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Show Journal of Clinical Neuro- ophthalmology 9( 2): 65- 70, 1989. Ocular Disease in Caribbean Patients with Serologic Evidence of Lyme Borreliosis Kirk E. Winward, M. D., and J. Lawton Smith, M. D. © 1989 Raven Press, Ltd., New York Four patients from Caribbean and Central American countries with ocular disease and serologic evidence of Lyme borreliosis are discussed. To our knowledge this is the first report of Lyme disease from this geographic area. Two patients exhibited ocular inflammatory disease, and two patients developed optic neuropathy. A brief discussion of Lyme borreliosis, its serologic diagnosis, and its treatment is presented. Key Words: Lyme borreliosis- Lyme disease- Ocular inflammatory disease- Optic neuropathy- Caribbean. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medlcme, Miami, Flor-ida. D K E Address correspondence and reprint requests to r. . . Winward at Bascom Palmer Eye Institute, P. O. Box 016880, Miami, FL 33101, U. s. A. Lyme borreliosis is an increasingly recognized multisystem disease with protean manifestations. It has now been reported from 32 states and six continents ( 1- 3). We describe patients from Haiti, Puerto Rico, Jamaica, and Honduras with ocular manifestations and serologic evidence of Lyme borreliosis. To our knowledge this is the first report of Lyme borreliosis from this geographic area. CASE REPORTS Case 1 A 28- year- old Haitian man was first seen at the Bascom Palmer Eye Institute on January 23, 1988, with a chief complaint of decreasing vision. The patient had lived in Haiti until 6 years earlier when he moved to Miami, Florida. One year prior to presentation, he developed a waxing and waning course of red eyes, mild pain and photophobia, and progressive deterioration of vision in both eyes. Several months earlier he had been seen by an ophthalmologist who performed severallaboratory tests and a chest radiograph; the patient was told that his eyes were normal and was treated with topical steroids and hyoscine. The past history was negative for arthritis, sexually transmitted disease, intravenous drug abuse, and homosexuality. He did recall having a diffuse skin rash on his back 6 months previously. Visual acuity was count fingers at 5 ft right eye and 20/ 400 left eye. Ocular motility was normal, and visual fields were full to confrontation. Pupils were irregular and minimally reactive. Intraocular tensions were 15 mm Hg right eye and 17 mm Hg left eye. Biomicroscopy showed bilateral mild conjunctival injection, scattered small, pigmented keratic precipitates, 1+ cell and flare, marked posterior synechiae ( Fig. I), cataracts, and 2+ anterior vitreous cells. Ophthalmoscopy revealed dense posterior inflammatory vitritis in both eyes, which 68 K. E. WINWARD AND f. L. SMITH result due to cross reactivity with Lyme disease or a laboratory error. The patient was treated with oral erythromycin for 1 month. Two months later he had a myocardial infarction and died. Commellt A 65- vear- old Honduran man presented with unilateral optic atrophy consistent with prior AlaN. Serologic testing demonstrated strong evidence for Lyme borreliosis as the patient was found to have significant Lyme titers by both IFA and ELISA testing methods while testing negative for syphilis. DISCUSSION Lyme borreliosis is a tick- transmitted spirochetal infection capable of producing a multisystem illness with diverse clinical manifestations. Initially the disease was named Lyme arthritis for the Connecticut community where a cluster of cases resembling juvenile rheumatoid arthritis was described in 1975 ( 7- 9). In 1982 Burgdorferetal. identified the causative organism, Borrelia bllrgdorferi ( 10). Since then, this disease has been increasingly recognized as the cause of significant morbidity. The disease has a global distribution, having been described in 32 states and six continents. To our knowledge this is the first report of serologic evidence of Lyme borreliosis in Central America and the Caribbean. The incidence of the disease appears to be rapidly increasing. From 1984 through 1986 the Centers for Disease Control received an average of 1,500 reports of Lyme disease annually ( 11). As this disease is not a reportable disease in most states, this undoubtedly underestimates the scope of the problem, and current estimates are that as many as 5,000- 15,000 new cases occur annually in the United States. This had led to the comment that next to the acquired immune deficiency syndrome, this is the number one new disease facing medicine today ( 3). The disease evolves in three stages. The hallmark of stage I is the annular erythematous rash termed " erythema migrans." It typically begins, after an incubation period of a few days to a month, at the site of a tick bite. This pathognomonic rash may be absent in 30- 50% of individuals and an even larger percentage may not recall a tick bite ( 3,11). Other symptoms associated with stage I include malaise, fatigue, fever, headache, arthrale; ias, and mVill. e, ias ( 9). Some patients may be en~ ir~:'" .,-. :,, 1' 1.' ~';~ fjr during this stage. I Clill Neuro- ophthalmol. Vol. 9. No. 2. 