarthropathy 12 causes of arthritis (Table 1) and served as the Septic arthritis 1 control group: 32 (46%) were male with a Vasculitis, non-classified 1 median age of 8 years 8 months (range 1 year–16 years 1 month). + Pauciarticular juvenile rheumatoid arthritis, Inflammatory eye lesions were reported in rheumatoid factor negative polyarticular 10 control patients and in nine patients with juvenile rheumatoid arthritis, and oligoar- Lyme arthritis. Transient conjunctivitis was ticular juvenile rheumatoid arthritis without found in four control patients (6%) and in six subclassification were diagnosed according patients with Lyme arthritis (7%). Of the 69 to the American College of Rheumatology, control patients, six patients had inflammatory formerly American Rheumatism Associ- eye lesions other than transient conjunctivitis ation, classification.22 (9%) and of the 84 patients with Lyme arthri- + Arthritis, including toxic synovitis of the tis, three patients had other inflammatory eye hip, having a duration of less than 6 weeks, lesions (4%) (Table 2). was classified as acute transient arthritis.23 Of the control patients, two male HLA B27 As stated in the study protocol, ocular mani- positive patients of 12 patients with juvenile festations were recorded by the attending phy- spondyloarthropathy (17%) had acute anterior sicians, mainly paediatric rheumatologists, at uveitis and four of 15 patients with early onset each scheduled visit 3 months, 1, 3, and 5 years pauciarticular juvenile rheumatoid arthritis after entering the study. In addition to routine (27%) had chronic anterior uveitis. Three of ophthalmological care provided as needed, all these patients were girls and all four were anti- patients were sent for ophthalmological assess- nuclear antibody positive. ment by an ophthalmologist of the patient’s Of 84 patients with Lyme arthritis, three preference at the 3 year follow up examination. patients (4%) had ocular lesions other than To ensure uniformity in ophthalmological transient conjunctivitis; clinical details are examination, patients were asked to present an shown in Table 3. All eye diseases came to light accompanying letter to the attending ophthal- following complaints by the patients and not as mologist explaining the purpose of the study. a result of the routine ophthalmological exami- The letter listed, in anatomical order, all ocular nations or during the 3 year examination done manifestations of Lyme borreliosis described with special reference to signs and symptoms in the literature so far, beginning with keratitis of ocular Lyme borreliosis. Two patients had and conjunctivitis and ending with retinal lagophthalmus and facial nerve palsy before problems. Neuro-ophthamological entities— the onset of Lyme arthritis. No other neuro- that is, papilloedema and neuritis, ophthalmological manifestations were noted and squint were also listed. Ophthalmologists during the entire period of observation. were asked to report all abnormalities irrespec- Patient no 1, a 13 year old girl, reported loss tive of their opinion on whether they were of vision 10 months after onset of episodic related to Lyme borreliosis or not. arthritis of the right knee. Intermediate uveitis The study was approved by the ethics was diagnosed and treated with topical and committee of the medical faculty of the systemic steroids. A diagnosis of Lyme borre- University of Würzburg. Informed consent was liosis was made when antibodies to B burgdor- obtained from the patients’ parents and from feri were detected in the patient’s serum and adolescent patients themselves. she was then treated with systemic tetracy- Statistical analysis was performed with the clines. Since arthritis recurred and vision dete- 24 help of the MEDAS system. riorated further, she was treated with ceftriax- one and bilateral vitrectomy. Arthritis disappeared and uveitis abated with Results permanently reduced visual acuity. The records of 153 children and adolescents Patient no 2 had episodic arthritis of the who had been examined at least once by one of knee which was diagnosed as Lyme arthritis 114 ophthalmologists in Germany and Swit- only 3 years after its onset. The patient was ini- zerland (n=1) were available for analysis. The tially given intravenous penicillin and then ceftriaxone when the arthritis recurred. Al- Table 2 Ocular involvement other than transient conjunctivitis in 153 children and though arthritis had disappeared 3 months adolescents with arthritis after a median follow up of 44 months later, the patient developed severe keratitis of 153 patients with arthritis the upper third of both with marked 84 patients with Lyme arthritis 69 patients with other causes neovascularisation, but without intraocular of arthritis inflammation. Keratitis resolved after treat- 3 patients with ocular involvement 15 patients with early onset 12 patients with juvenile pauciarticular JRA spondyloarthropathy ment with topical steroids, but corneal scars keratitis (n=1) chronic anterior uveitis (n=4) acute anterior uveitis (n=2) were still present 2 years later. anterior uveitis (n=1) Patient no 3 had episodic arthritis of the intermediate uveitis (n=1) right knee and elbow which was treated with Ocular manifestations in children and adolescents with Lyme arthritis 1151

