Optic Disc Edema in Syphilis

Background: Syphilis is an uncommon cause of optic nerve head edema; however, differentiating syphilis from other etiologies of optic nerve head swelling may be challenging. We describe 4 cases of ocular syphilis presenting with swollen optic nerve head(s) without overt signs of intraocular inflammation to better define the phenotypic presentation of this condition to allow its early recognition and treatment and discuss potential pathophysiological mechanisms of syphilitic optic neuropathy. Methods: Retrospective case series of patients presenting to a tertiary neuro-ophthalmology practice with a swollen optic nerve head(s) but no overt signs of intraocular inflammation, which was eventually determined to be secondary to syphilis. Results: Four patients were included in the study. The mean age was 43 years, 2 were women and 2 had bilateral involvement. Two patients had a recent history of skin rash, and one patient was investigated for abdominal pain and elevated liver enzymes. Two patients presented with photopsias and preserved visual function, whereas 2 presented with vision loss. Although chorioretinitis was present in all cases, it was very subtle in all and was only appreciated on fundus autofluorescence (FA) in 3 of 4 cases. Three patients demonstrated evidence of optic perineuritis on neuro-imaging. All patients were treated with a course of intravenous penicillin with a variable degree of visual recovery. Conclusions: Systemic symptoms are common in patients with syphilic optic neuropathy. Optic disc edema as a manifestation of syphilis is usually accompanied by subtle chorioretinitis, which is best appreciated on FA. Optic perineuritis is common in patients with syphilitic optic neuropathy, with its pathophysiology likely similar to meningitis seen in neurosyphilis.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Disc Edema in Syphilis Anna Kabanovski, BHSc, Laura Donaldson, MD, Trishal Jeeva-Patel, MD, Edward A. Margolin, MD Background: Syphilis is an uncommon cause of optic nerve head edema; however, differentiating syphilis from other etiologies of optic nerve head swelling may be challenging. We describe 4 cases of ocular syphilis presenting with swollen optic nerve head(s) without overt signs of intraocular inflammation to better define the phenotypic presentation of this condition to allow its early recognition and treatment and discuss potential pathophysiological mechanisms of syphilitic optic neuropathy. Methods: Retrospective case series of patients presenting to a tertiary neuro-ophthalmology practice with a swollen optic nerve head(s) but no overt signs of intraocular inflammation, which was eventually determined to be secondary to syphilis. Results: Four patients were included in the study. The mean age was 43 years, 2 were women and 2 had bilateral involvement. Two patients had a recent history of skin rash, and one patient was investigated for abdominal pain and elevated liver enzymes. Two patients presented with photopsias and preserved visual function, whereas 2 presented with vision loss. Although chorioretinitis was present in all cases, it was very subtle in all and was only appreciated on fundus autofluorescence (FA) in 3 of 4 cases. Three patients demonstrated evidence of optic perineuritis on neuroimaging. All patients were treated with a course of intravenous penicillin with a variable degree of visual recovery. Conclusions: Systemic symptoms are common in patients with syphilic optic neuropathy. Optic disc edema as a manifestation of syphilis is usually accompanied by subtle chorioretinitis, which is best appreciated on FA. Optic perineuritis is common in patients with syphilitic optic neuropathy, with its pathophysiology likely similar to meningitis seen in neurosyphilis. Journal of Neuro-Ophthalmology 2022;42:e173–e180 doi: 10.1097/WNO.0000000000001302 © 2021 by North American Neuro-Ophthalmology Society Faculty of Medicine, University of Toronto (AK); Department of Ophthalmology and Vision Sciences, Faculty of Medicine (LD, TJ-P, EM); Division of Neurology, Department of Medicine, Faculty of Medicine (EM), University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, FRCSC, Dipl, ABO, University of Toronto, Department of Ophthalmology and Visual Sciences, Department of Medicine, Division of Neurology Chief of Service, Neuro-Ophthalmology 801 Eglinton Avenue West, Suite 301, Toronto, ON M5N 