Journal of Neuro-Ophthalmology:
Reactive Lyme Serology in Optic Neuritis
Sibony, Patrick MD; Halperin, John MD; Coyle, P K MD; Patel, Kartik DO
Department of Ophthalmology and Neurology (PS, PKC, KP), State University of New York at Stony Brook and the Department of Neurology at North Shore University Hospital (JH), Manhasset, New York.
Address correspondence to Patrick Sibony, MD, Department of Ophthalmology, Health Sciences Center, Level II-152, SUNY Stony Brook, Stony Brook, NY 11794; E-mail: firstname.lastname@example.org
Background: Establishing a causal relationship between optic neuritis and Lyme disease (LD) has been hampered by technical limitations in serologic diagnosis of LD. Even so, there is a general impression that optic neuritis is a common manifestation of LD.
Methods: Retrospective case analysis of Lyme serology in 440 patients with optic neuritis examined between 1993 and 2003 in a single neuro-ophthalmic practice at Stony Brook University Medical Center, Suffolk County, New York, a region hyper-endemic for LD.
Results: Lyme enzyme-linked immunosorbent assay (ELISA) was positive in 28 (6.4%) patients with optic neuritis, three of whom had syphilis with cross-reactive antibodies. Among the remaining 25 ELISA-positive patients, optic neuritis could be confidently attributed to LD in only one case, a patient with papillitis. The other 24 cases had reactive Lyme serologies related to a history of LD years earlier, asymptomatic exposure, false-positive results, or non-specific humoral expansion. The ELISA in these 24 cases were weakly positive and the Western blots were negative by Centers for Disease Control criteria. There were no significant clinical differences between the 25 seropositive optic neuritis cases and 50 seronegative optic neuritis cases.
Conclusions: Based on these cases and a review of the literature, there is insufficient evidence for a causal link between LD and retrobulbar optic neuritis or neuroretinitis. There is sufficient evidence to establish a causal link between LD and papillitis and posterior uveitis.
The clinical manifestations of Lyme disease (LD) were first described in 1977 (1). Anecdotal descriptions of associated ocular manifestations began to appear in the mid 1980s. Early reports on the ophthalmic manifestations relied on indirect immunofluorescence or enzyme-linked immunosorbent assay (ELISA). Limitations in the serological diagnosis of LD have cast doubts about a link between LD and optic neuritis (2-6). Even so, there is a widespread impression that optic neuritis is a well-documented and common manifestation of LD (7-14). Based on a review of optic neuritis cases in our practice in a region hyper-endemic for LD and a thorough review of the published literature, this impression is largely unjustified.
We retrospectively identified 632 cases coded for a diagnosis of optic neuritis (retrobulbar neuritis, papillitis, or neuroretinitis) between 1993 and 2003 in the database of Stony Brook University Medical Center, a tertiary referral center that predominantly serves residents of Suffolk County on eastern Long Island, New York, a region hyper-endemic for LD. All patients were from Long Island. The Institutional Review Board at University Medical Center approved the study.
We excluded 192 cases because the charts were incomplete (no follow-up after the initial encounter, charts or serologies unavailable or incomplete, or a diagnosis inconsistent with optic neuritis). Complete medical records, including serological testing for Borrelia burgdorferi, were available in 440 cases. We performed a detailed analysis of the clinical and serological features of all cases with a positive Lyme ELISA who underwent a confirmatory Western blot. All cases underwent a complete neuro-ophthalmic evaluation and were specifically questioned for a history of tick bite, erythema migrans (EM), and other symptoms and signs of LD.
Of the 440 cases of optic neuritis, 361 (82%) had retrobulbar neuritis, 55 (12.5%) had papillitis, and 24 (5.5%) had neuroretinitis.
The diagnosis of optic neuritis required a history of rapid vision loss over hours to weeks, an afferent pupillary defect or optic disc edema in association with diminished visual acuity, dyschromatopsia, or a visual field defect not otherwise attributable to retinal disease. Cases were subcategorized as retrobulbar neuritis if the onset was rapid (hours to days), usually in association with pain and a normal or mildly congested optic disc; papillitis if the same features occurred with significant disc edema; and neuroretinitis if the disc was swollen with stellate macular exudates with or without posterior vitreous cells. We encountered five cases with bilateral disc edema, with relatively normal vision and intracranial hypertension caused by LD meningitis. We considered them separately as papilledema.
