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Show Tounta! of C! ulIca! NeurtJ- oF'hthallllo! oSY 9( 3': 148- 155, 1989 © 1989 Raven Press, Ltd., New York The Prevalence of Lyme Disease In a Nonendemic Area A Comparative Serologic Study in a South Florida Eye Clinic Population J. Lawton Smith, M. D., Timothy M. Parsons, D. O., Annette J. Paris- Hamelin, and Richard K. Porschen, ph. D. Summary: Serologic tests for Lyme borreliosis and for syphilis were performed on 75 patients seen in a I- week period at the Bascom Palmer Eye Institute in Miami. The incident of syphilis was 8% and of Lyme borreliosis 3% in this study in a nonendemic area. The most common cause for a high titer serologic response for Lyme borreliosis in this group was a prior Treponema pallidllm infection. The importance of getting VDRL, FTA- ABS, Lyme IFA, and Lyme ELISA tests in all suspected cases was emphasized. Key Words: Lyme borreliosis- Lyme diseaseSyphilis- Treponema pallidllm- Borrelia bllrgdorferi- Eye clinic population. From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine ( J. L. S., T. M. P.), Miami, Florida, USA, and Reference National Center for Treponematoses, Alfred Fournier Institute ( A. J. P.- H.), Paris, France, and Microbiology Referenct' Laboratory ( R. K. P.), Cypress, California, U. 5 A ', dlh,.'" '-" rro:- sr" ndo:- nCl' , md rt'print requests to Dr. J. L. · " 1,, 1,' P () Bm 1l1h880, Miami, 148 Lyme disease, a tick- borne infectious disease due to a spirochetal organism, Borrelia burgdorferi, is being increasingly recognized as a cause for significant ocular and neurologic disease ( 1). Since its initial description in 1975, and recognition of the causative organism in 1981, more than 13,000 cases of the disease have now been reported in 43 states ( 2), as well as in Europe, Scandinavia, Australia, and other nations. One problem in diagnosis has been the existence of serologic cross- reactivity with other spirochetal diseases. In one study ( 3) 9 of 40 patients' sera with known Lyme disease showed a positive serum fluorescent treponemal antibody absorption ( FTA- ABS) test, the test generally used for specific serodiagnosis of present or former Treponema pallidum infection. Because of a known high incidence of reactive serum FTA- ABS tests in the eye clinic population at the Bascom Palmer Eye Institute ( BPEI) in Miami ( 4), Florida, the following study of comparative seroreactivity for both B, burgdorferi and T. pallidum was undertaken. MATERIALS AND METHODS During a I- week interval in late March 1988, blood tests were drawn on 75 patients presenting to the Bascom Palmer Eye Institute in Miami, Florida. The study group consisted of three subsetscases 1- 36 were sera obtained on March 30, 1988 at the time of routine preoperative cataract blood work. Cases 37- 49 were obtained on patients seen by neuro- ophthalmic fellows at a return visit during 1 week to the outpatient clinic. Finally, cases 50- 75 consisted of 25 patients who presented to the outpatient eye triage/ emergency clinic during 2 consecutive days during the same period. These LYME DISEASE IN NONENDEMIC AREA 149 TABLE 1. California ( MRL) data: all cases with any positive Lyme data All empty spaces were negative ( Le., IgG < 1 : 16 and IgM < 1 : 40). " Cutoff 0.648. b Cutoff 0.683 3. Positive ELISA but negative IFA tests for Lyme disease = 3 cases ( 3/ 75 = 4%). 4. Number of cases showing some seropositivity for Lyme disease = 17 cases ( 17/ 75 = 23%). 5. Both IFA and ELISA tests negative for Lyme disease = 58 cases ( 58/ 75 = 77%). The Fournier Institute reported the following data ( Table 2). In Paris some positive serologic reactivity was noted in 8 of the 75 cases ( 11 %), and 67 were reported as negative ( 89%). Of the eight positive cases, two showed seropositivity for Lyme disease with no evidence of reactive tests for syphilis, whereas six cases ( 8%) showed definite serologic evidence for prior syphilitic infection. Thus, eight cases showed some seropositivity for spirochetal infection in Paris, whereas 17 were reported as showing some seropOSitivity from California on the same matched sera. Another interesting point was that only five of the cases overlapped, and four of these were due to syphilis. A chart review of all cases showing some seroreactivity was therefore undertaken to evaluate the clinical data and see if further light could be shed on these findings. ELISA Repeatb 1.058 (+) 1.356 (+) 0.314(-) 1.190(+) 0.907 (+) 0.896 (+) 0.770 (+) 0.594 (-) 0.631 (-) 0.726 (+) 0.697 (+) 1.110 (+) 0.260 (-) 0.697 (+) 0.951 (+) 0.802 (+) 0.772 (+) 0.748(+) 0.752 (+) 0.664 (+) 0.426 (-) 0.751(+) 0.650 (+) 0.442 (-) 1.102 (+) 0.247 (-) 1.511 (+) 0.503 (-) 0.832 (+) Initial run" IFA Case no. IgG IgM 10 116 13 1: 16 17 1: 256 18 1: 16 20 1: 16 21 1: 32 22 24 1: 32 31 1: 16 32 1: 40 41 51 1: 160 56 1: 16.000 65 1: 160 73 1: 64,000 74 1: 16 75 FINDINGS t~ ree subsets- routine preoperative cataract patie~ ts ( 35 cases), routine neuro- ophthalmic clinic p~ tients ( 15 cases); and consecutive consenting eye mage/ emergency clinic visits ( 25 cases)- for a total of 75 patients- were selected to be representative of the entire eye clinidhospital population seen at th~ D~ partment of Ophthalmology, University of MiamI School of Medicine. The blood tests were drawn by routine venipu~ cture. after informed consent and kept under refrigeration until all tests had been obtained. Serum was separated from clotted blood, and 2 ml of fresh frozen s. erum packed in dry ice was sent by overrught mail to Microbiology Reference Laboratory, Inc. ( MRL) ( Cypress, CA) for Lyme Disease antibody testing. This consisted of immunofluorescent antibody ( lFA) IgG and IgM testing as well as Lyme enzyme- linked immunosorbent assay ( ELISA) testing on each of the 75 sera, which were marked as nos. 1- 75. Matched samples of an additional 3 ml of fresh frozen serum from each case were similarly sent packed in dry ice to the Institut Alfred Fournier, which is the National Center of Reference for the Treponematoses, in Paris, France. This is the French national equivalent of the Communicable Disease Center in the United States, and they participated in providing quantitative serologic studies with 11 different tests on each of the sera. The studies performed in Paris consisted of the following six serologic tests for syphilis: Venereal Disease Research Laboratory ( VDRL), TPHA, Treponema pallidum immobilization ( TPI), FTA- ABS, IgM/ FTA ( 5,6), IgM/ SPHA ( 7), and the following five serologic tests for Lyme disease: immunofluorescent assay ( lFA) IgG to the Fournier Institute ( IF) Borrelia burgdorferi antigen; IFA IgG to the National Center of Blood Transfusion ( CNTS) of Lille, France antigen; passive hemagglutination testing to the Lille antigen; and IFA IgM to both IF and CNTS antigens. No clinical information was provided to either of the two cooperative laboratories, and specimens were reported by number as cases 1- 75. MRL Laboratory in California repeated both IFA and ELISA testing on all sera with borderline or conflicting results. They reported the following data ( Table 1). 1. Positive IFA and ELISA tests for Lyme disease = 9 cases ( 9/ 75 = 12%). 2. Positive IFA but negative ELISA tests for Lyme disease = 5 cases ( 5/ 75 = 7%). REVIEW OF DATA MRL Laboratory in California reported some seropositivity for Lyme disease in 17 of 75 cases, an incidence of 23%. The data are summarized in Table 1. A negative Lyme IFA in that laboratory is reported as IgG < 1: 16 and IgM < 1: 16. IgG titers 1Clin Ncuro- ophthalmol, Vol. 9. No. 3. 1989 150 f. L. SMITH ET AL. TABLE 2. Fournier Institute data Treponematoses Lyme Case IgM- IgM- IF- IF- HA- IAF- CNTS-no. TPI FTA TPHA VDRL FTA SPHA IAF CNTS CNTS IgM IgM 4 0% Neg Neg Neg Neg Neg 200 512 Neg Neg Neg 20 0% Neg Neg Neg Neg Neg 200 512 Neg Neg Neg 41 80% ( 40) 4 + ( 800) 4+ ( 320) 3+ ( 4) Neg Neg Neg Neg Neg Neg Neg 56 100% ( 800) 4 + ( 25,600) 4+ ( 10,240) 4+ ( 32) Neg Neg 400 512 +++ Neg Neg 57 0% 2 + ( 200) 2+ ( 80) Neg Neg Neg Neg 512 + Neg Neg 60 100% ( 320) 4+ ( 800) 4+ ( 320) :!:: ( 0) Neg Neg Neg 256 ++ Neg Neg 73 100% ( 650) 4+ ( 25,600) 4+ ( 20,480) 4+ ( 256) 4+ ( 400) 4+ ( 2,560) 3000 > 4,096 ++++ 100 256 75 40% ( 10) 4+ ( 800) 4+ ( 640) Neg Neg Neg Neg Neg + Neg Neg TPI, Treponema pallidum immobilization test; FTA, fluorescent treponemal antibody absorbed test; TPHA, T. pallidum hemagglutination test; VDRL, venereal disease research laboratory test; IgM- FTA, fluorescent treponemal antibody absorbed- lgM; IgM- SPHA, solid phase hemadsorption assay- lgM; IF- IAF, immunofluorescent IgG Fournier Institute Lyme antigen; IF- CNTS, immunofluorescent IgG Lyme CNTS antigen; HA- CNTS, hemagglutination IgG Lyme CNTS antigen; IAF- lgM, immunofluorescent IgM Fournier Lyme antigen; CNTS- lgM, immunofluorescent IgM Lyme CNTS Lyme antigen; CNTS, National Center for Blood Transfusion, Lille, France. between 1: 16 and 1: 64 warrant further evaluation, and an IgG titer of 1: 128 or greater is considered positive. Note the cutoff points on optical densities obtained with the Lyme ELISA tests by MRL Laboratory. Thus, both the IFA titers and the relative