Birdshot Chorioretinopathy and Lyme Borreliosis

Birdshot Chorioretinopathy and Lyme Borreliosis M. S. A. Suttorp-Schulten, M.D., 1. Luyendijk, M.S., A. P. van Dam, M.D., R. J. W. de Keizer, M.D., G. S. Baarsma, M.D., P. J. M. Bos, M.D., and A. Rothova, M.D.

Two patients in whom ocular Lyme disease was suspected and who had antibodies to Borrelia burgdorferi developed birdshot chorioretinopathy and carried the HLA-A29 antigen. In a series of 11 patients with birdshot chorioretinopathy who carried the HLA-A29 antigen, three patients had antibodies against B. burgdorferi as determined by either immuno8.uorescence assay, enzyme-linked immunosorbent assay, Western blot analysis, or a combination of these tests. Further studies will be necessary to evaluate whether this is a false-positive reaction or whether B. burgdorjeri has a causative role in the pathogenesis of birdshot chorioretinopathy. BIRDSHOT CHORIORETINOPATHY is a specific clinical syndrome of unknown origin, characterized by multiple cream-colored patches at the level of the pigment epithelium and choroid in the postequatorial fundus.' In addition to chorioretinal lesions, birdshot chorioretinopathy includes the following symptoms also common in intermediate uveitis (pars planitis): vitreitis, vasculopathy with leakage, cystoid macular edema, and occasionally optic disk edema.P This disease is strongly associated with the HLA-A29 antigen; up to 95% of patients carry this antigen.v' Although the specific cause re-

Accepted for publication Oct. 20, 1992. From the Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands (Drs. Suttorp-Schulten and Rothova and Mr. Luyendijk); Department of Medical Microbiology, University of Amsterdam, Amsterdam, The Netherlands (Dr. van Dam); Department of Ophthalmology, Academic Hospital, Leiden, The Netherlands (Dr. de Keizer); Eye Hospital, Rotterdam, The Netherlands (Dr. Baarsma); and Department of Ophthalmology, Academic Hospital, Amsterdam, The Netherlands (Dr. Bos). Reprint requests to M. S. A. Suttorp-Schulten, M.D., Netherlands Ophthalmic Research Institute, P.O. Box 12141, 1100 AC Amsterdam, The Netherlands.

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mains unknown, birdshot chorioretinopathy is considered to represent a single disease entity. Birdshot lesions, however, have been associated with other ocular diseases such as sarcoidosis confirmed by biopsy." We observed fundus lesions typical for birdshot chorioretinopathy in two patients with positive immunofluorescence antibody titers against Borrelia burgdorferi. To evaluate a possible relation between birdshot chorioretinopathy and Lyme borreliosis, we evaluated all sera available in our laboratory from patients with HLA-A29-associated birdshot chorioretinopathy by using the following three serologic tests: an immunofluorescence assay, an enzyme-linked immunosorbent assay (ELISA), and Western blot analysis.

Patients and Methods Antibodies against B. burgdorferi were determined in sera of all patients by using an immunofluorescence assay, an ELISA, and Western blot analysis. The immunofluorescence test was performed by using a commercially available kit that included a nonviable antigen (8. burgdorferi) fixed on multiwell glass slides (PROGEN, Biotechnik, Heidelberg, Germany). The cutoff point for IgG titers in this test was 1:256; if the titer was lower, the test was considered negative. All assays were performed according to manufacturer's guidelines. An ELISA for IgG antibodies was performed with a commercially available kit that contained a flagellum of a European strain of B. burgdorferi as test antigen (DAKO ELISA kit, Glastrup, Denmark). Results were classified and interpreted as negative (-), borderline (1:), positive (+), and strongly positive (+ +) in comparison to the control samples supplied by the manufacturer and assayed at the same time. Western blot analysis was performed by elecFEBRUARY,