Anti-B. burgdorferi antibodies were measured by ELISA and Western blot performed in the Clinical Immunology Laboratory at University Hospital, Stony Brook. The ELISA result, expressed as optical density (OD), was considered positive if it exceeded the mean OD of a seronegative control panel by ≥3.0 standard deviations (negative cutoff). We expressed serum Lyme ELISA as the ratio of the patient's OD to the negative cutoff; a ratio ≥1 was considered positive. Western blots were interpreted based on Centers for Disease Control (CDC) criteria (15,16). IgM blots were considered positive if at least two of the following three bands were present: 23, 39, or 41 kD, and developed within 1 month of the onset of vision loss. IgG blots were considered positive if at least five of the following 10 bands were present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93 kD. Cerebrospinal fluid (CSF) was examined for local production of anti-B. burgdorferi antibodies, with correction for CSF and serum immunoglobulin concentration. A CSF-to-serum Lyme antibody index of ≥1.0 was considered indicative of intrathecal antibody production (17-19).
Criteria to Establish Causation
To assess whether optic neuritis was caused by LD in our cases and in the published literature, we incorporated surveillance criteria used by the Centers for Disease Control (15,16). This approach is similar to one previously described by Halperin et al (19) to evaluate the central nervous system manifestations of LD.
Category I. Definitive proof requires culture or histologic demonstration of B. burgdorferi in the CSF or optic nerve of a patient with active LD and optic neuritis.
Category II. Strong evidence requires the following core elements: optic neuritis, endemic exposure, negative Venereal Disease Research Laboratory Slide Test (VDRL) or Rapid Plasma Reagin (RPR), exclusion of definite multiple sclerosis (MS) by Poser criteria (20), and a positive serum Lyme titer (ELISA or Indirect Fluorescent Antibody [IFA]), in association with at least one of the following: (a) encephalitis or meningitis with CSF pleocytosis, intrathecal antibody production, or CSF polymerase chain reaction (PCR) positive for B. burgdorferi DNA, and a positive Western blot; (b) recent signs of LD, such as facial nerve palsy, arthritis, or radiculoneuritis, with positive serum ELISA confirmed by Western blot; and (c) recent physician-diagnosed EM, usually with flu-like symptoms.
Category III. Possible connection would include the core elements described and one of the following: (a) central nervous system involvement that does not meet grade IIa criteria (lack of a confirmatory positive Western blot or the absence of intrathecal antibodies); (b) compelling clinical signs of LD without a positive Western blot or documented syphilis serologies (this group would include cases of “possible EM” that was not physician-diagnosed); and (c) seropositivity by ELISA and Western blot without symptoms or signs of LD.
Category IV. Causal linkage is unlikely because the serological or clinical evidence is lacking (IVa) or an alternative diagnosis such as MS or syphilis is more likely (IVb).
Category V. There is insufficient information on the optic neuropathy or the diagnosis of LD.
Among the 440 cases with optic neuritis in whom serological tests for LD were available, 28 (6.4%) cases had reactive Lyme serologies by ELISA. Three of the 28 had papillitis with cross-reactive antibodies because of syphilis (cases 26-28). Among the 25 remaining cases, 20 (80%) had retrobulbar neuritis, 4 (16%) had papillitis, and 1 (4%) had bilateral neuroretinitis. There were 5 cases with papilledema caused by LD meningitis (cases 29-33). The clinical and serological findings on all cases are summarized in Table 1.
No cases with retrobulbar neuritis or neuroretinitis met criteria for category I (“definitive proof”) or category II (“strong evidence”) of a causal link to LD. One case with bilateral papillitis (Case 1) and a very high Lyme ELISA ratio met category II evidence for a causal link to LD.
Two patients with retrobulbar neuritis (Cases 2 and 3) who met category III criteria had a history of LD treated 9 to 13 years before the onset of optic neuritis. Although their ELISA were positive (Fig. 1) when they presented with optic neuritis, their Western blots were negative. Optic neuritis developed many years after antibiotic treatment (in one case with IV ceftriaxone) and vision improved before they were retreated with antibiotics. Neither had other signs of LD at the time optic neuritis developed.