degree of positivity of the ELISA tests should be noted. At least some seropositivity from the laboratory point of view was reported in 17 cases ( nos. Ia, 13, 17, 18, 20, 21, 22, 24, 31, 32, 41, 51, 56, 65, 73, 74, 75). It is seen from Table 1 that both a positive IFA IgGlIgM titer and a positive ELISA test were found in nine cases ( cases 13, 17, 18, 20, 21, 24, 32, 56, 73). A positive IFA test but a negative ELISA test was reported in five cases ( cases 10, 31, 51, 65, 74). A negative IFA test but a positive ELISA test was reported in three cases ( cases 22, 41, 75). The serologic findings for Lyme disease were negative to both IFA and ELISA testing in California in 58 of the 75 cases ( 77 C7c). In summary, the MRL Laboratory in California reported positive IFA and ELISA tests in 9 of 75 sera ( a 12( 7c incidence), positive IFA but negative ELISA tests in 5 of 75 sera ( a 7% incidence); and a negative IFA but positive ELISA test in 3 of 75 sera ( a 4(, 1". incidence). Of note, however, was the fact that at least some seropositivity was found in 17 of the 75 cases, or an incidence of 23%. The Fournier Institute in Paris reported some seropositivity in 8 of the 75 cases, an incidence of 11 %. These were cases 4, 20, 41, 56, 57, 60, 73, and 75. The data from this laboratory are summarized in Table 2. Not only was the incidence of at least some seropositivity notably lower in the results of studying the identical matched sera in Paris than .~ (- : , " "''-'. hut ' lf1] 1 fi" l' cases were reported as I, "" th laboratories ( cases 20, 41, 56, 73, and 75). It was also evident from the Paris data that four of the latter five cases showed serologic evidence of infection with syphilis rather than with Lyme disease. It should be recalled that MRL Laboratory performed IFA and ELISA tests for Lyme disease only, whereas Paris performed a battery of tests for both syphilis and Lyme disease. Paris reported only two cases as showing some seroreactivity to Lyme disease despite a completely negative battery of six serologic tests for syphilis ( cases 4 and 20). It is obviously important that a serologic survey of patients in an eye hospital population in a nonendemic area revealed that 11- 23% of the patients showed some serologic positivity for either B. burgdorferi or T. pallidum. It should be noted that MRL Laboratory performed three tests on each of the 75 sera, a total of 225 tests, and the Fournier Institute performed 11 tests on each of the 75 sera, a total of 825 tests on the 75 sera, so that this survey was based on an analysis of 1,050 serologic tests on the 75 sera, not counting any repeat testing. Because of the significant differences between the reports from MRL and Fournier Institute laboratories, the charts of all patients reported with any evidence whatever of seroreactivity were reviewed, and other data were assessed to try to establish a clinical correlation with the serologic findings. A brief summary of these cases is presented in Table 3. Some particularly instructive cases were as follows: Case 4 A 12- year- old Puerto Rican boy came to the BPEI because of a painless loss of vision in the left eye for 6 months. He had been hospitalized several LYME DISEASE IN NONENDEMIC AREA 151 TABLE 3. Chart review on seropositive cases Case no. Age ( yr) Race Sex Clinical data Past history Examination Conclusion 4 12 H M Loss of vision LE FUa Bell's palsy Chronic iritis LE Lyme uveitis 6 months 10 67 W M Glaucoma au Left bundle Cataract su rgery Normal branch block cancelled/ heart 13 disease 58 B F Cataracts Diabetes on insu- Cataract surgery Normal lin 3- 30- 88 17 63 H M Ischemic optic Angina Neg temporal A Latent Lyme sus- 18 neuropathy biopsy pect 74 W M Cataracts Pseudoexfoliation Cataract surgery Normal 3- 30- 88 20 76 W M Cataracts Cataract surgery Latent Lyme dis- 3- 31- 88 ease 21 66 H M Cataract Arteriosclerotic Cataract surgery Latent Lyme/ lab disease, diabe- 3- 31- 88 overcall tes 24 83 W F Cataract Myocardial infarct Cataract surgery Normal 25 years before 3- 31- 88 31 64 W M Cataract Malaria World War Cataract surgery Normal II past cranioto- 3- 31- 88 my/ trauma 32 82 W M Cataract Myocard. infarct Cataract surgery Latent Lyme/ lab x 2, arrhythmia 3- 31- 88 overcall 41 63 H M Cataract Glaucoma Afferent pupil RE Syphilis 51 49 H M Left VI palsy Diabetes Diabetic retinopa- Syphilis thy 56 47 B M Plaster in eye Neg Corneal abrasion Syphilis 57 45 M M Battery acid in eye Neg Conjunctivitis Syphilis 60 52 B F Irritated eyes Conjunctivitis Syphilis 65 22 H M Foreign body sen- LE enucleated age Irritated RE Latent