Papilledema Secondary to Neurologic Lyme Borreliosis: A Meta-Case Series

Papilledema can be a manifestation of neurologic Lyme borreliosis (LB). The clinical manifestations and progression of these cases have not been comprehensively documented to date. We aimed to describe clinical and diagnostic features and to assess patient outcomes in cases of papilledema secondary to neurologic LB.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Papilledema Secondary to Neurologic Lyme Borreliosis: A Meta-Case Series Elizaveta E. Vaysbrot, MD, MS, Raveendhara R. Bannuru, MD, PhD, Mia-Cara Christopher, MPH, Mikala C. Osani, BA, John J. Halperin, MD Background: Papilledema can be a manifestation of neurologic Lyme borreliosis (LB). The clinical manifestations and progression of these cases have not been comprehensively documented to date. We aimed to describe clinical and diagnostic features and to assess patient outcomes in cases of papilledema secondary to neurologic LB. Methods: We searched MEDLINE, EMBASE, and the Cochrane Database from inception to August 2019. We did not restrict our search by study design or by publication date, status, or language. Results: Twenty-eight studies describing 46 cases of papilledema secondary to neurologic LB were included. Common clinical features included cranial neuropathy (68%) and diplopia (61%). Most patients did not recall tick bite (71%) and were afebrile (74%). Brain imaging was normal in 64% cases. Cerebrospinal fluid analysis showed lymphocytic pleocytosis (77%). Initial treatment with intravenous ceftriaxone was given in 52% of cases and resulted in a 100% resolution rate. Concomitant treatment with acetazolamide resulted in favorable outcomes. Conclusions: For patients in endemic regions who describe symptoms suggestive of intracranial hypertension and papilledema, especially accompanied by facial nerve palsy and other cranial nerve palsies, underlying neurologic LB should be considered. Journal of Neuro-Ophthalmology 2021;41:e498–e508 doi: 10.1097/WNO.0000000000000983 © 2020 by North American Neuro-Ophthalmology Society Center for Treatment Comparison and Integrative Analysis (CTCIA) (EEV, RRB, M-CC, MCO), Tufts Medical Center, Boston, Massachusetts; and Department of Neurosciences (JJH), Overlook Hospital, New York University School of Medicine, Summit, New Jersey. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Raveendhara R. Bannuru, MD, PhD, Division of Rheumatology, Center for Treatment Comparison and Integrative Analysis (CTCIA), Box 406, Tufts Medical Center, 800 Washington Street, Boston, MA 02111; E-mail: [e-mail] e498 L yme borreliosis (LB) is a multisystem zoonotic disease caused by the spirochete Borrelia burgdorferi sensu lato and transmitted by hard-shelled Ixodes ticks (1). LB is endemic in many regions in the Northern Hemisphere, particularly in the Northeastern and upper Midwestern United States, Central Europe, and coastal Sweden (2). Several heterogeneous genotypes of the B. burgdorferi sensu lato genospecies have been identified since the spirochete was first isolated. The causative agents primarily responsible for LB are B. burgdorferi sensu stricto, observed in both North American and European cases, and Borrelia afzelii and Borrelia garinii, found exclusively in Europe and Asia, with all 3 strains varying in their organotropism and predilection for certain clinical manifestations (1,3). Clinical manifestations of LB are categorized into early localized (with erythema migrans [EM], as the main attribute), early disseminated, and late disease (4). During disseminated disease, B. burgdorferi spread to various tissues and organs, predominantly affecting the skin, heart, joints, and nervous system. Among rare manifestations of LB, ocular symptoms may present during both early and late disease. Ocular manifestations of LB may involve any part of the eye and include conjunctivitis, keratitis, uveitis, iritis, choroiditis, episcleritis, vitritis, neuroretinitis, orbital myositis, optic neuritis, and papilledema (5). The disease may also present with ocular motility disorders, most commonly involving the sixth and, more rarely, the third and the fourth cranial nerves (6). Papilledema is a swelling of the optic disc due to increased intracranial pressure (ICP) (7). Although typically resolved with treatment, severe papilledema may result in permanent visual loss (8). A case of papilledema in connection with putative LB was first described in the literature in 1979, although the diagnosis was questionable, since the case predated serological assessment of LB and described the presence of serum cryoglobulins, which is unusual in this disease; the case also lacked confirmation of raised ICP Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (9). A syndrome involving elevated ICP in LB was first described in 1985 in 2 cases without initial cerebrospinal fluid (CSF) signs of meningitis (10). Since then, a few dozen case reports of LB accompanied by papilledema have been published. However, no systematic summary of such cases has been attempted until now. We conducted a systematic literature review to summarize all the extant reports of papilledema in LB. We aimed to describe common clinical and diagnostic features and to analyze treatment patterns in connection with possible outcomes of Lyme papilledema. The