Twelve cases (Cases 4-15) met category IVa (“causal linkage unlikely because serological or clinical evidence is lacking”), all with negative Western blots. None had a history of EM, facial nerve palsy, radiculoneuritis, or arthritis. One case (Case 12) had a questionable history of a tick bite followed by arthralgias that had resolved without treatment 7 years earlier. Another case (Case 8) had four IgG bands on Western blot, had worked outdoors, and had a history of back pains and periodontal disease. Among three cases with antecedent febrile syndromes (cases 10, 11, 14), Case 14 had pharyngitis with a positive Monospot and Case 10 had bilateral neuroretinitis with a positive Bartonella titer. Three cases (Cases 8, 9, 13) had a history of periodontal disease.
Ten cases (Cases 16-25) were categorized as IVb (“causal linkage unlikely because an alternative diagnosis is more likely”) because they met Poser criteria for definite MS (20). Despite relapsing neurologic events, none of the nine patients who underwent lumbar puncture had intrathecal production of anti-B. burgdorferi antibody. Only one case (Case 16) had a positive Western blot (5 IgG bands) but no suggestive symptoms or signs of LD. One case (Case 25) who had 4 IgG bands on Western blot had a longstanding history of relapsing neurologic episodes that included brainstem and cerebellar signs at different times. He had been treated previously with intravenous ceftriaxone and never had arthritis, EM, facial nerve paresis, or radiculoneuritis. One case (Case 21) with papillitis had four IgG bands on Western blot with a 3-week episode of limb weakness and paresthesias 3 months before the onset of optic neuritis. These manifestations were followed 6 months later with new white matter lesions on brain MRI. One case (Case 23) had two IgM bands on Western Blot alone, but had a 13-year history of relapsing and progressive weakness, paresthesias, ataxia, and optic neuritis. Another case (Case 18) with definite MS had two IgM bands and three IgG bands on Western blot and a questionable history of LD based on the patient's description of an EM-like rash 7 years before the onset of optic neuritis. The remaining five patients with MS had Western blots that were unequivocally negative.
Three cases with papillitis (Cases 26-28) that had significantly elevated Lyme ELISA ratios met criteria for syphilis (Fig. 1). One case (Case 28) had an associated vitreitis. All three had a positive VDRL and FTA. Only one case had CSF pleocytosis with a positive CSF VDRL. Lyme Western blots, performed in two cases, were negative.
Five cases with LD (4 boys, 1 girl, aged 6-11 years) had bilateral optic disc edema associated with meningitis and increased intracranial pressure (Cases 29-33). Each had normal acuity, pupils, and color vision and visual field enlargement of the blind spots. The optic disc edema was diagnosed as papilledema in these five cases. Four had headaches, four had diplopia caused by sixth cranial nerve palsy or divergence paresis, and one had a facial nerve palsy. Lyme ELISA ratios in each case were elevated between 6.75 and 9.70 (Fig. 1). Four of the five had undergone Western blot testing, three of whom were positive for both IgM (2-3 bands) and IgG (6-7 bands); one was positive for IgG (6 bands) alone. The case that did not have a Western blot performed had EM diagnosed by an experienced physician. Opening pressures on lumbar puncture ranged between 240 and 360 mm water, and cerebrospinal protein was elevated in two of four patients. Cerebrospinal fluid pleocytosis was present in all but one patient (16-48 cells/mm3); intrathecal antibody index was elevated in one patient. All symptoms and signs resolved after treatment with intravenous ceftriaxone; there were no recurrences.
Table 2 compares the demographic, clinical, and laboratory features of the 25 seropositive optic neuritis patients to 50 seronegative optic neuritis cases. There were no statistically significant differences between the two groups with respect to age, gender, eye involvement, follow-up, pain, visual acuities at presentation and follow-up, or the frequency of papillitis, MRI abnormalities, CSF abnormalities, and MS. Vision improved spontaneously or before initiation of antibiotic treatment of LD in 17 (68%) of the 25 seropositive cases.