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trophoresis of a reduced whole-cell lysate of B. burgdorferi strain A405 on an 8% to 25% sodium dodecyl sulfate polyacrylamide gel (Pharmacia, Biotechnology AB, Uppsala, Sweden). Strain A405 has been isolated from a Dutch patient with erythema migrans. The gel was blotted onto Immobilon paper (0.45 J-Lm, Millipore, Millipore Corp., Bedford, Massachusetts). The blots were then incubated with patient's sera diluted 1:200 and thereafter incubated with peroxidase-conjugated goat antihuman immunoglobulin (1:100 dilution). The blots were stained with diaminobenzidine. Analysis was based on comparison with a positive control sample, a marker, and the presence of more than six bands. Birdshot chorioretinopathy was diagnosed on the basis of the following typical clinical manifestations as described previously by Ryan and Maumenee": (1) symmetrically scattered, small cream-colored flecks on the retina; (2) retinal vasculopathy; (3) optic disk edema or optic atrophy; and (4) inflammatory signs in the vitreous. As mentioned previously, all patients carried the HLA-A29 antigen. Fluorescein angiography of all patients was evaluated in the European Fluorescein Angiography Club and the diagnosis of birdshot chorioretinopathy was confirmed in all cases. Index patients-A 40-year-old man (Patient 1) developed blurred vision in May 1989. On examination, best-corrected visual acuity was 20/30 in both eyes and except bilateral papilledema, no abnormalities were noted. The patient's medical history was not contributory. Neurologic examination, computed tomography of the brain, and cerebrospinal fluid analysis disclosed no abnormalities. A complete blood cell count was normal, serologic tests for syphilis, angiotensin-converting enzyme, and lysozyme were negative, and thoracic radiography disclosed no abnormalities. Viral papilloretinitis was tentatively diagnosed. Despite oral therapy with prednisone, there was no improvement, visual symptoms progressed, and within half a year his best-corrected visual acuity decreased to 20/40 in both eyes. Sporadic cells in the vitreous, edema of the optic disk, and massive macular edema were found. No other retinal abnormalities were noticed and fluorescein angiography confirmed massive macular edema. The patient was reexamined for his uveitis and a Lyme immunofluorescence assay was positive (1:320). This positive test result was confirmed by another laboratory by an immunofluorescence assay (1:1,024). The

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patient recalled no tick bite, erythema migrans, or any other clinical signs compatible with Lyme borreliosis. A Lyme immunofluorescence assay with cerebrospinal fluid was negative, but was positive with aqueous fluid (1:8). The Goldmann-Wittmer coefficient, however, did not confirm an active intraocular production of anti-Borrelia antibodies." However, the production of specific antibodies in the eye cannot be reliably determined in patients with high antibody titers in serum." Lyme borreliosis was tentatively diagnosed and the patient was treated with intravenous ceftriaxone (2 g a day for two weeks), which resulted in a slight improvement, followed by progressive loss in visual acuity. Three months after treatment, best-corrected visual acuity was R.E.: 20/60 and L.E.: 20/70. There was moderate vitreitis in the left eye. On fundus examination, multiple cream-colored spots extending from the optic disk to the equator in both eyes had developed, which strongly suggested birdshot chorioretinopathy (Fig. 1). Fluorescein angiography was repeated and showed findings typical for birdshot chorioretinopathy, including extensive vascular leakage with cystoid macular edema. The patient carried the HLA-A29 antigen. Because of the progressive loss in visual acuity, we decided to re-treat the patient (four-

Fig. 1 (Suttorp-Schulten and associates). Patient 1, Right eye. The margins of the optic disk are blurred and multiple depigmented lesions, concentrated nasal to the optic nerve, are seen.

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week course with intravenous ceftriaxone, 2 g a day), but no improvement occurred. As bestcorrected visual acuity continued to decrease to R.E.: 20/160 and L.E.: 20/125 within six months after this therapy, treatment with oral prednisone was started with a dosage of 30 mg daily. After 16 months of this treatment, visual acuity stabilized at R.E.: 20/160 and L.E.: 20/ 125 and massive macular edema is still persisting. A 68-year-old man (Patient 2) was examined in October 1990 for blurred vision of two years' duration. His best-corrected visual acuity was R.E.: 20/30 and L.E.: 20/25. Ophthalmic examination disclosed cells in the vitreous bilaterally, macular and optic disk edema, and multiple cream-colored spots, located in the inferior nasal region (Fig. 2). On fluorescein angiography, extensive vascular leakage with cystoid macular edema and disk edema was seen. The patient carried the HLA-A29 antigen. The patient's history disclosed no diagnostic clues for any systemic disease. The patient could not recall a tick bite or erythema migrans. Additional screens were negative for uveitis. A complete blood cell count was normal, serologic tests for syphilis, angiotensin-converting enzyme, and lysozyme were negative, and thoracic radiography disclosed no abnormalities. Lyme immunofluorescence assay was positive (1:512) and in an assay by another laboratory, a

borderline result was observed (1:80). The result of the ELISA was borderline. Birdshot chorioretinopathy was diagnosed on the basis of typical retinal findings and the finding that he was HLA-A29 positive. We decided not to treat this patient for Lyme borreliosis, but to treat macular edema symptomatically with acetazolamide tablets, 250 mg twice daily. The treatment resulted in improvement of best-corrected visual acuity up to 20/20 in both eyes and the blurring of vision decreased subjectively. At the last follow-up, six months after initiation of this treatment regimen, best-corrected visual acuity was maintained and no change in the fundus was observed.