1E3, Canada; E-mail: edward. [e-mail] Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 S yphilis is an infection caused by the spirochete Treponema pallidum and is currently showing a resurgence in many regions of the world including North America. The incidence is particularly high in specific populations including men who have sex with men (MSM) and HIV-positive individuals (1). Clinical manifestations of syphilis are highly variable and it may be challenging to arrive at this diagnosis when the clinician does not have a high index of suspicion. If left untreated, the disease is associated with significant morbidity and mortality. Primary syphilis manifests as a painless ulcer or chancre at the site of inoculation. These lesions are often overlooked and resolve spontaneously. Secondary syphilis presents 6–8 weeks later and results from hematogenous spread of infection. Patients commonly present with generalized symptoms such as fever and malaise, as well as a generalized rash, but may also have ocular, gastrointestinal, musculoskeletal, renal, and neurological symptoms. As these symptoms resolve, the latent phase begins and may last decades. In approximately 15%–40% of untreated individuals the disease progresses to tertiary syphilis, which is characterized by the presence of gummas or tumors of granulation tissue containing T. pallidum affecting any body organ. The most common manifestations involve the cardiovascular and nervous systems (2). Ocular involvement is rare in primary syphilis, although eyelid or conjunctival chancres may occur. In later stages, any part of the eye can become involved. The most common presentation is uveitis, most commonly panuveitis. Chorioretinitis commonly occurs in the secondary stage and can present clinically as acute syphilitic posterior placoid chorioretinis, acute zonal occult outer retinopathy (AZOOR), and necrotizing retinitis (3,4). Optic disc edema may accompany chorioretinitis or uveitis; the optic nerve may also be involved in the form of optic neuritis, perineuritis, or papilledema. Ocular involvement is presumed by most to represent a form of neurosyphilis and should prompt further investigations including neuroimaging and analysis of cerebrospinal fluid (CSF) composition (5). e173 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution We describe a series of 4 cases of ocular syphilis presenting with optic disc edema without overt signs of intraocular inflammation. The differential diagnosis for optic disc edema is broad and must be refined by determining the degree of afferent visual dysfunction and considering associated findings such as chorioretinitis. The pathophysiology of this finding in syphilis is not clearly elucidated, and these cases illustrate that multiple mechanisms may be involved. METHODS Records of all patients seen at a tertiary neuroophthalmology practice since 2015 with a positive rapid plasma reagin (RPR) were reviewed. Patients were included if they presented with unilateral or bilateral optic nerve swelling without overt signs of intraocular inflammation and had infection confirmed with specific antitreponemal antibodies. Results of neuro-ophthalmic examination, including formal visual fields, optical coherence tomography, and fundus autofluorescence, as well as brain and orbital MRI findings and lumbar puncture results were reviewed. Case 2 A 35-year-old man presented with photopsias in the temporal visual field of both eyes for the past 2 months. Three months ago, he experienced flu-like symptoms and noticed a rash on his trunk. Visual acuity was 20/20 in each eye; there was no RAPD. Ophthalmoscopy demonstrated bilateral asymmetric optic nerve head swelling and scattered tiny punctate white dots in the retina (Fig. 2). Fundus autofluorescence demonstrated hyperautofluorescent dots corresponding to white dots seen on retinal examination. There were no cells in the anterior chamber and no vitritis. Visual field testing (Automated 24-2 algorithm) showed only a mild enlargement of the blind spot in the RE. An initial diagnosis of multifocal evanescent white dots syndrome (MEWDS) was made, but further testing revealed a positive RPR titer of 1:256 and positive antitreponemal antibodies. Lumbar puncture (LP) also revealed a positive Venereal Disease Research Laboratory test and mild pleocytosis in CSF. Mild bilateral enhancement of the optic nerve sheath was seen on contrast-enhanced MRI of