Establishing a causal relationship between optic neuritis and LD requires a rigorous and restrictive analysis of the evidence (19,21-24). Despite a number of case reports claiming an association, strong evidence of a causal relationship has only been clearly established for papillitis (Table 3, and see Literature Review). Our experience, accumulated more than 10 years in a region hyper-endemic for LD, indicates that optic neuritis is an exceedingly uncommon manifestation of LD. During this time, we encountered only one case-a patient with papillitis-that could be confidently attributed to active B. burgdorferi infection. Notably, asymptomatic seropositivity to B. burgdorferi in an endemic region such as Suffolk County is 5% to 10%, (25,26), matching the 5.7% (25 of 440) seropositivity of our optic neuritis patients.
A positive serology does not differentiate between active infection and previous exposure. Patients may remain seropositive for years, even after adequate antibiotic treatment (16,27,28). This probably explains the two category III cases (Cases 2 and 3) and possibly two category IV cases (Cases 12 and 18) in subjects who may have had LD 7 to 13 years before optic neuritis developed. The remote history of LD, the absence of any coexistent signs of recurrent infection, the negative Western blots at the time of vision loss, and visual improvement without antibiotic treatment suggest that the optic neuritis was probably unrelated.
False-positive Lyme serologies can occur in patients with other spirochetal infections (syphilis, periodontal disease, and relapsing fever) (29-32). This was evident in three of our cases with syphilis (Cases 26-28) who had quite elevated ELISA ratios (>5.00). Three seropositive category IVa patients (cases 8, 9, 13) had a history of periodontal disease. Serum Lyme ELISA may also be non-specifically elevated in patients with autoimmune diseases and other infections (33,34). Three of the category IVa cases (Cases 10, 11, 14) had false-positive Lyme serologies caused by previous exposure or non-specific humoral expansion from an unrelated viral or bacterial infection.
Lyme-seropositive optic neuritis in a patient with MS is often incorrectly attributed to Lyme disease. To qualify for a diagnosis of Lyme disease, such patients, who generally have longstanding and persistent immune CSF abnormalities, should have evidence of a specific CSF immune response to B. burgdorferi (35-39). Because none of our 10 patients with MS (Cases 16-25) had evidence of intrathecal production of anti-B. burgdorferi antibody or a clinical history compatible with LD, we believe that a causal relationship to LD is unlikely. Although case 16 had a positive Western blot, there were no other manifestations of LD and vision recovered before antibiotic treatment was instituted. The reactive Lyme serology in this patient presumably reflected a previous unrelated exposure.
Whereas the Western blot has eliminated many of the difficulties in the interpretation of the ELISA, it still has limitations. Although its specificity is high, its sensitivity is not. Interpretation is somewhat subjective and the procedure lacks standardization across laboratories. IgM criteria are only considered meaningful in cases with acute disease (16,19,33,34,40,41). Cases with non-Lyme spirochetal infections may have false-positive Western blots (31,33,34).
Nonetheless, we found the Western blot useful to confirm neurologic LD with optic neuritis. Blots were positive in the only category II patient (Case 1) with papillitis and in all four patients (Cases 30-33) with papilledema in whom the Western blot test was performed. Each of these had ELISA ratios of more than 4.0 and positive Western blots that exceeded the minimum CDC requirements. In contrast, the two cases with syphilitic papillitis (Cases 27 and 28) in whom Western blots were obtained, and 18 of the remaining 24 optic neuritis patients, had ELISA ratios less than 3.00 and Western blots that were unequivocally negative (≤1 IgM band, ≤3.0 IgG bands). Among five remaining cases (Cases 8, 18, 21, 23, 25) with formally negative Western blots (2 IgM bands and longstanding neurologic disturbances or 4 IgG bands), four had MS (Cases 18, 21, 23, 25).
There are several reported cases of papillitis that appear to meet category II evidence for a causal link to LD. Burkhard (42) described a 59-year-old woman with EM, facial nerve palsy, lymphocytic meningitis, and “papilledema.” Although the lumbar puncture opening pressure was not reported, a central scotoma in one eye and an arcuate scotoma in the other were more typical of papillitis than papilledema. Similarly, Rothermell et al (43) described three compelling cases of unilateral and bilateral papillitis in children with high serum titers, positive Western blots with 8 to 10 IgG bands, and other signs of LD.