Lyme sus-sation RE 5 pect 73 45 B F Acute iritis Acute iritis Syphilitic iritis 74 65 H F Vitreous Vitreous detach- Latent Lyme sus-ment pect 75 31 W M LE hit by rake External trauma Syphilis LE. lef1 eye: au, both eyes: FUa, fever of undetermined origin: A. artery: RE, right eye. times in the past for an unexplained febrile illness. One year earlier, he had a left Bell's palsy from which he recovered spontaneously. Examination revealed 20/ 20 vision in the right eye, but only 20/ 400 in the left eye. There was evidence of old uveitis with anterior and posterior synechiae as well as a dense cataract in his left eye. He was operated on March 20, 1988 and a peripheral retinal granuloma was described at vitrectomy surgery. Comment: A 12- year- old Puerto Rican boy presented with a history of recurrent unexplained febrile illness, had a left Bell's palsy a year earlier, and showed chronic ocular inflammation in the left eye. Serologic testing in Paris revealed six types of blood tests for syphilis to all be nonreactive. Both Lyme IFA and ELISA test results were negative in California. However, the Fournier Institute reported an IFA IgG titer of 1: 200 to their B. lJllrgdorjeri antigen, and an IgG titer of 1: 512 to the Centre National de Transfusion Sanguine de Lille ( Nord de la France) ( CNTS) antigen. The clinical interpretation, therefore, was that this 12- year- old patient had Lyme borreliosis as the explanation for his fever, prior Bell's palsy, and ocular granulomatous inflammatory disease. In this instance, the serologic findings from the Fournier Institute were more consistent with the clinical picture than those from MRL Laboratory. The fact that the patient was from Puerto Ric~, previously considered a nonendemic area, was also of interest. This case is being reported in detail elsewhere with other instances of Lyme borreliosis in patients from the Caribbean region. The etiologic diagnosis was only established in this patient because of this serologic survey. Case 17 A 63- year- old Hispanic man from Honduras presented with anterior ischemic optic neuropathy in the left eye. Results of a temporal artery biopsy on March 31, 1988 were negative. Paris reported all blood test results as negative on this patient. However, MRL Laboratory reported a Lyme IFA IgM as < 1: 40 but IgG as 1: 256. The Lyme ELISA was also , Clill NfurO- t1/, htltalmol, Vol. 9, No. 3, 1989 152 f. L. SMITH ET AL. reported as positive on both of two runs. In Miami the chart revealed RPR- nonreactive but FTAABS- reactive. The latter test was done at a laboratory in Hialeah, Florida, which was later terminated because of several false- positive FTA- ABS tests. A follow- up revealed that that patient had a nonreactive VORL in Honduras, but he died a few months later of a cardiac cause. Comment: An absolute difference existed between reports from MRL and IAF laboratories in this patient. Although all test results were negative in Paris, the California laboratory reported a positive IFA IgG as well as a repeatedly positive ELISA. The positive FTA- ABS reported in Miami may have been a low titered false positive or a laboratory error. This patient may represent a laboratory overcall or he may have had Lyme borreIiosis in the past, of interest in that he was from Honduras, a nonendemic area. Case 20 A 76- year- old white man was admitted to BPEI on March 31, 1988 for cataract surgery. MRL Laboratory reported Lyme IFA IgG as 1: 16 and IgM as < 1: 40, but noted a positive Lyme ELISA test, confirmed on a second run. Paris revealed that results of all six blood tests for syphilis were negative. However, Lyme IFA IgM titers were negative, but IgG titer to the Fournier Institute ( IF) antigen was 200 and to the CNTS antigen was 512. Thus, laboratory correlation of some seroreactivity to Lyme borreliosis was found in both laboratories in this patient. The conclusion was that there was serologic evidence that this 76- year old man had pnor contact with Lyme borreliosis. Case 41 A 63- year- old Hispanic man presented on March 25, 1988 with decreasing vision for 2 years. He had hand- motion acuity in his right eye and 20/ 30- 1 in his left eye. An afferent pupil was noted on the right. The impression was of a mature cataract In his right eye and old glaucoma in the left eye, with a history of trauma. . The laboratory findings in this patient done simply as part of this survey were of great importa~ ce. MRL reported normal Lyme IFA titers but posItive Lyme ELISA tests. Paris reported all five Lyme test results were negative. However, VORL was 3 + reactive ( 4 dils); FTA- ABS was 4 + reactive ( titer 320); TPHA 4 + reactive ( titer 800); and TP~ was >< W7c i""-" T:" hilizati" ll ftit", r 40). Therefore, thiS pa- - ,.