Table 3 Clinical data of three patients with ocular borreliosis

Lymphocyte Patient Age Elisa HAT Immunoblot proliferation PCR in Outcome no (years) Sex Ocular symptoms Other symptoms IgM/IgG (1:n) IgM/IgG assay urine Treatment (visual acuity) 1 13 F bilateral intermediate arthritis right +/+ 5120 +/+ + + systemic/topical R 0.25 uveitis, right retinal knee steroids detachment tetracyclines, L0.8 ceftriaxone bilateral vitrectomy 2 14 M bilateral superior keratitis arthritis right −/+ 20.480 −/+ + − topical steroids recovery with with neovascularisation knee penicillin G, corneal scars ceftriaxone 3 6 F bilateral anterior uveitis arthritis right −/+ 10.240 −/+ + − topical steroids recovery knee and right ceftriaxone R 1.0 elbow L1.0

ceftriaxone. Arthritis recurred 3 years later, six of our control patients. Because of these however, and the patient developed blurred observations, the existence of a causal relation vision along with a continuously high titre between anterior uveitis and infection with B for antibodies to B burgdorferi. Bilateral burgdorferi was questioned,27 but the subse- anterior uveitis was detected. The parents of quent isolation of B burgdorferi from the the patient withheld their consent to start inflamed is evidence to support a borrelial antibiotic treatment although no other cause aetiology of some cases of anterior uveitis.28 of the inflammatory eye and joint disease Although anterior uveitis is rarely observed in was found. Symptoms abated spontaneously children with Lyme borreliosis,811 no alterna- during the next few months and did not recur tive explanation for its occurrence in patient no during the following 3 years, when the 3 was found. Despite the fact that antibiotic antibody titre began to decline. treatment was refused, articular and ocular inflammation disappeared when antibody ti- tres declined. As with other manifestations of Discussion Lyme borreliosis, the disease may disappear We have described three patients with Lyme spontaneously in the absence antibiotic treat- arthritis who developed ocular borreliosis. In ment, but there is a risk that it may recur and the group of patients examined by us, this rep- even progress to more serious manifestations. resents a frequency of 4% which is the same as The recommended treatment is therefore that found in American children with Lyme 9 administration of antibiotics—ceftriaxone to- arthritis. Whereas the American children gether with topical steroids and, in severe developed keratitis however, the clinical mani- cases, systemic steroids—prednisone at 1–2 festations in the German children were more mg/kg body weight.34 varied and included intermediate uveitis and Transient conjunctivitis occurring at the anterior uveitis, in addition to keratitis. time of erythema migrans and influenza-like Keratitis, occurring in the absence of live symptoms have been described in the early spirochaetes and being associated with the stage of Lyme borreliosis.3 Since in this study deposition of antigen-antibody complexes, is a late manifestation rarely seen in children9 and all patients with Lyme borreliosis were in the in adults with Lyme borreliosis.3 Although sev- late stage of the disease, conjunctivitis, which eral types of keratitis have been associated with was observed in six patients with Lyme arthri- Lyme borreliosis, peripheral ulcerative keratitis tis, is not considered to be due to infection with with abundant neovascularisation, as seen in B burgdorferi. This conclusion is corroborated patient no 2, seems characteristic.25 In patient by the observation that conjunctivitis occurred no 2, keratitis occurred after successful anti- with a similar frequency among the control biotic treatment of Lyme arthritis. Although patients. corneal scars may occur, the treatment of Eye involvement in Lyme borreliosis occurs choice is topical .4 most frequently in the course of neuroborrelio- Intermediate uveitis due to infection with B sis: in addition to facial nerve palsy, a variety of 5 29–31 burgdorferi is also rarely seen in children.11 12 14 manifestations have been reported. In this In adults, Lyme borreliosis has been described study, in children with Lyme arthritis, these as a cause of intermediate uveitis with manifestations were not seen. vitreitis.34 Recommended treatment includes Although the patient data in this study were the use of antibiotics and good results have contributed by a large number of ophthalmolo- been reported with