Results

The laboratory results of all serologic tests (including the two index patients) were compared (Table) (the first index patient is Patient 1 and the second index patient is Patient 2). Three patients had a positive immunofluorescence assay against B. burgdorieri, and one additional patient had borderline results. The ELISA was positive in two patients and a third

TABLE SEROLOGIC TESTS FOR BORRELIA BURGDORFERI IN PATIENTS WITH HLA-A29-ASSOCIATED BIRDS HOT CHORIORETINOPATHY

PATIENT

IMMUNOFLUORESCENCE

NO.

ASSAY'

1 2 3 4 5 6 7 8 9 10 11

1:320 1:512 1:2048

WESTERN ANALYSIS*

BLOT

+ :t'

++

+

1:256'

+

• - indicates negative titer. indicates negative. :t indicates borderline. + indicates positive. and ++ indicates strongly positive titers. *+ indicates more than six bands; - indicates less than six bands. 'Borderline results. t-

Fig. 2 (Suttorp-Schulten and associates). Patient 2, Left eye. Depigmented lesions are seen in the inferonasal region.

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patient had borderline test results. One patient (Patient 3) had both a positive immunofluorescence assay and a positive ELISA. Western blot analysis showed positive results in two patients (Patient 1 with seven bands and Patient 3 with eight bands) and both of these patients had antibodies in their serum as demonstrated by immunofluorescence assay or ELISA.

Discussion

The precise origin of birdshot chorioretinopathy is still unknown, but it is strongly associated with HLA-A29. 1•3•4 It is not clear whether this disease is caused by one causative agent or whether the presence of the class I antigen, HLA-A29, is required to form a common pathway that may be initiated by different causative agents. This last hypothesis may be sustained by a study on the association of birdshot chorioretinopathy and sarcoidosis confirmed by biopsy." Concerning Lyme borreliosis, an association with HLA class II alleles has been described in chronic Lyme arthritis, but not in other clinical forms of Lyme disease." The association of birdshot chorioretinopathy and positive Lyme serologic tests, also noted by other investigators (Holack, H.; and Horst, H.: Ophthalmic complications of Lyme borreliosis. In Dernouchamps, J. P. (ed.): Program and Abstracts of the 3rd International Symposium on Uveitis, Brussels, 1992, p. 77), could be explained either by genuine infection with B. burgdorferi or by serologic tests in which falsepositive results of unknown origin are obtained. Lyme borreliosis is increasingly recognized as a cause of intermediate uveitis and papillitis and includes multifocal choroiditis." The pathogenesis of ocular Lyme borreliosis is not yet known. Two concepts have been put forward: dissemination of B. burgdorferi to the eye or an immunologic reaction initiated by an infection elsewhere in the body. The combination of both of these phenomena may also be involved in the disease process. Borrelia burgdorferi has been cultured from vitreous aspirate in one case." The long-term persistence of B. burgdorferi in the vitreous of experimentally infected animals has also been described." The interpretation of serologic test results in Lyme borreliosis is difficult because false-positive and false-negative results frequently occur. Serologic cross-reactions occur between B.

burgdorferi and other spirochetes, the most important of which is Treponema pallidum. Infrequently, false-positive reactions have been found in patients with autoimmune diseases and infectious mononucleosis.l':" These falsepositive reactions generally produce a lower titer than observed in our Patients 1, 2, and 3. Low positive titers against B. burgdorferi were found in 20% to 30% of a series of patients with uveins.P:" Adgitionally, antibody titers against B. burgdorferi are frequently seen in persons with a high occupational risk for Lyme borreliosis, suggesting that asymptomatic infection can also occur. 16 These findings show that Lyme borreliosis cannot be diagnosed exclusively on the basis of laboratory investigative examinations. In addition to having a positive immunofluorescence assay and a positive ELISA, two patients in our series were also seropositive according to Western blot analysis, a test that is considered to be more specific.P-" This findiI\~ may suggest that our patients with birdshot chorioretinopathy who had anti-Borrelia burgdorferi antibodies had been previously infected with B. burgdorferi. Whether this previous infection is related to symptoms of birdshot chorioretinopathy remains to be established. Persistence of viable spirochetes, deposits of antigens, or an immunologic cross-reaction triggered by B. burgdorferi and directed to a target in the eye, could all account for the symptoms. As diagnosis of ocular Lytpe borreliosis becomes more reliable by the analysis of intraocular fluids for antibodies and by antigen detection by polymerase chain reaction techniques, the coincidental or the causal basis for this association will be classified.