\ " knee of syphilis I Clin Neuro- ophthalmol. Vol. 9. No. 3, 1989 picked up simply on survey. The positive Lyme ELISA noted at MRL probably was a serologic cross- reaction. The patient was advised to come back for repeat testing and for appropriate treatment. Case 51 A 49- year- old Hispanic man presented in 1983 with a 24- year history of adult- onset diabetes mellitus and a left VI nerve palsy. Background diabetic retinopathy was noted. Marked improvement in diplopia was noted when he returned a month later. He had a stroke in 1986 and in 1987 had photocoagulation for rubeotic glaucoma in his left eye. On a follow- up visit March 25, 1988 a blood test was drawn as part of this survey. MRL reported this as Lyme IFA positive ( lgM < 1: 40 but IgG 1: 160). The Lyme ELISA test results were negative, however. Paris reported all test results as negative in this patient. On a return visit May 2, 1988 another blood test was done that revealed RPR = nonreactive but FTA- ABS = reactive. Because the latter was done at a laboratory later terminated when a few false- positive FTA- ABS tests had been reported, a third blood specimen drawn on August 10, 1988 was sent to MRL and was reported as follows: RPR = reactive ( 1 dil), FTA- ABS = reactive, Lyme IgG = < 1: 16, and IgM = < 1: 16. Comment: This patient illustrates the extreme variability that can be noted by different laboratories on different occasions in the same patient. Blood tests were drawn on three occasions within 5 months and tested in three different laboratories on this patient. With a 1: 160 Lyme IgG and a positive Lyme ELISA at the original survey, a repeat FTA- ABS at two different laboratories thereafter, and variable serum reagin test, despite negative studies in Paris, and a negative history for known prior venereal infection, the impression was that this patient probably had been exposed to T. pa/~ ldum in the past. He had no antibiotic therapy In the interim and yet showed a 1: 160 IgG titer in March and a 1: 16 IgG titer at the same laboratory in August. He was given 4.8 million U of Bicillin intramuscularly every 2 weeks for three doses. Case 56 A 47- year- old black man came to BPEI after getting some plaster in his eye on March 25, 1988. He was found to have a corneal abrasion, which had healed when he was seen again 3 days later. A routine blood test done while he was seen in the LYME DISEASE IN NONENDEMIC AREA 153 triage clinic was extremely important in this patient! MRL reported Lyme IFA with IgM < 1: 40 but the IgG titer was 1: 16,000. Lyme ELISA was positive. The Fournier Institute revealed the cause of this, however. They found positive Lyme titers to three of five tests ( IF- IAF = 400; IF- CNTS = 512; Lyme HA- CNTS = 3 +). However, there was no doubt that the patient had serologic evidence for syphilis. VDRL was reactive 4 + ( 32 dils); TPI = 100% immobilization ( titer 800); TPHA = 4 + reactive ( titer, 10,240); and FTA- ABS was 4 + reactive ( titer 25,600). This patient showed the second highest Lyme titer ( 1: 16,000 IgG) in the entire series, but this was a cross- seroreactivity from a strongly seropositive T. pallidum infection. Patient was written and advised to return for repeat testing and appropriate treatment. Case 57 This Hispanic man came to the Bascom Palmer triage clinic on March 26, 1988 because of transient injury to the right eye from a battery acid explosion the day before. Routine blood tests drawn as part of this survey were notable. MRL reported negative Lyme IFA and Lyme ELISA tests. However, Paris found a 512 Lyme IF- CNTS titer and a 1 + Lyme HA- CNTS titer, although three other Lyme tests were negative. Serologic testing for syphilis was again extremely important. VORL was nonreactive and TPI test results were also negative. However, serum TPHA was 2 + reactive ( titer 80) and FTA- ABS was 2 + reactive ( titer 200). The patient was recalled and a repeat blood test was drawn June 9,1988 and sent to MRL. This revealed again a normal Lyme IFA and a nonreactive VORL, but the serum FTA- ABS was reactive. The clinical conclusion was late syphilis with slight false positivity due to sero- cross- reactivity to two tests in Paris. Note that the serodiagnosis of syphilis would have been missed in this patient if only a serum VORL test had been obtained. Case 60 A 52- year- old black woman was seen at BPEI on two occasions complaining of ocular irritation in the past