intravenous ceftriaxone.26 gists, sampling errors do not seem to be The recommended dose of ceftriaxone is 50 present. This conclusion is supported by two mg/kg body weight although larger doses have observations: (i) the frequency of transient also been used. As seen in patient no 1, conjunctivitis due to viral infection or allergy however, visual acuity may remain diminished was nearly identical in patients with Lyme after inflammation has abated. arthritis and in the control group; (ii) acute Anterior uveitis is the most frequent in- anterior uveitis was found in two of 12 children traocular inflammatory disease and is associ- with juvenile spondyloarthropathy and anterior ated with a large variety of infectious disorders uveitis in four of 15 children with early onset and autoimmune diseases including early onset pauciarticular juvenile rheumatoid arthritis. pauciarticular juvenile rheumatoid arthritis The type of ocular involvement, the association and juvenile spondyloarthropathy as found in with specific rheumatic disease and the 1152 Huppertz, Münchmeier, Lieb

observed frequency were in accordance with 7 Philipp M, Aydintug MK, Bohm RP, et al. Early and early 32 disseminated phases of in the rhesus monkey: current knowledge. a model for infection in humans. Infect Immun 1993;61: In addition to seronegative Lyme arthritis,33 3047–59. 8 Winward KE, Smith JL, Culbertson WW, et al.Ocular Lyme choroiditis and vitritis due to infection with B borreliosis. Am J Ophthalmol 1989;108:651–7. burgdorferi has been described in a single 9 Szer IS, Taylor E, Steere AC. The long-term course of Lyme arthritis in children. N Engl J Med 1991;325:159–63. patient negative for antibodies to B 10 Mombaerts IM, Maudgal PC, Knockaert DC. Bilateral fol- burgdorferi.34 In the present study, the diagnosis licular conjunctivitis as a manifestation of Lyme disease. Am J Ophthalmol 1991;112:96–7. of Lyme borreliosis required the presence of 11 Reim H, Reim M. Augenbefunde bei Infektion mit Borrelia high titres of antibodies specific for B burgdor- burgdorferi. Klin Monatsbl Augenheilkd 1992;201:83–91. feri and therefore cases of seronegative Lyme 12 Guex-Crosier Y, Herbort CP. Maladie de Lyme en Suisse: atteintes oculaires. Klin Monatsbl Augenheilkd 1992;200: borreliosis would have been missed. However, 545–6. such cases occur only rarely and diagnosis 13 Karma A, Pirttilä TA, Viljanen MK, et al. Secondary retini- tis pigmentosa and cerebral demyelination in Lyme borre- should be confined to centres with special liosis. Br J Ophthalmol 1993;77:120–2. expertise in this regard. 14 Karma A, Seppälä I, Mikkilä H, et al. Diagnosis and clinical charateristics of ocular Lyme borreliosis. Am J Ophthalmol Although this was not examined in the 1995;119:127–35. present study, the comparison of our data in 15 Huppertz HI, Karch H, Suschke HJ, et al, Pediatric Rheumatology Collaborative Group. Lyme arthritis in children and adolescents with those reported European children and adolescents. Arthritis Rheum 1995; in adult patients with ocular manifestations in 38:361–8. 16 Huppertz HI, Bentas W, Haubitz I, et al. Diagnosis of pedi- Lyme borreliosis does not reveal major atric Lyme arthritis using a clinical score. Eur J Pediatr diVerences.34 1998;157:304–8. 17 Recommendations for test performance and interpretation Patients with early onset pauciarticular juve- from the second national conference on serologic diagnosis nile rheumatoid arthritis may develop anterior of Lyme disease. MMWR 1995;44:590. uveitis in the absence of signs or symptoms and 18 Dressler F, Whalen JA, Reinhart BN, et al. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 1993;167: severe intraocular damage may occur before 392–400. the disease is detected. Therefore, regular oph- 19 Huppertz HI, Mösbauer S, Busch DH, et al. Lymphoprolif- erative responses to Borrelia burgdorferi in the diagnosis of thalmological examination is recommended in Lyme arthritis in children and adolescents. Eur J Pediatr these patients. In all three patients with Lyme 1996;155:297–302. 20 Karch H, Huppertz HI, Böhme M, et al. Demonstration of arthritis reported here, ocular inflammation Borrelia burgdorferi DNA in urine samples from healthy was first seen following the reporting of signs humans whose sera contain Borrelia burgdorferi-specific antibodies. J Clin Microbiol 1994;32:2312–14. and symptoms by the patient and/or their par- 21 Dougados M, van der Linden S, Juhlin R, et al. The ents and did not come to light as the result of European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. the routine ophthalmological examination. In Arthritis Rheum 1991;34:1218–27. fact, neither the special ophthalmological 22 Cassidy JT, Levinson JE, Bass JC, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid appointment 3 years after the onset of arthritis. 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