the brain and orbits. Treatment with IV penicillin was initiated and resulted in complete resolution of his visual symptoms, whereas central acuity remained normal. Case 3 RESULTS Four patients fulfilled the inclusion criteria (Table 1). Two were men, and the mean age was 43 years (range 25–62 years). Bilateral optic nerve involvement was seen in 2 patients. Case 1 A 58-year-old man presented with a complaint of intermittent blurry vision in the right eye (RE) for 4 weeks. He described his vision transiently closing in and a new onset of photopsias and floaters. A skin rash on the upper arms and trunk had been present approximately 8 weeks earlier; otherwise review of symptoms was negative. On examination, visual acuity was 20/20 in both eyes with a very mild right relative afferent pupillary defect (RAPD). Anterior segment examination was normal. Ophthalmoscopy demonstrated a few vitreous cells without significant haze in the RE along with marked optic nerve head edema and peripapillary flame hemorrhages (Fig. 1). Examination of the left eye (LE) was normal. Automated perimetry (Automated 24-2 algorithm) was normal in both eyes. MRI of the brain and orbits revealed very mild enhancement of the right optic nerve sheath seen on postcontrast sequences. Serology testing revealed a positive RPR test (titer = 1:512) and treponemal-specific testing. He was treated with intravenous (IV) penicillin for 14 days, after which his optic nerve edema resolved completely. His visual symptoms resolved, and central acuity remained normal. e174 A 62-year-old previously healthy woman noticed worsening vision in both eyes and new onset of left flank pain 5 months ago. Visual acuity was counting fingers in the RE and 20/400 in the LE. Both erythrocyte sedimentation rate and C-reactive protein were elevated; thus, investigations for giant cell arteritis were initiated. Oral prednisone was started, and she underwent bilateral temporal artery biopsies. When seen in neuro-ophthalmological consultation, vision was hand motions in the RE and 20/50 in the LE. Biomicroscopic examination showed evidence of previous inflammation in the LE with inactive keratitic precipitates and posterior synechiae. There was temporal pallor and mild elevation of optic discs bilaterally (Fig. 3). fundus autofluorescence showed areas of hyperautofluorescence around optic nerves in both eyes. Further investigations were initiated to look for infectious or inflammatory causes of her presentation; however, she returned only 2 weeks later with light perception vision in both eyes and panuveitis. RPR titers came back positive at 1:2048, confirmed with antitreponemal antibodies. MRI of the orbits showed mild perineural enhancement of the right optic nerve. LP showed positive syphilis serology with a mild pleocytosis. Treatment with a 14-day course of IV penicillin and topical steroid drops resulted in resolution of the panuveitis and improvement of vision to hand motion in the RE and 20/50 in the LE. Unfortunately, she later developed a rhegmatogenous retinal detachment in the RE, and despite undergoing vitrectomy and scleral buckle treatment, visual acuity remained unchanged. Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Presentation of 4 cases of ocular syphilis with optic disc edema Case 1 Case 2 Case 3 Case 4 Demographics Laterality Vision at presentation Symptoms 58M Unilateral 20/20 OU 30M Bilateral 20/20 OU 62F Bilateral CF, 20/400 25F Unilateral 20/400, 20/20 OD photopsias and truncal rash Mild Mild vitritis OD Visual fields Normal OU OD BSE and normal OS HIV serology MRI Negative Right ON slightly prominent, with faint enhancement of ON sheath Not done Visual symptoms and edema resolved Negative Mild perineural enhancement OU Bilateral progressive decreased vision and abdominal pain Present OS AC cells, KPs, bilateral vitritis, and punctate hyperAF OD diffuse depression and OS nasal Negative Mild perineural enhancement right ON Blurry vision OD RAPD Other ocular findings Bilateral photopsias and rash on palms and soles None Chorioretinitis OU and punctate hyperAF LP Outcome Indeterminate serology Visual symptoms and edema resolved Positive serology Vision improved to OD HM, OS 20/50, and developed RD in OD Present OD vitritis and chorioretinitis, punctate hyperAF OD central scotoma Negative No contrastenhanced study performed Negative serology Vision improved to 20/50, 20/20 AC, anterior