References 1. Priem, H. A., and Oosterhuis, J. A.: Birdshot chorioretinopathy. Clinical characteristics and evolution. Br. J. Ophthalmol. 72:646, 1988. 2. Ryan, S. J., and Maumenee, A. E.: Birdshot retinochoroidopathy. Am. J. Ophthalmol. 89:31, 1980. 3. Priem, H. A., Kijlstra, A., Noens, L./Baarsma, G. S., De Laey, J. J., and Oosterhuis, J. A.: HLA typing in birdshot chorioretinopathy. Am. J. Ophthalmol. 105:182, 1988. 4. LeHoang, 'P., Ozdemir, N., Benharnou, A., Tabary, T., Edelson, C,; Betuel, H., Semiglia, R., and Cohen, J. H. M.: HLA-A29.2 subtyping associated with birdshot retinochoroidopathy. Am. J. Ophthalmol. 113:33, 1992. 5. Bred, R. D.: Presumed sarcoid choroidopathy

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mimicking birdshot retinochoroidopathy. Am. J. Ophthalmol. 109:357, 1990. 6. Kijlstra, A., Breebaart, A. c., and Baarsma, G. S.: Aqueous chamber taps in toxoplasmic chorioretinitis. Doc. Ophthalmol. 64:53, 1986. 7. Steere, A. E., Dwyer, E., and Winchester, R.: Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N. Engl. J. Med. 323:219, 1990. 8. Winterkorn, J. M. S.: Lyme disease. Neurologic and ophthalmic manifestations. Surv. Ophthalmol. 35:191, 1990. 9. Steere, A. c., Duray, P. H., Kauffmann, D. J. H., and Wormser, G. P.: Unilateral blindness caused by infection with the Lyme disease spirochete, Borrelia burgdorferi. Ann. Intern. Red. 103:382, 1985. 10. Johnson, R. c., Marek, N., and Kodner, c.: Infection of Syrian hamsters with Lyme disease spirochetes. J. Clin. Microbiol. 20:1099, 1984. 11. Magnarelli, L. A., Anderson, J. F., and Johnson, R. C.: Cross reactivity in serological tests for Lyme disease and other spirochetal infections. J. Infect. Dis. 156:183, 1987.

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12. Luger, S. W., and Krauss, E.: Serologic tests for Lyme disease, interlaboratory variability. Arch. Intern. Med. 150:761, 1990. 13. Rosenbaum, J. T., and Rahn, D. W.: Prevalence of Lyme disease among patients with uveitis. Am. J. Ophthalmol, 112:462, 1991. 14. Isogai, E., Isogai, H., Kotake, S., Yoshikawa, K., Ichiishi, A., Hosaka, S., Sato, N., Hayashi, S., Oguma, K., and Ohno, S.: Detection of antibodies against B. burgdorferi in patients with uveitis. Am. J. Ophthalmol. 112:23, 1991. 15. Kuiper, H., de [ongh, B. M., Nauta, A. P., Houweling, H., Wiessing, L. G., Moll van Charante, A. W., and Spanjaard, L.: Lyme borreliosis in Dutch forestry workers. J. Infect. 23:279, 1991. 16. Grodzicki, R. L., and Steere, A. c.: Comparison of immunoblotting and indirect enzyme-linked immunosorbent assay using different antigen preparations for diagnosing early Lyme disease. J. Infect. Dis. 157:790, 1988.

OPHTHALMIC MINIATURE

We were so proud, so vain, and so ignorant of Japanese capability. It never entered our consciousness that they'd have the temerity to attack us. We knew the Japanese didn't see well, especially at night-we knew this as a matter of fact. We knew they couldn't build good weapons, they made junky equipment, they just imitated us. All we had to do was get out there and sink 'em. It turns out they could see better than we could and their torpedoes, unlike ours, worked. Studs Terkel, The Good War: An Oral History of World War Two New York, Ballantine Books, 1985, p. 186