goals of this study are to aid clinicians with recognition and timely and appropriate therapeutic intervention in this disorder and to provide information that may assist health care professionals in distinguishing Lyme papilledema from papilledema arising from other diagnostic entities—in particular, from idiopathic intracranial hypertension (IIH) and from nonborrelial lymphocytic meningitis. METHODS Data Sources/Searches We conducted a systematic search of MEDLINE, Web of Science, EMBASE, Google Scholar, and the Cochrane Central Register of Controlled Trials to identify all relevant publications involving neurologic and ophthalmic presentations of LB. We followed PRISMA guidelines (See Supplemental Digital Content, Table E1, http://links.lww.com/ WNO/A401). We did not restrict our search by study design, publication date, publication status, or language. We hand-searched reference lists of relevant studies and searched within supplements of conference proceedings published up until August 2019. Foreign language papers were translated. Study Selection and Inclusion Criteria Literature screenings were performed in duplicate by 3 independent reviewers (any paired combination among the following pool: E.E.V., M.-C.C., and M.C.O.), with conflicts resolved by a fourth reviewer (R.R.B.). We gathered all existing case reports and case series involving presentations of papilledema that were associated with LB through positive 2-tier serology alone or in combination with 1 or more of the following: CSF analysis suggestive of LB (including intrathecal antibody production and/or CSF positivity for Borrelia through culture or polymerase chain reaction (PCR) in combination with CSF pleocytosis, patient history, or residence in an endemic area). In further review of the literature, we referenced the Centers for Disease Control and Prevention (CDC) criteria to confirm cases of LB, which require either a history of EM or an Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 objective neurologic manifestation (“any of the following, alone or in combination: lymphocytic meningitis; cranial neuritis, particularly facial palsy [may be bilateral]; radiculoneuropathy; or, rarely, encephalomyelitis”) confirmed by 2-tiered laboratory testing (11). Relevant cases that did not fit strictly within these case definitions were reviewed by a neurologist (J.J.H.). We collected data on ICP values as reflected in the CSF opening pressure obtained by lumbar puncture (LP). Although there is no universally applicable ICP threshold, opening pressure $200 mm H2O is considered abnormal in adults; in children ,8 years of age, lower cutoffs may be appropriate, but by age 8, adult values are considered applicable (12,13). We took note of any cases in which LP was not conducted or in which the opening pressure was not recorded. Because we did not have conclusive information to exclude these cases, we performed a separate descriptive analysis isolating the cases with documented increased ICP, as a sensitivity measure. We excluded studies involving patients diagnosed with unilateral optic disc swelling because this may be indicative of an alternative diagnosis in need of differentiation from typical papilledema, which is caused by increased ICP and thus is almost always bilateral. We took care to differentiate papilledema from papillitis, and we excluded cases with diagnoses of papillitis and/or optic neuritis. Data Extraction Two investigators (M.-C.C. and M.C.O.) collected data on the following variables: age, sex, residence in an endemic region, history of EM, tick bite history, presenting symptoms, duration of symptoms, presence of cranial neuropathy, serologic response, CSF opening pressure and other aspects of LP if performed, MRI or computed tomography (CT) results, antibiotic therapy given, route of administration and duration of antibiotic therapy, adjuvant therapy with corticosteroids or acetazolamide, and patient outcome. Extracted data were reviewed for accuracy in their entirety by a clinician (E.E.V. or R.R.B.). The quality of the included studies was assessed using the tool proposed by Murad et al (14) to evaluate case series and case reports. Each case was evaluated based on selection, ascertainment, causality, and reporting, with 1 point being allocated for adequate reporting in a domain. High-quality cases received scores of 4/4, moderatequality cases received scores of 3/4, and low-quality cases received scores of 2 or less. High and moderate quality studies were deemed to have adequate data to make inferences related to clinical practice. Publication quality was assessed independently by 2 investigators (M.M.O. and R.R.B.). Any disagreements or discrepancies were resolved by consensus. e499 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Descriptive statistics about the patient characteristics, case management, and other variables were presented in tables and figures. We evaluated cases published before 1995 separately from cases published after 1995; the introduction of 2-tiered serologic testing as a diagnostic paradigm in 1995 greatly improved specificity of serologic testing, and we aimed not to combine confirmed cases with potentially false positive cases (15). We also evaluated cases originating in the United States separately from cases originating in Europe to