1989 characterized by aseptic meningitis, cranial neuropathies, radiculoneuritis, cardiac involvement, and migratory musculoskeletal pain. These symptoms generally resolve within weeks to months but may recur ( 12,13). Stage III develops months to years after the tick bite and is manifested by oligoarthritis in 60% of patients. Profound fatigue, chronic dermatologic syndromes, neurologic demyelination syndromes, dementia, and permanent paralysis have also been reported ( 14- 16). Ophthalmic manifestations of Lyme borreliosis are multiple and, while generally occurring in stage II of the disease, can be seen in all stages. Photophobia, conjunctivitis, and periorbital edema are seen in stage I ( 2,9). Keratitis, iritis, vitritis, retinitis, diffuse choroiditis with exudative retinal detachments, papilledema, ocular motor cranial nerve palsies, optic neuritis, ischemic optic neuropathy, optic atrophy, Argyll Robertson pupils, and cortical blindness have been observed in later stages ( 2,14,17- 22). In both its systemic and ocular manifestations, the disease has a remarkable similarity to syphilis. Diagnosis The skin lesion of stage I, erythema migrans, is pathognomonic and is all that is necessary to establish the diagnosis. A definitive diagnosis can also be made by culture or by direct examination of patient specimens, but both are low- yield procedures. Serologic testing, therefore, becomes the most useful laboratory tool for diagnosis and is considered diagnostic if high antibody titers to B. burgdorferi are present. Both IFA and ELISA tests are available to detect class- specific Igs directed against B. burgdorferi ( 23). Antibody response is slow and can be variable. Specific IgM antibody titers generally peak between 3 and 6 weeks after infection; however, they may also persist in prolonged illness ( 24). Consequently, an elevated IgM antibody titer, as in Case 1, does not necessarily imply disease of recent onset. Specific IgG antibody titers generally rise more slowly and peak late when arthritis is present ( 24). Serologic testing for Lyme borreliosis is, however, far from ideal, and interpretation of results may not be straightforward. Testing for Lyme disease has not been standardized, and considerable interlaboratory variability exists ( 11,25). Significant numbers of both false- positive and false- negative results occur ( 2). Of 14 culture- proven cases of Lyme borreliosis, 7 cases had negative serologic studies, suggesting that Lyme borreliosis may be seronegative in up to OCULAR DISEASE AND LYME BORRELIOSIS 69 50% of cases ( 26). Serovariability, meaning that one laboratory will report a patient's serum as testing positive for the disease while a different laboratory will report the same serum as negative, is well documented in Lyme borreliosis and was seen in two of our four patients ( 25,27). Serologic cross reactions have been reported or proposed between Lyme borreliosis, syphilis, leptospirosis, relapsing fever, yaws, and pinta ( 23,25,28). Of these, cross reaction between Lyme borreliosis and syphilis is the most clinically significant problem, and cross reactivity of Lyme IFA and syphilis FTA ABS has been reported in 22.5- 54% of patients ( 23,29). Quantifying titers can prove helpful as often false- positive results due to cross reactivity typically produce only low titers. In one study 9 of 40 sera from patients with known Lyme disease were reactive at 1: 5 dilution with antigen from T. pall id 1I 111 . At a dilution of 1: 10 only one serum was reactive. When both antigens were tested, titer against B. burgdorferi was always higher than against T. pallidu11l ( 29). Some have suggested that Lyme borreliosis will not produce false- positive RPR or MHA TP tests and that consequently these tests can be used to differentiate the two diseases ( 23). However, reservations must be raised as at least one reported case of Lyme disease demonstrated a positive MHA TP ( 21). Additionally, immunosuppressed patients may manifest atypical serologic responses, and some patients may