Several additional case reports of papillitis caused by LD fall short of category II requirements (44-49) because syphilis serologies were not reported (45, 48), serum titers were negative (49), or Western blot was either not reported (44,45,48) or did not meet CDC criteria (47,46). These category III cases, considered individually, would not be sufficient to establish a causal linkage, but taken as a whole, support the category II cases of papillitis.
Four previously reported cases had features of both papilledema and papillitis, characterized by rapid vision loss, bilateral optic disc edema, and intracranial pressures ranging between 240 to 570 mm (43,46,47,50). Some of these cases might be grouped with the papilledema-meningitis cases, but the rapidity and severity of vision loss was more typical of papillitis.
Among the nine published cases of retrobulbar neuritis reportedly caused by LD (51-54), none meets rigorous criteria for a causal link to LD. Jacobson (51) described four patients with typical retrobulbar optic neuritis and positive serological and CSF findings of LD. However, in a follow-up letter to the editor 12 years later (52), two of the original four patients ultimately had MS diagnosed, and another, in retrospect, was believed to have a questionable link of LD. Although the remaining case nearly satisfied category II criteria, the IgG Western blot (with 3 bands) does not meet CDC requirements. Apart from a history of tick exposure, the patient had no features suggesting LD.
Lesser (53) described three patients (his cases 2, 3, and 5) with painless retrobulbar optic neuropathies and significantly elevated Lyme titers. The clinical evidence for LD in his cases 3 and 5 is compelling. However, these cases predate the widespread use of the Western blot, syphilis serologies were not reported, the single patient who underwent a lumbar puncture only showed nonspecific spinal fluid abnormalities and vision loss developed despite antibiotic treatment.
Scott (54) reported a 10-year-old girl with arthralgias and unilateral painful retrobulbar optic neuropathy, chiasmal MRI enhancement, elevated Lyme IgG IFA of 1:512, and four bands on the IgG Western blot. Spinal fluid and intrathecal antibody assays were negative. The clinical manifestations did not improve after antibiotic treatment. This case is similar to three of our cases (Cases 8, 21, 25) who had 4 IgG bands on Western blot. MS developed in two of them (Cases 21, 25). It is likely that all three had been previously exposed to the Lyme spirochete and the optic neuritis was probably not caused by LD. Strominger and Slamovits (84) described a 58-year-old seronegative woman with subclinical retrobulbar optic neuropathy, chronic radiculoneuritis, a positive CSF PCR and T cell proliferation assay, and a Herxheimer reaction. However, this case does not meet the CDC criteria for the diagnosis of LD.
Based on the published literature, the causal link between neuroretinitis and LD has not been clearly established. Analysis is complicated by the varying clinical criteria used for diagnosis. Neuroretinitis (Leber's idiopathic stellate neuroretinitis) is strictly defined as a form of papillitis characterized by disc edema, stellate macular exudates, and posterior vitreous cells. The occurrence of non-inflammatory macular star with disc edema in severe papilledema, ischemic optic neuropathy, or acute hypertensive retinopathy, may be confused with neuroretinitis (55-58). Some authors have also applied the term neuroretinitis to any type of disc edema with uveitis or retinitis, even in the absence of a macular star (59-64), a condition we call “uveitis.”
The detection of B. burgdorferi DNA by PCR in the vitreous of a patient with pars planitis (65), the observation and culture of B. burgdorferi from intraocular specimens of patients with panuveitis (66), and its demonstration in the eye of an animal model with spirochetemia (67,68) all meet category I criteria and establish that B. burgdorferi can cause intraocular inflammation. Although neither we nor others (69,70) have seen cases of Lyme uveitis, these experimental studies, together with many reports on a variety of uveitic syndromes implicating LD (65,66,70-81), are sufficient to establish a plausible linkage between LD and uveitis (60,62,64,81-84).