assess the potential impact of variation in the genospecies of B. burgdorferi acquired in each geographic region and resulting differences in diagnostic features and clinical presentations. Differences across groups were tested with either the chi-square test or Fisher exact test. All analyses were conducted in R 3.6.0. RESULTS Our initial search identified 1,837 published studies pertaining to neurologic and ophthalmic presentations of LB (Fig. 1). Finally, 28 studies (published between 1985 and 2019) describing 46 cases of papilledema secondary to LB met the eligibility criteria. Thirty two of these cases (70%) originated in the United States (10,16–28), and the other 30% of cases originated in Europe. All patients were either residents or visitors of regions endemic for LB. The majority of cases (38 cases, 83%) occurred after the 1995 cutoff date. Thirty-one cases (67%) were considered confirmed cases of LB by the CDC criteria, and 10 (22%) were considered to be “probable cases.” Five cases were classified as “unclear”; in each of these cases, there was no history of EM or other hallmark symptoms of LB, no indication of intrathecal antibody production, and no indication of 2-tiered testing to confirm LB (18,26,29–31). Most cases (89%) were pediatric patients with a mean age of 12 years and a median age of 9 years; of the 41 cases for which the sex of the patient was reported, 61% involved men, which is consistent with the general predominance of male sex in pediatric cases of LB (32). For cases reporting followup time after treatment, the time ranged from 2 to 426 days. The study characteristics for all patients and for FIG. 1. Study selection flow chart. e500 Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution subgroups of interest are shown in Tables 1 and 2. The majority of cases (67%) were assessed to be of moderate to high quality; however, ascertainment of the exposure and outcome was assessed to be adequate in 96% of cases (See Supplemental Digital Content, Table E2, http:// links.lww.com/WNO/A402). Diagnostic/Laboratory Findings Nearly all of the patients (97%) presented with positive serology by enzyme-linked immunosorbent assay (ELISA) or other serologic testing methods in cases that reported serologic testing results (N = 37). Thirty of 38 cases (79%) used ELISA, and all of these reported positive results; 27 of these 30 cases were confirmed by 2-tier testing with Western blot. In 7 other cases, the testing method was not specified; the case which reported “indeterminate” serologic testing results was included in this group (19,23,26,27,36). For 2 of these 7 cases, positive Western blot results were reported, but 2-tier testing could not be confirmed (23,27). In 14 cases (37%), the CSF was analyzed for the presence of B. burgdorferi DNA by PCR, and in 9 cases, the results were positive; of PCR-positive cases, 3 cases (33%) demonstrated evidence of intrathecal antibody production, and 7 cases (78%) were found to have lymphocytic pleocytosis (23,24,27,33,36). CSF examination demonstrated lymphocytic pleocytosis in over three-fourths of the 35 cases for which results were reported (N = 27; 77%) and intrathecal antibody synthesis in half of the 21 cases for which results were reported (N = 11). Cases Reported From 1995 to Present Clinical Characteristics From 1995 to 2019, 38 cases of LB presenting with papilledema were reported; 68% occurred in the United States (Table 1). The mean age of patients was 12.5 years (median 9 years), and 57% of patients were men. The history of EM was only documented in 27% of patients, and only 27% recalled a tick bite. The most common initial presenting symptom was headache (N = 33; 87%), often accompanied by nausea and/or vomiting (N = 17; 45%). Only 26% of patients were febrile on presentation. Elevated ICP was reported in 35 cases, with 86% of these cases providing specific measurements of opening pressure. Three additional cases did not report whether or not the ICP was elevated and did not provide the results of a lumbar puncture (31,33,34). In cases that reported LP findings (N = 24), it documented opening pressures ranging from 240 mm H2024 to 600 mm H2022 (median 403 mm H20). Cerebral imaging results by MRI and/or CT were normal in 64% of cases (N = 23). Cranial neuropathy was documented in 20 patients (67% of all cases reporting on either presence or absence of this manifestation) and predominantly involved the sixth (N = 17; 85% of all reported palsies) and seventh (N = 3; 15% of all reported palsies) cranial nerves. One case involved a palsy of the fourth cranial nerve (35). Treatments The majority of patients (N = 23; 66%) in the post-1995 era received intravenous (IV) ceftriaxone as their initial treatment, and all of these patients experienced complete resolution of signs and symptoms after 1 treatment course lasting from 14 to 28 days, with a follow-up period ranging from 2 to 426 days (Fig. 2). Only 2 patients received IV penicillin as their first-line treatment (37,38). Both of these patients were switched from penicillin to ceftriaxone treatment before completing a full treatment course: 1 patient experienced an allergic reaction to penicillin (38) and the TABLE 1. Demographic, clinical, and diagnostic characteristics All Cases (N = 46) Mean age (years) Median age (years) Male (%) History of