decade. On March 28, 1988 viral conjunctivitis and staphylococcal marginal corneal infiltrates were noted. The latter resolved after topical antibiotics. Routine blood testing during this survey revealed a completely negative report from MRL Laboratory ( negative IFA and Lyme ELISA). How-ever, Paris again found definite serologic evidence of syphilis in this patient. VORL was ± titer 0, TPI 100% ( titer 320), TPHA = 4 + reactive ( titer 320), and FTA- ABS was 4 + reactive ( titer 800). Three Lyme tests were negative in Paris, but the IF- CNTS titer was 256 and HA- CNTS was 2 +. These were thought to be sero- cross- reactions because of strongly positive evidence for syphilis in this patient. She was seen on July 26, 1988 and a further history was obtained. She stated that she had " bad blood" 35 years ago, and had received one injection of penicillin at that time. One could have missed this diagnosis if only a VORL test had been obtained because a ± ( equivocal) result is reproducible in only - 50% of laboratories. Case 73 A 45- year- old black woman was seen at the BPEI with acute iritis. Routine blood testing was done as part of this survey. MRL Laboratory reported a Lyme IFA IgG titer of 1: 64,000. Lyme ELISA was also positive. Paris reported this patient as the most seropositive individual of the entire survey. VORL was 4+ reactive ( 256 dils), TPI = 100% immobilization ( titer 650); TPHA = 4 + reactive ( titer 20,480); FTA- ABS = 4 + reactive ( titer 25,600). IgMIFTA was 4 + reactive and a IgMiSPHA test was 4 + reactive to a titer of 2,560. Paris found strongly positive Lyme titers also in this patient. IF- IAF was 3,000, IF- CNTS > 4,096; HA- CNTS was 4 +; IF- IgM IAF titer was 100; IF- IgG CNTS titer was 256. She was recalled and gave a history of suspected venereal exposure 6 months earlier and showed slit- lamp findings typical of acute syphilitic iritis. She was undergoing penicillin treatment at the county health department at that time. Comment: The highest Lyme titer of the survey ( lgG 1: 64,000) was found in this woman with acute syphilitic iritis. This was considered a falsepositive Lyme test from crossover seroreactivity to syphilis. Case 75 This patient was seen in the eye triage clinic on March 29, 1988 when her left eye was hit by a rake. Results of a routine blood test were reported from MRL as negative IFA but Lyme ELISA results were positive on both of two testings. Paris reported four of five Lyme test results as negative in this patient with only a 1 + HA to the CNTS antigen as the only Lyme activity. However, there was also definite evidence of syphilitic infection in this patient. VORL was again nonreactive, but TPHA was I Clin Neuro- ophthalmol, Vol. 9, No. 3, 1989 154 f. L. SMITH ET AL. 4+ reactive ( 640 U); FTA- ABS was 4+ reactive ( 800 U); and TPI was 40% immobilization ( 10 U). Comment: Late seronegative syphilis was picked up on a routine eye triage clinic visit when a man was struck in the eye by a rake. This would have been missed by routine VORL or routine Lyme IFA. A false- positive Lyme ELISA was probably sero- Goss- reactivity to definite evidence of syphilitic infection in this patient. The patient was written to and advised to return for repeat testing and for treatment. DISCUSSION A serologic survey of 75 patients seen during a I- week interval at the BPEI in late March 1988 was performed to try to study the incidence of serologic reactivity for Lyme borreliosis in the nonendemic area of south Florida. Matched specimens of serum drawn from these patients were sent to MRL Laboratory in California, where both Lyme IFA IgG and IgM titers were obtained as well as Lyme ELISA tests. The other tube of serum was sent to the Alfred Fournier Institute ( lAF) Laboratory in Paris, which performed six different quantitative serologic tests for syphilis ( VORL, TPI, FTA- ABS, TPHA, FTA- IgM, and SPHA) as well as five different tests for Lyme borreliosis ( lgG and IgM testing) to two different B. burgdorferi antigens ( lFA and CNTS) and a hemagglutination test to one of these as well ( CNTS). There were several interesting findings from this study. First of all, MRL Laboratory in California reported at least some seropositivity for Lyme disease in 17 cases ( 23%) with completely negative results in the other 58 patients ( 77%). This report of serologic abnormality was double that found at the Paris laboratory, which reported 8 patients with some serologic abnormality ( 11 %) and found negative results in the other 67 patients ( 89%). Both laboratories reported the serum abnormal in five