have or have had both diseases ( 30). Nevertheless, in the patient with appropriate clinical findings in whom other etiologies ( notably syphilis) can be reliably excluded, a Lyme IFA and/ or ELISA titer considered significant by the evaluating laboratory, particularly if confirmed at a second laboratory or if rising titers are demonstrated, is sufficient evidence of neuro- ophthalmic Lyme borreliosis to warrant antibiotic therapy. The four cases we describe demonstrate a spectrum of serologic findings. Case 1 with chronic active panuveitis had positive Lyme titers at two laboratories, and extensive testing failed to suggest another etiology for his disease. He responded rapidly to antibiotic therapy. In our opinion this undoubtedly represents Lyme uveitis. In our other three cases, the etiologic relationship between the ocular disease and Lyme borreliosis is speculative. Nonetheless, each demonstrated definite serologic evidence of Lyme disease. Case 2 had inactive uveitis with a history of fevers and Bell's palsy. He tested negative for Lyme disease at one laboratory but had significant titers to two distinct Lyme antigens at another. No other apparent etiology was discovered for his ocular inflammatory disease. The ocular disease in Cases 3 and 4 may, in fact, represent Jamaican optic neuropathy and AION, respectively. Nevertheless, Case 3 had a high Lyme IFA antibody titer at a dilution of 1: 1,024 with a strongly positive Lyme ELISA, and Case 4 had positive Lyme antibody titers on both IFA and ELISA assays. Treatment Treatment is more effective early in the course of the disease. Tetracycline and penicillin are the drugs of choice for early Lyme borreliosis. Erythromycin or doxycycline can be used for those allergic to these medications ( 14,19). Treatment should be continued for 10- 20 days. For the later stages of disease, parenteral antibiotics are required. Intravenous aqueous penicillin G for 10 days has been recommended as standard treatment, but intravenous ceftriaxone may be the drug of choice ( 31). Dattwyler and co- authors reported a series of 23 patients with active late Lyme disease ( 32). Five of 10 patients treated with penicillin were considered treatment failures, while only 1 of 13 patients treated with ceftriaxone did not respond. Their study also suggested that prior treatment with glucocorticoids may make eradication of the organism more difficult. Recommendations Lyme borreliosis is an infrequently recognized but treatable cause of ophthalmic disease. The increasing incidence and worldwide distribution of this disease emphasize the importance of not ignoring its testing in patients of any geographic origin. The existence of otherwise unexplained ocular inflammatory disease, optic neuropathies, or cranial nerve palsies presenting to the ophthalmologist should prompt a search for evidence of Lyme disease. We recommend screening such patients with an RPR or VDRL, FTA ABS or MHA TP, and Lyme IFA and ELISA. On occasion, additional serologic tests may be required to establish or rule out the diagnosis. Prompt treatment with appropriate antibiotics and avoidance of systemic steroid therapy offer the best chance of eradicating the organism and preserving vision. Acknowledgment: Acknowledgement is gratefully extended to Mme A. Paris- Hamelin and the Institut Alfred Fournier, National Reference Center for the Treponematoses, Paris, France, and to Bascom Palmer laboratory technicians Alicia Muniz, Rosa Pelaez, Harry Mayans, Elvia Ramirez, and Raquel Toledano. J Clin Neuro- ophthalmol. Vol. 9. No. 2. 1989 72 M. ZIERHUT ET AL. FIG. 2. A: Fundus of the right eye ( February 1987). Depigmented scars are present in the entire anterior retina. B: Enlargement of Fig. 2A. At the posterior pole, there is a chorioretinallesion extending from the inferior temporal arcade to the macular area. The view of the posterior pole is hazy due to vitreous infiltration ( 1 +). CASE REPORT A 64- year- old woman first consulted her ophthalmologist in April 1986 for an acute decrease in visual acuity. Examination revealed that visual acuity was 20/ 50 00 and 20/ 30 as. The vitreous had 1+ cellular infiltration, and atrophic scars in the anterior retina were present in the right eye. In July 1986, corneal precipitates were noted, and the macula was described as " slightly edematous." The medical laboratory test results showed wellcontrolled diabetes mellitus and no pathologic con- ,<, (" r s\' philis were not per: pnljd tlwrapy, the J Clin Neuro- ophthalmol. Vol. 9. No, 2, 1989 intraocular inflammation disappeared. In December 1986 and February 1987, an extreme