erythema migrans (%) Recalled tick bite (%) Fever (%) Cranial nerve palsy (%) Diplopia (%) Intracranial hypertension (%) Normal MRI/CT (%) Seropositive by ELISA (%) Seropositive by other methods [IFA or unspecified] (%) Both IgG/IgM (%) IgG only (%) Confirmed Western blot (%) 11.7 9.0 61.0 34.2 29.0 26.2 68.4 61.0 95.1 63.6 100 83.3 75.0 9.4 63.0 (N = 41)* (range 4–51) (N = 41) (N = 41) (N = 31) (N = 42) (N = 38) (N = 41) (N = 41) (N = 44) (N = 33) (N = 12) (N = 32) (N = 32) (N = 46) 1995 to Present Only (N = 38) 12.5 9.0 56.7 27.3 26.9 25.7 66.7 60.6 94.3 63.9 100 85.7 71.4 10.7 76.3 (N = 33) (range 4–51) (N = 33) (N = 33) (N = 26) (N = 35) (N = 30) (N = 33) (N = 35) (N = 36) (N = 30) (N = 7) (N = 28) (N = 28) (N = 38) Pre-1995 Only (N = 8) 8.4 8.0 62.5 62.5 40.0 28.6 75.0 62.5 100 62.5 100 80.0 100.0 0.0 0.0 (N = 8) (range 6–13) (N = 8) (N = 8) (N = 5) (N = 7) (N = 8) (N = 8) (N = 6) (N = 8) (N = 3) (N = 5) (N = 4) (N = 4) (N = 8) *Throughout the table, N is equal to the total number of cases that reported the data for a given variable. CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; IFA, indirect immunofluorescence assay. Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 e501 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Demographic, clinical, and diagnostic characteristics, separated by location All Cases (N = 46) Mean age (years) Median age (years) Male (%) History of erythema migrans (%) Recalled tick bite (%) Fever (%) Cranial nerve palsy (%) Diplopia (%) Intracranial hypertension (%) Normal MRI/CT (%) Seropositive by ELISA (%) Seropositive by other methods [IFA or unspecified] (%) Both IgG/IgM (%) IgG only (%) Confirmed Western blot (%) 11.7 9.0 61.0 34.2 29.0 26.2 68.4 61.0 95.1 63.6 100 83.3 (N = 41)* (range 4–51) (N = 41) (N = 41) (N = 31) (N = 42) (N = 38) (N = 41) (N = 41) (N = 44) (N = 33) (N = 12) 75.0 (N = 32) 9.4 (N = 32) 63.0 (N = 46) US Only (N = 32) 10.2 9.0 64.3 43.3 27.3 35.5 73.1 71.4 93.8 62.5 100 80.0 Europe Only (N = 14) (N = 28) (range 4–34) (N = 28) (N = 30) (N = 22) (N = 31) (N = 26) (N = 28) (N = 32) (N = 32) (N = 22) (N = 10) 77.3 (N = 22) 9.1 (N = 22) 65.6 (N = 32) 15.0 8.0 53.9 9.1 33.3 0.0 58.3 38.5 100 66.7 100 100 (N = 13) (range 4–51) (N = 13) (N = 11) (N = 9) (N = 11) (N = 12) (N = 13) (N = 9) (N = 12) (N = 11) (N = 2) 70.0 (N = 10) 10.0 (N = 10) 57.1 (N = 14) US 1995 to Present (N = 26) 10.8 9.0 68.2 33.3 21.1 34.6 70.0 68.2 92.3 61.5 100 83.3 (N = 22) (range 4–34) (N = 22) (N = 24) (N = 19) (N = 26) (N = 20) (N = 22) (N = 26) (N = 26) (N = 20) (N = 6) 75.0 (N = 20) 10.0 (N = 20) 80.8 (N = 26) Europe 1995 to Present (N = 12) 16.0 8.0 45.5 11.1 42.9 0.0 60.0 45.5 100 70.0 100 100 (N = 11) (range 4–51) (N = 11) (N = 9) (N = 7) (N = 9) (N = 10) (N = 11) (N = 9) (N = 10) (N = 10) (N = 1) 62.5 (N = 8) 12.5 (N = 8) 66.7 (N = 12) *Throughout the table, N is equal to the total number of cases that reported the data for a given variable. CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; IFA, indirect immunofluorescence assay. other patient was switched from benzylpenicillin to ceftriaxone to allow for outpatient treatment (37). After a full course of ceftriaxone treatment, symptoms in both of these patients completely resolved, with follow-up periods of 49 and 60 days. Eight patients (23%) received oral doxycycline as their initial treatment (22,28,33). Of these 8 patients, only 1 patient (13%) experienced complete resolution of symptoms after treatment with 1 course of 4 mg/kg doxycycline within a maximum follow-up period of 2 months; the duration of doxycycline treatment was not provided (28). Six patients required retreatment, using IV ceftriaxone; 5 patients experienced complete resolution of signs and symptoms after completion of their second treatment within a 2-month follow-up period. For the one case, which adequately reported initial treatment details, 1 month of IV ceftriaxone was given within 1 week of doxycycline treatment, but the patient experienced persistent blindness after 1 year of follow-up (22). Another patient who received between 200 and 400 mg doxycycline per day for 10–14 days as his initial treatment experienced optic disc atrophy and continued visual field abnormalities at the final 1month follow-up period (33). In addition, 1 case report stated that the patient had initially been treated with “a short course of oral antibiotics” but did not fully recover until after retreatment with IV ceftriaxone (36), and another report stated that the patient had initially received “appropriate antibiotics” but experienced incomplete symptom resolution with permanent damage to the optic nerve FIG. 2. Treatment selection and course. *Each bar represents a total number of cases which reported on the use of that particular treatment, normalized to 100%. IV, intravenous. e502 Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (34). The 2 patients who were ultimately diagnosed with optic atrophy had no notable ocular history before being diagnosed with papilledema associated with Lyme disease. They presented with severe papilledema and decreased vision and were found to have optic atrophy at follow-up consistent with postpapilledema optic atrophy (33,36). Over half (N = 19; 56%) of all patients received adjuvant treatment with acetazolamide (Fig. 3). Only 3 patients (9%) received symptomatic treatment