patients, and this revealed definite evidence of Lyme borreliosis in one patient but unequivocal serologic evidence of syphilis was found in all four of the other patients with serologic abnormalities found by both laboratories. Because of the discrepancy in results between the two laboratories, the charts of all patients with any reported serologic abnormality were reviewed to make a clinical assessment of the data. Those patients with unresolved findings at that point were written to and invited to return for repeat testing and further study. The following conclustem" wt:> re drawn from this study. " " I,;! j<; was found in 6 I Clin Neuro- ophtha/ mo/, Vol. 9, No. 3, 1989 of 75 patients in this survey, for an incidence of 8% of patients seen in this facility. 2. The highest Lyme IgG titers found in the study were found in a patient with serologic high titers of both nonspecific ( VORL, RPR) and specific ( TPI, TPHA, FTA- ABS) tests for syphilis ( 8). Thus, the most common cause for a very high titered blood test for Lyme borreliosis in this department is a serologic cross- reactivity for syphilis. 3. Two cases of Lyme borreliosis were found in this survey, or an incidence of 3% of patients seen in this eye hospital. One was a 12- year- old boy from Puerto Rico with chronic ocular granulomatous inflammation, recurrent unexplained fever, and who had a left Bell's palsy 1 year earlier, which had not been explained despite previous hospital investigations, until positive blood test results for Lyme disease were found in Paris. The other patient with definite serologic evidence of Lyme borreliosis was a 76- year- old man admitted for cataract surgery who had a positive Lyme ELISA test at MRL but IgG titers of 200 to one antigen and 512 to another antigen in Paris. This was thought to indicate prior contact with Lyme borreliosis in this patient. There were three other cases that might possibly represent former borrelia infections ( cases 17, 65, 74) but the data were insufficient to be conclusive at that time. 4. The importance of getting both IFA and ELISA tests on a patient with suspected Lyme borreliosis was evidenced in this study, as well as repeat testing or using different laboratories. Of the 17 cases reported as positive from California, 9 of 75 ( 12%) were positive to both IFA and ELISA; 5 of 75 ( 7%) were positive to IFA but negative to ELISA; 3 of 75 ( 4%) were positive to ELISA and negative to IFA. The significance of low and variable titers must be carefully evaluated in each patient ( 9,10). We have recently seen a 25- year- old white man from Broward County, Florida who presented with blurred vision of 6 weeks' duration. He had bilateral iritis and vitritis, and gave a history of three episodes of facial palsy in the past 3 years ( the first becoming a facial diplegia within 2 days and had been suspected of having Guillain- Barre syndrome at that time). All three episodes of facial palsy had cleared with oral steroid therapy. He had severe arthralgic pain in both knees for 2 months 4 years before, and had noted intermittent transient episodes of palpitation for - 5 years. He picked a tick off his leg after hunting in the Everglades 10 years before, and had vacationed in Cape Cod, Massachusetts at ages 11 and 14 years. The clinical diagnosis was active ocular Lyme borreliosis. The laboratory studies were quite important, however ( 9). LYME DISEASE IN NONENDEMIC AREA 155 A Lyme ELISA test was positive ( 1.54 in one laboratory). One week later a repeat test by MRL showed IFA < 1: 16 IgM and a 1: 16 IgG, and the Paris laboratory confirmed a negative Lyme IFA in this patient. However, the MRL Laboratory again found the ELISA test to be definitely positive ( 1.81). It is obvious that if only a Lyme IFA test had been obtained for this patient that the serologic response would have been called negative, whereas the ELISA test confirmed the clinical diagnosis and was significantly abnormal in two laboratories on two occasions ( 11,12). Other questions that could be raised from this study would be the significance of low- titered and/ or variable responses, particularly in elderly patients who might have retired from an endemic area in New England into south Florida ( 9,10). This might raise the serologic comparison with the frequent finding of nonreactive VDRL but reactive FTA- ABS tests found in the hospital population in patients with clinical signs of late ocular or neurosyphilis. The incidence of heart disease in that population is of interest and might warrant further study. Patients are now being increasingly