The case for classically defined neuroretinitis is less clear. Our series included only one case of Lyme-seropositive neuroretinitis. The negative Western blot, the positive Bartonella titer, and the absence of any other clinical signs of LD make it unlikely that this patient had LD. Our case is similar to most of the other reported seropositive cases of neuroretinitis (2,6a,53,64,80,85). Although some had systemic prodromes consisting of fatigue (80), arthralgias (53,80) fever (2,85), or mild CSF pleocytosis (79), these findings cannot be used to support a diagnosis of LD because such findings are common in patients with neuroretinitis. Reactive Lyme serologies in these cases may represent previous exposure or a virus-related humoral expansion.
One case (50) meets category III criteria for a neuroretinitis link to LD, that of a 7-year-old with a facial nerve palsy, followed 5 weeks later by acute vision loss, meningeal symptoms, bilateral disc edema, and “macular exudates” (but no posterior vitreous cells). The case had elements of both papillitis and papilledema, with intracranial pressure of 400 mm H2O, acellular CSF, positive serum and CSF Lyme antibody tests, and a positive CSF Lyme PCR. Western blot testing was not reported. This case unquestionably had LD but it was unclear if the macular exudates were the result of classic neuroretinitis or severe papilledema.
Some published cases that describe the ophthalmic manifestations of LD have omitted serological testing for syphilis (53,86,87). In others, serological testing indicated that syphilis was at least as likely to be the cause of the optic neuropathy (88,89). Our three cases of luetic papillitis underscore the importance of obtaining syphilis serologies in cases with optic neuropathies and reactive Lyme serologies. Because spirochetes share common antigens, serological tests frequently cross-react. Depending on the method, Lyme ELISAs may be positive in approximately 20% to 60% of cases with syphilis, whereas 20% of cases with LD may have a weakly positive FTA-ABS (usually <1:10). Reaginic tests, such as the RPR or VDRL, are usually negative in LD (31,90,91).
In contrast to most of our cases with optic neuritis, the five cases with papilledema consistently met category II evidence of a causal link to LD, with very high Lyme ELISAs, positive Western blots, or a physician-diagnosed EM (29). Among seven previously published case reports that provided detailed eye findings, four cases (43,92,93) meet category II criteria and three cases (53,94,95) meet category III criteria. In addition, at least five published series described “papilledema” in patients with neuroborreliosis, (96-100), although these reports did not always provide the opening pressure or the specifics about the eye findings. In some reported cases of LD with intracranial hypertension, the CSF protein concentration and cell count were normal, presumably because the spinal tap was performed either before or after a transient pleocytosis (53,92). In two cases (92) with initially normal CSF, lumbar puncture was repeated and demonstrated a pleocytosis in one case and elevated protein in the other. This may explain why some LD patients have a “pseudotumor-like” syndrome (53). The occurrence of papilledema in patients with Lyme meningitis is well-established and consistent with our experience.
In summary, there seems little doubt that LD can affect the optic nerve. The most common manifestation occurs in children with early disseminated disease: Lyme meningitis, intracranial hypertension, and papilledema. These patients have high serum Lyme ratios and unequivocally positive Western blots. Optic neuritis in LD is rare and usually expressed as a unilateral or bilateral papillitis during the early disseminated stage. Optic disc edema in posterior uveitis can also be caused by LD, although we have encountered this clinical presentation in only one patient with syphilis with a false-positive Lyme titer. There is no convincing evidence that LD causes retrobulbar neuritis. Although there is suggestive evidence (51,53,54) that a painless retrobulbar optic neuropathy may occur in chronic neuroborreliosis, this requires further confirmation. LD may ultimately be shown to cause classic neuroretinitis but compelling evidence of a causal linkage is lacking. Nonetheless, the workup for neuroretinitis should include testing for LD, particularly if there are signs of intraocular inflammation.
Optic neuropathy in LD does not generally occur in isolation; it is usually accompanied by meningeal symptoms, antecedent febrile illness, EM, facial nerve palsy, or arthritis. Positive Lyme serology in patients with isolated retrobulbar optic neuritis in the absence of other signs, or in patients with otherwise typical MS, may be misleading.
The authors are particularly grateful to Marc G. Golightly, PhD, Director of the Clinical Immunology Laboratory at University Medical Center, Stony Brook, for his invaluable technical advice and support.
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