with corticosteroids (22,31,36). One patient received IV methylprednisolone and a subsequent course of oral prednisone (22); corticosteroid treatment in the other cases was not described in sufficient detail (31,36). Only one of the patients who received corticosteroids experienced complete resolution (31). This patient received a 30-day course of IV ceftriaxone as first-line treatment. The second patient who received corticosteroids experienced persistent blindness 1 year after treatment (22), and the third patient experienced ongoing optic atrophy and slow improvement of visual acuity (36). Both these patients had been initially treated with oral antibiotics (22,36). all of these patients experienced a palsy of the sixth cranial nerve, and 1 patient experienced palsies of both the sixth and seventh cranial nerves in addition to a severe bulbar palsy (30). Cases Reported Before 1995 Diagnostic/Laboratory Findings Seven patients (88%) presented with positive serology; the indirect immunofluorescence testing method was used in 1 of these cases (30), ELISA was used in 3 cases (18,29), and in 3 cases (10,17), insufficient information was provided to determine the serologic testing method. None of the seropositive cases had explicitly been confirmed by 2-tiered testing by ELISA and Western blot. One patient initially presented with negative serologic results and was treated for LB regardless of the results, but the testing method in this case was not described. Of 8 cases that reported results of CSF analyses, over one-third (N = 3) showed signs of lymphocytic pleocytosis. In the majority of cases (N = 7; 88%), there were no reports of measuring intrathecal antibody synthesis, and in 1 case, the results of CSF analysis for Borrelia-specific antibodies were negative (30). Detection of B. burgdorferi DNA by PCR was not conducted in any case. Clinical Characteristics Of the 8 cases reported before 1995 (10,16–18,29,30), 75% originated in the United States (Table 1). The mean age of these patients was 8.4 years (median 8 years) and 63% were male. All patients were residents of endemic regions, and 63% (N = 5) had documented a history of EM; however, of 5 cases that reported obtaining a tick bite history, only 2 patients recalled that they had experienced a tick bite. Most patients (5 of 7) were afebrile on presentation and experienced headaches. Elevated ICP was diagnosed in 100% of cases (N = 6); raised ICP could not be confirmed in the other 2 cases because it was not adequately reported or measured. Opening pressures documented in cases reporting LP results (N= 4) ranged from 300 mm H2010 to over 500 mm H2017. MRI and/or CT imaging results were normal in most cases (5 of 8). Six patients (75%) had confirmed a palsy of at least 1 cranial nerve; Treatments Four patients (50%) received oral penicillin (10,16,18); of 3 patients on oral penicillin, for whom treatment course was adequately described, none experienced complete resolution of signs and symptoms after this treatment alone (Fig. 2). One of the patients with incomplete resolution had taken oral penicillin for only 5 of the 10 days that it was prescribed and received a subsequent 10-day course of IV penicillin G 1 month later when symptoms persisted; this patient continued to receive maintenance acetazolamide approximately 1 year after initial presentation. Another patient had only received oral penicillin for 4 days with concomitant acetazolamide and was switched to a 10-day course of IV penicillin when headache and photophobia recurred and the opening pressure remained elevated; this patient experienced complete symptom resolution, which FIG. 3. Adjuvant treatment patterns. Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 e503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution was maintained for approximately 8 months of follow-up. (10), The third patient was initially treated with oral penicillin for 10 days and experienced resolution of her presenting symptom of EM but received IV ceftriaxone retreatment about 4 months later when she began to experience persistent diplopia and, papilledema was diagnosed; the patient experienced complete resolution that was confirmed at a follow-up 2 months later (16). Two patients received IV penicillin as their initial treatment; of these 2 patients, only one patient fully recovered after 1 course of IV benzylpenicillin (30), and 1 patient experienced complete symptom resolution after undergoing a second course of IV penicillin G (17). One patient had a particularly unusual presentation of LB involving, besides papilledema, 2 seizures, which were reported as being related to cerebral vasculitis. This patient received 1 course of IV ceftriaxone (in conjunction with phenobarbital) as his initial treatment and experienced complete resolution of signs and symptoms as reported 28 weeks after treatment (29). Two patients received acetazolamide as adjuvant symptomatic treatment (Fig. 3). One of these patients, who had an extremely high opening pressure on presentation (.500 mm H20), was continued on daily acetazolamide (10) Two patients received adjuvant symptomatic treatment with corticosteroids (10,17). Both patients who received corticosteroids experienced complete resolution of their symptoms after 2 courses of antibiotic treatment, with 1 of these patients