frequently encountered in the BPEI with iritis, vitritis, optic neuritis, history of Bell's palsy, and other neuroophthalmologic syndromes in whom all diagnostic parameters are negative except for positive blood test results for Lyme borreliosis. Furthermore, recently encountered young adult patients, generally male, with active anterior and posterior granulomatous uveitis who present with iritis, vitritis, and some variations of necrotizing retinitis are now being recognized as mixed infections in patients with acquired immune deficiency syndrome ( AIDS). Two recent patients with this syndrome presented with nonreactive serum VORL but reactive FTA- ABS tests and were found to have definite evidence of AIDS. Both responded to 12 million U/ day of intravenous aqueous penicillin within 1- 6 days in the hospital, attesting to the activity of syphilitic retinitis in both cases. We recommend the following tests in patients with iritis, vitritis ( 13), optic neuritis ( 14,15), retinitis, facial palsy ( 16), aseptic meningitis, Alzheimer- dementia syndromes, amyotrophic lateral sclerosis- like syndromes, or other clinical signs consistent with Lyme borreliosis ( 17). A routine screen includes serum VORL with titer, FTA- ABS, Lyme IFA ( IgG and IgM) and Lyme ELISA, and, when indicated, serum HIV. Other studies ( chest x- ray film, PPO, and mumps control ski~ te~ t) and serum toxoplasma titers are ordered as IndICated. A low peripheral blood white blood cell count and a negative mumps antigen skin test in an adult with one of the syndromes described strongly warrant serum HIV testing and confirmatory Western blot studies. The increasing incidence of all forms of syphilis ( ocular and neurosyphilis being the most frequently encountered in this hospital), along with the definite occurrence of active acute and chronic ocular Lyme borreliosis even in south Florida and in patients from Caribbean and Central American regions, as well as the difficulties encountered in diagnosis in patients with suppressed immune responses, makes the clinical awareness of these newly emerging serologic patterns important not only to the ophthalmologist and neurologist but also to all physicians encountering these individuals. REFERENCES 1. MacDonald AB. Lyme disease: a neuro- ophthalmologic view. J Clin Neuro- ophthalmoI1987; 7: 185- 90. 2. Schmid GP. The global distribution of Lyme disease. Rev Infect Dis 1985; 7: 41- 50. 3. Hunter EF, Russel H, Farshy CE, et al. Evaluation of sera from patients with Lyme disease in the fluorescent treponemal antibody- absorption test for syphilis. Sex Transm Dis 1986; 13: 232- Q. 4. Hamer RE, Smith JL, Israel CWo The FTA- ABS test in late syphilis. A serological study in 1,985 cases. JAm Med Assoc 1968; 203: 545- 8. 5. Paris- Hamelin A, Vaisman A, Fustec- Ibarboure S, et aI. Recherche et dosage des IgM treponemiques par une methode immuno- enzymologique ( Elisa). Comparaison avec Ie FTA- Abs- IgM et Ie SPHA modifie. WHOIVDT/ RES/ 83.371: 1- 11. 6. Paris- Hamelin A, Andre J, Merlin S, Vaisman A, et al. Recherche des IgM specifiques de la syphilis par une methode d'immunocaptation sur plaque. WHO/ VDT/ RES/ 83.372: 1- 15. 7. Paris- Hamelin A, Vaisman A, Deregnaucort J. Actualites 1986 sur la syphilis. Le Biologiste 1986; 20: 19- 32. 8. Magnarelli LA, Anderson JF, Johnson RC. Cross reactivity in serological tests for Lyme disease and other spirochetal infections. I Infect Dis 1987; 156: 183- 8. 9. MacDonald AB. Ambiguous serologies in active Lyme borreliosis. I Clin Neuro- ophthalmal 1988; 8: 79- 80. 10. Dattwyler RJ, Volkman DJ, Luft BJ, et al. Serologic Lyme disease. New Engl J Med 1988; 319: 1441...( i. 11. Russel H, Sampson JS, Schmid GP, et al. Enzyme- linked immunosorbent assay and indirect immunofluorescence assay for Lyme disease. Ilrlfect Dis 1984; 149: 465- 70. 12. Rawlings JA, Fournier PV, Teltow GJ. Isolation of borrelia spirochetes from patients in Texas. J elin Microbial 1987; 25: 114S- 50. 13. Steere AC, Duray PH, Kauffmann DJH, et al. Unilateral blindness caused by infection with the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985; 103: 382- 4. 14. Wu G, Lincoff H, Ellsworth RM, et al. Optic disc edema and Lyme disease. AIm Ophthalnml 1986; 18: 252- 5. 15. Farris BK, Webb RM. Lyme disease and optic neuritis. I Clin Neuro- ophthalmol 1988; 8: 73-- 8. 16. Finkel MF. Lyme disease and its neurologic complications. Arch Neurol 1988; 45: 99- 104. 17. Johnson RC. Lyme borreliosis: a disease that has come into its own. lAb Management 1988; 26: 34- 40. I Cli" Neuro- ophthalmol, Vol. 9, No. 3, 1989 |