visual acuity decrease and cells in the vitreous caused the ophthalmologist to refer the patient to the Department of Vitreous and Retinal Surgery at the University Eye Clinic in Tiibingen. The ocular findings showed a visual acuity of 20/ 300 00 and 20/ 20 as. There was 1 + cellular infiltration in the right eye and minor rubeosis in all quadrants ( stage 1), with a posterior synechia at the 5 o'clock position ( Fig. 1). The vitreous had 3+ cellular infiltration. The left eye was normal. Both eyes had extensive depigmented choroidal atrophy in the entire anterior retina, accompanied by pigment clumping similar to retinitis pigmentosa ( Figs. 2A and Band 3). In addition, in the right eye, acute inflammation extended along the temporal inferior vessel arcade into the macular area ( Fig. 2A). The blood sedimentation rate was 32/ 45 mmlhr; leukocytes were 1O, 2001J. Ll. The serologic test results for syphilis were as follows: TPHA titer, 1: 10,240 ( 3 +); VORL, 1: 20 ( 3 +); and FTA- ABS, 1: 16 (+). The following serologic tests were normal: varicella zoster, herpes simplex, cytomegaly, Toxocara canis, Leptospira sp., Candida albicans, toxoplasmosis, human immunodeficiency virus, and histoplasmosis. The urological, dermatological, medical, and gynecological laboratory findings were normal. The only conclusive pathological data so far were a highly positive serologic finding for syphilis; however, the patient denied having had a syphilitic infection. To rule out a false positive reaction, the FIG. 3. Left eye ( February 1987). In the anterior retina there are pigment clumpings similar to pseudopigmentosa ( arrows). PANUVEITIS POSITIVE FOR SYPHILIS 73 serum was tested for 19S- IgM antibodies, a test highly specific for syphilis. This test was slightly positive; a control test, however, was negative. Following the advice of the consulting dermatologist, we added a serologic test for Lyme disease ( borreliosis), which was highly positive with 980 units for IgG ( the upper limit is 200 units). The test for IgM was negative. A lumbar puncture was then performed. Cerebrospinal fluid ( CSF) revealed 2- 3 cells, and the cytological smear showed a monocytic reaction representing an unspecific irritation of the leptomeninges; however, there was no indication for the presence of an inflammation. Due to the lack of a conclusive CSF finding, the test for Lyme disease was repeated in two additional laboratories. The first test was slightly positive for Lyme disease; the second was negative for Lyme disease but highly positive for syphilis. The Western blot test with antigens against Treponema and Borrelia was then performed but could not resolve this diagnostic problem. The patient received laser treatment for a neovascular membrane that had originated from a depigmented scar in the macular area. Later on, there was a cystoid macular edema ( Fig. 4). The intraocular inflammation had disappeared after treatment with topical and systemic corticosteroids. Because the leaking neovascular membrane had been successfully treated by laser photocoagulation, and the intraocular inflammation disappeared, there seemed to be no indication for systemic treatment with penicillin. After 9 months' FIG. 4. Fluorescein angiogram of the right eye ( April 1987). A: After 50 s, a primary hypofluorescence is visible at the border of the chorioatrophic area. B: After 5 min, massive leakage is visible along the temporal inferior vessels. There is a cystoid edema in the macula area. C: After 5 min, old scars peripherally from the central leakage show only a window defect with visible choroid. , Clin Neuro- ophthalmol. Vol. 9. No. 2. 1989 74 M. ZIERHUT ET AI. follow- up observation, no recurrence has developed. Visual acuity at the last examination was 20/ 300 00 with the macula flat and 20/ 20 as ( Fig. 5). DISCUSSION Borrelia sp., the cause of Lyme disease, are spirochetes ( 8). Therefore, the possibility of a false positive reaction is not surprising ( 9). In Germany, Borrelia sp are transmitted by the tick Ixodes ricinus ( 10), which is endemic around Tubingen ( 11). In Europe, the most common species is B. bllrgdorferi. When our patient was questioned, she recalled having had tick bites on several occasions in 1986. In the American literature, borreliosis is known as Lyme disease. The name originated in Old Lyme, Connecticut, where in 1975 a strange disorder accompanied by juvenile arthritis was described in 59 patients ( 12). These patients were children and young adults living in heavily wooded areas. Years later, the spirochetal cause was found. In more than 50' 1( of the patients, the primary effect is manifest as an erythema migrans chronicum 4- 8 weeks following the tick bite ( 13,14). Ten percent of patients have accompanying influenza, and organic manifestations can occur in the joints, heart, or nervous system ( 15). There are several reports in the literature of Lyme disease ( borreliosis) in the eye. The most common symptom seems to be a conjunctivitis ( 12,16,17). FIG. 5. Right eye ( November 1987). There was no leakage in the area of the chorioretinal scar. However, vi: cl, I::> 1 url'it" r: " ir" I'Y, Cc" P to more than 20/ 300 due to J Clin Neuro- ophthalmol. Vol. 9. No, 2. 