being the patient described above who received ongoing acetazolamide maintenance (10). Comparison of US Cases vs European Cases (1995–Present) Although the small number of cases precluded any statistically significant conclusions, we did compare US (N= 26) (19228) and European (N= 12) (31,33243) cases, restricting the analysis to cases published in or after 1995, when 2-tier serologic testing was broadly adopted in the United States (Table 2). Clinical and Diagnostic Characteristics Rates of cranial nerve palsy were comparable, largely involving the same nerves. CSF lymphocytic pleocytosis was reported in 22 of 26 US patients and 5 of 9 European patients. Intrathecal antibody synthesis was described in 5 of 14 US patients vs 6 of 7 European patients, likely reflecting differences in the diagnostic criteria used in the United States vs Europe. Eight of 24 US patients recalled EM and 9 of 26 presented with a fever, whereas only 1 of 9 European patients recalled EM and none presented with a fever. Treatments Rates of IV ceftriaxone as initial and second treatments were similar in US and European cases, with consistently high rates of symptom resolution. Interestingly, although all e504 studies of oral doxycycline treatment of neuroborreliosis have been from Europe, this was used as the first-line treatment in 30% of US cases but only 1 European case (33) (notably, 6 of 8 patients treated initially with doxycycline originated from 1 2016 publication (28)). Of the US patients receiving doxycycline initially, 86% were subsequently retreated with IV ceftriaxone; the 1 European patient treated with doxycycline developed optic disc atrophy and continued visual field abnormalities. Use of adjuvant therapy was comparable in the 2 geographic groups; acetazolamide was used in 61% of US patients vs 45% of European patients, whereas corticosteroids were used in just 4% of US patients vs 18% of European patients. Additional Cerebrospinal Fluid Findings (All Cases) Of all 46 cases, 23 cases reported CSF glucose levels, with 9% (N = 2) of these patients displaying glucose levels below the normal range of 45–80 mg/dL (10,22). Of 31 cases that reported CSF protein levels, 45% (N = 14) of patients had elevated values (10,20,22,24–26,28,30,42). Forty-one cases in total reported on lymphocytic pleocytosis, with 73% (N = 30) of these cases showing evidence of this finding. CONCLUSIONS To the best of our knowledge, our study is the largest and most comprehensive review of published reports of papilledema associated with Lyme disease. This review reveals certain clinical characteristics that may help distinguish Lyme papilledema from papilledema of another origin or other diagnostic entities, in particular, from IIH and from nonborrelial lymphocytic meningitis; it also shows a difference in clinical outcomes of such patients depending on the treatment regimen. Clinical Characteristics Generally, papilledema is a manifestation of increased ICP; an increased ICP can also manifest itself in typical symptoms of headache, nausea and vomiting, and diplopia, all of which were commonly observed in the cases assembled in our review. Other common manifestations in our study were cranial nerve palsies, observed in about two-thirds of patients, with predominant involvement of the sixth cranial nerve. These findings could be explained in part by the elevated ICP causing inferior displacement of the pons with traction on the abducens nerve (44). The incidence of sixth and seventh cranial nerve palsies observed in our case set differed from that in other conditions, in particular, IIH, which could help differentiate between papilledema associated with Lyme disease vs IIH. The rate of sixth cranial nerve palsies (50%) in our review was higher than the reported range for IIH of 12% in adults and 9%–47% in children (45). This could potentially be explained with the fact that most patients in our Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution study were prepubertal children who have been reported to have a greater likelihood of sixth and other cranial nerve deficits than older children in situations with an increased ICP (59% vs 39%) (46). Further, some of the cases of sixth cranial nerve palsy in our set may be ascribed to Lyme disease itself, rather than an increase in ICP. Our group of LB cases also had a higher rate of seventh nerve palsies (9%) than the reported incidence of only 2%–6% in pediatric IIH (47). The higher rate of facial palsy in our review is in line with previous observations that this manifestation is one of the more prevalent neurologic abnormalities in both pediatric and adult Lyme disease (48). Therefore, the sixth or/and seventh nerve palsy accompanying papilledema in a patient from an endemic area should point toward a greater likelihood of Lyme disease. All of the patients in our study resided in regions endemic for LB. Despite that, a minority of the patients had a history of tick bite (29%) or EM; EM was reported in 33% of the US patients and only in 11% of European patients with confirmed neurologic LB (1995–present), reflecting the regional differences in cutaneous LB (49,50). Unsurprisingly, the rates of positive reports on both EM and tick bites were noticeably higher pre-1995 than post1995 (Table 1), likely due to differences in diagnostic standards, because EM