1989 Baum et al. ( 18) describe a young girl with disciform keratitis with a positive serologic test for B. burgdorferi. The FTA- ABS result was 2 +; however, other syphilis tests were negative. Bialasiewicz et al. ( 19) have just reported a bilateral diffuse choroiditis with exudative retinal detachment. They were the first investigators who found an elevation of the IgM antibody titer in a patient with ophthalmological complications. Reik et al. ( 20), Wu et al. ( 21), and Schechter ( 22) reported a papilledema in seven patients. Steere et al. ( 17) described the histologic findings in an enucleated eye that was amaurotic due to an iritis followed by a panophthalmitis. In their specimen, spirochetes in the vitreous were found to be morphologically similar to B. burgdorferi. The antibody titers for Borrelia sp were increased. On histologic examination, demarcated necrosis was present in the choroid, as well as granulary depositions of retinal pigment and massive infiltration by polymorphonuclear leukocytes with few lymphocytes. Further serologic tests were not performed. CONCLUSION The ophthalmological manifestation of Lyme disease can be very similar to such classical findings in syphilis ( 23) as conjunctivitis, disciform keratitis, anterior uveitis, panuveitis, and even panophthalmitis, as well as papilledema and oculomotor and abducens nerve paresis ( 24,25). This case report demonstrates that a highly positive syphilitic serologic finding does not necessarily confirm the existence of a T. pallidum infection. The 19- 1gM FTA- ABS ( 26) and all serologic tests for Lyme disease are required for differential diagnosis. Enders et al. ( 27) reported a crossreaction between T. pallidum and B. burgdorferi antibodies in a pregnant woman. In this case, the Western blot technique confirmed the presence of an infection with Borrelia. Hunter et al. ( 9) found that nine of 40 serum samples from patients with known Lyme disease were reactive at a 1: 5 dilution on a serum FTA- ABS. The Lyme- IgM antibody titer will be positive only in the 1st weeks and should decline after therapy ( 19). To date, there seems to be no specific method of diagnosing a recurrence of Lyme disease when only the Lyme IgG antibodies are elevated or of differentiating it from syphilis. Tests for Lyme disease are certainly indicated in the presence of a tick bite in the patient's history. It should be mentioned, however, that only 20% of patients with Lyme disease are aware of tick bites ( 15). No therapeutic consequences ensue when syph- PANUVEITIS POSITIVE FOR SYPHILIS 75 ilis is misdiagnosed instead of Lyme disease. In the acute phase of both diseases, the therapy of choice consists of the administration of penicillin G or tetracycline ( 28). However, in spite of high doses of p~ nicillin, there are reports of recurrences of Lyme dIsease, ( 26) the cause of which is still unknown. Such a misdiagnosis results in unjustifiable and irreparable consequences for the patient. When syphilis is misdiagnosed as Lyme disease, a venereal disease that should be reported to the Department of Health is not reported; when Lyme disease is misdiagnosed, the patient has a disease caused by an anthropozoophile requiring systemic treatment without further social consequences. Further study and research of the ophthalmological manifestations of Lyme disease seem necessary. For this reason, Schuman et al. ( 29) have recently introduced an animal model. Note added itl proof: After this article was sent for publication, the patient was examined again in November 1988. She told us that she underwent penicillin therapy, outside of our clinic, 4 months ago. Also the syphilis serology of the patient's husband was negative. REFERENCES 1. Campbell KE. Oral sepsis as a cause of iritis. Lancet 1905; 83( 2): 219- 20. 2. Clapp CA. Significance of syphilis as an etiologic factor in acute iritis. Am I OphthalmaI1921; 4: 194--- 6. 3. Bruns HD. Syphilis and iritis. 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