was once the principal diagnostic feature of LB before more widespread availability of improved serologic testing methods. Diagnostic/Laboratory Findings The most prevalent diagnostic tests or procedures performed in our patients were LP with CSF analysis, brain imaging (MRI and CT scans), and tests aimed at identifying antibodies to B. burgdorferi in the blood and/or CSF. Brain imaging was most commonly conducted to rule out other possible causes of increased ICP and returned normal results in most applicable cases. If brain abnormalities were described, they mostly involved signs of raised ICP (e.g., optic nerve sheath expansion) and a possible inflammatory reaction (e.g., enhancement of dura and/or leptomeninges) or cranial neuritis (e.g., enhancement of cranial nerves III– VII). In contrast to largely normal brain imaging results, the patients’ LPs revealed an increased opening pressure, with CSF analysis typically showing lymphocytic pleocytosis (77% patients) and elevated levels of CSF protein (44% patients), and in some cases, normal to slightly decreased glucose concentrations, consistent with the diagnostic profile of lymphocytic meningitis. Of note, in some patients, in our review, the abnormal CSF findings were only revealed upon a second LP, whereas the first LP appeared “normal.” These results suggest that CSF abnormalities in a pediatric patient presenting with tentative IIH, particularly 1 potentially exposed in a Lyme-endemic area, should raise suspicion for the diagnosis of Lyme disease. Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Discriminating between Lyme meningitis and other causes of lymphocytic meningitis is a diagnostic challenge, especially considering that many patients with neurologic LB have no recollection of either a tick bite or EM. However, it is important to note that both cranial neuropathy and papilledema are significantly more likely to occur in patients with Lyme meningitis than in patients with non-Lyme lymphocytic meningitis; the latter has been observed to have a very low frequency of facial palsy (about 1%) or other cranial nerve palsies and only a 2% rate of papilledema itself (51). Several studies suggested that a longer duration of headache, lower-grade fever, papilledema, predominantly mononuclear pleocytosis of CSF and higher CSF protein levels, and the presence of cranial nerve palsies (the seventh nerve in particular) were predictive of neurologic LB (51–56). An early ex juvantibus treatment with antibiotics has been advocated for patients who display these clinical signs in an endemic area (52). Another diagnostic challenge for a clinician who might suspect Lyme disease as an underlying cause of a patient’s papilledema lies in the accuracy of B. burgdorferi (Bb)-specific diagnostic tests. Although both sensitivity and specificity of serum antibody tests in later stages of neurologic LB approach 100%, in earlier stages (,6 weeks) of neurologic LB, these tests suffer from relatively low sensitivity (57,58). Even intrathecal Bb antibody index (AI)—one of the diagnostic criteria for neurologic LB in Europe—while highly specific, has been reported to have only a moderate sensitivity in early neurologic LB, ranging from 75% to 86% (58,59). Furthermore, there is currently no FDA-approved AI test assay available for the US subtypes of Bb. This disparity was reflected in our results with strikingly different proportions of patients showing evidence of intrathecal antibody production (36% in the United States vs 83% in Europe). Treatments Papilledema can cause permanent visual impairment; hence, prompt treatment is essential (60–63). Patients in our study received 3 major categories of treatments: IV and/or oral antibiotics, acetazolamide, and glucocorticosteroids (GCs). The most common antibiotics administered were IV ceftriaxone and oral doxycycline. Most patients who received IV ceftriaxone (first or second treatment) in our study experienced complete symptom resolution; 100% of patients who received 2–4 weeks of IV ceftriaxone as their initial treatment experienced complete resolution of symptoms. By contrast, 6of 8 (75%) of those patients who initially received oral doxycycline required a retreatment with IV ceftriaxone before symptoms resolved in 5 of them, and 1 more patient was left with substantial negative visual sequelae after a 2-week course of doxycycline (33). This observation seems to be at odds with the results of available randomized (64–66) or nonrandomized trials (67) that e505 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution indicated no significant difference between doxycycline (oral (65,66) or IV (64)) and IV beta-lactam antibiotics (IV penicillin (64,65) or ceftriaxone (66)) in the treatment of neurologic LB (68). However, the conclusions of these trials may not be applicable to the patient population described in our review because none of the patients enrolled in these trials were noted to have an increased ICP and/or papilledema. The poor outcomes after treatment with doxycycline in our review could be explained by the rare, potential deleterious effect doxycycline may have on ICP, which sets it apart from other antibacterial agents used against LB. Doxycycline, along with the other tetracyclines, has been implicated as a potential trigger for secondary intracranial hypertension (69,70). Some case series reporting on the association between tetracyclines and elevation of ICP cited high rates of a sustained visual loss in the affected patients, for example, in 25% of 12 patients with minocyclineassociated elevation of ICP (71) and 5 of 7 with doxycycline-associated elevation of ICP (72). It may be advisable to select IV ceftriaxone over doxycycline in any patient with neurologic LB in whom the disease is complicated with papilledema, to avoid the possibility of any adverse effect on ICP and prolonged harmful impact on the optic disc. GCs were used as an adjuvant treatment in 11% of patients in our case series. The majority (60%) of these patients sustained some degree of residual symptomatology after the treatment. However, the poor outcomes cannot definitively be attributed to the use of GCs because patients in the cases with poor outcomes also received initial treatment with oral antibiotics rather than IV ceftriaxone; furthermore, GCs may have been prescribed in more severely affected patients. Although the use and especially withdrawal of GCs have been associated with increased ICP (69), there have been reports of beneficial effects after GCs treatment combined with repeated LP or acetazolamide in small series of patients with severe acute visual loss due to IIH (73,74). However, usage of GCs in treating IIH has declined in recent years with the preference given to therapy with acetazolamide; this trend was reflected in our case series (75). As to neurologic LB, the 2007 American Academy of Neurology guidelines stated no clear benefit or harm of GCs in this condition insofar as the patients concurrently received appropriate antibacterial agents (76). Nearly half of the patients in our review were treated with acetazolamide, and its use among our cases rose sharply over the recent decades in comparison with the frequency of its utilization before 1995. Virtually, all the patients who were prescribed acetazolamide in our review experienced full recovery. This finding suggests a positive effect of acetazolamide in Lyme-associated papilledema and parallels the conclusions of a recent randomized trial of this medication in IIH that showed a greater reduction of papilledema for acetazolamide over placebo (77), although this outcome did e506 not match the observations made in an earlier pilot study in IIH (78). Whereas evidence is still insufficient as to the extent of the benefit of acetazolamide in IIH (79); the results of our review support the current trend of using this treatment in cases of Lyme disease–associated papilledema. Limitations The results of our study should be interpreted with caution because of its design limitations. This study may be prone to publication bias because it is possible that only particularly challenging cases found their way to publication. Thus, the possibility exists that the frequencies of signs and symptoms observed do not reflect actual clinical trends. As is true for any compilation of case reports, our study also did not allow us to estimate the incidence of papilledema among all patients with Lyme disease or neurologic LB. Furthermore, we had to rely on the accuracy of the original reports regarding clinical details, such as funduscopic examinations, and on the primary authors’ precision in ruling out differential diagnostic entities. In many cases, there was insufficient information provided to fully assess the timeline of treatment(s) and resulting clinical outcome(s). Nevertheless, by presenting an overview of the diagnosis and treatment of Lyme disease–associated papilledema, this study could aid physicians in their clinical practice. CONCLUSIONS Papilledema can be a rare complication or even the most prominent initial manifestation of Lyme disease in various age groups. In patients in Lyme disease–endemic areas who present with papilledema, underlying Lyme disease should be considered, particularly if accompanied by abnormal CSF findings (lymphocytic pleocytosis and/or raised CSF protein levels), low grade fever, and cranial nerve palsies, even in the absence of a history of a tick bite or EM. Clinicians should be aware that serologic antibody tests for Lyme disease and the intrathecal AI offer only modest sensitivity in early stages of neurologic LB (,6 weeks). Although a reliable AI test for the US subtypes of Borrelia burgdorferi has not yet been approved for widespread use by the FDA, the use of validated alternative techniques for assessing AI is widely accepted in US laboratories. Although most cases of papilledema will resolve with treatment, a proportion of patients may suffer permanent visual loss; hence, prompt empirical intervention may be required even before the results of serologic tests become available. IV ceftriaxone may be suggested as the first line antibiotic of choice so as to mitigate the risk of further dissemination of LB and/or exacerbation of elevated ICP and associated symptoms in the event of treatment failure or slower response rate with oral antibiotics. Adjuvant therapy with acetazolamide resulted in favorable outcomes, whereas the role of GCs in treating this patient population is yet unclear. Vaysbrot et al: J Neuro-Ophthalmol 2021; 41: e498-e508 Copyright © North American Neuro-Ophthalmology Society. 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