chamber; AF, autofluorescence; BSE, blind spot enlargement; HM, hand motions; KPs, keratitic precipitates; LP, lumbar puncture; ON, optic nerve; OU, both eyes; OD, right eye; OS, left eye; RAPD, relative afferent pupillary defect; RD, retinal detachment. Case 4 A 25-year-old woman presented with blurry central vision in the RE for one month and no other systemic symptoms. Visual acuity was 20/400 in the RE and 20/20 in the LE with a minimal right RAPD. Slit-lamp examination initially showed no anterior chamber or vitreous cells. She had a swollen optic nerve head on the right on ophthalmoscopy. fundus autofluorescence demonstrated numerous hyperautofluorescent dots scattered throughout the posterior pole of the RE (Fig. 4). Formal visual fields demonstrated a paracentral scotoma in the RE and were normal in the LE. RPR titer was 1:32 with positive antitreponemal antibodies. MRI of the brain and orbits was performed without contrast and did not demonstrate any obvious abnormalities. She received a 14-day course of IV penicillin and vision improved to 20/50 in the RE. DISCUSSION There is paucity of literature about the phenotypic presentation of patients with syphilitic optic neuropathy. Thus, this study was aimed at collecting historical and examination data on patients presenting with optic nerve head swelling without overt signs of intraocular inflammation, which was later determined to be secondary to syphilis. We also attempted to better understand the mechanism of optic nerve swelling caused by syphilis. Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 Three of 4 patients included in this series had systemic manifestations of secondary syphilis on history taking: 2 had a recent history of skin rash and one was recently investigated for abdominal pain and elevated liver function tests. Three of 4 patients were in the high-risk group for syphilis: 2 were men who had sex with men and one eventually disclosed that she was a sex worker. However, none of the patients disclosed this during their first visit and only provided this information after learning about their positive syphilis serology. Two of the patients had photopsias as a main presenting complaint and had normal visual function (normal central acuities and normal formal visual fields); they both had an excellent visual outcome. Two other patients had severely decreased acuity with an obvious RAPD at presentation. Although all patients eventually developed various degree of vitritis or chorioretinitis, it was either very subtle or absent at presentation. All 3 patients who had fundus autofluorescence performed at their first visit demonstrated abnormal autofluorescence signifying that subtle chorioretinitis was present despite absence of obvious signs of posterior segment inflammation. Three of the patients included in this series demonstrated perineuritis on neuroimaging. Although not every case of syphilitic optic neuropathy has definitive evidence of CNS disease, such as positive syphilis serology in the CSF, most clinicians consider ocular syphilis to be either coincident with neurosyphilis or a limited form of it. Optic nerve involvement usually occurs in the secondary and early latent phase of infection that corresponds to the early e175 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Case 1. A. Optical coherence tomography of the peripapillary RNFL showing marked edema of the right optic disc. B. 24-2 visual field testing with enlargement of the blind spot in the right eye. C. Postcontrast T1 axial fat sat MR image showing very subtle enhancement of the right optic nerve sheath (arrow). D. Fundus photograph of the right disc edema with peripapillary hemorrhages. phase of neurosyphilis, syphilitic meningitis (6). Thus, one likely mechanism for optic neuropathy in patients with syphilis is the direct involvement of the optic nerve’s meningeal sheath by the infection-causing optic perineuritis, which was seen on neuro-imaging in all 4 patients in our series (7,8). A second potential mechanism for optic disc edema with preserved visual function in patients with syphilis is papillitis secondary to intraocular inflammation. Transient swelling of the optic nerve head is often seen in the setting of posterior uveitis or vitritis and has been reported to have a favorable visual outcome in ocular syphilis. Optic disc edema in patients with syphilis is e176 also often accompanied by other signs of ocular inflammation as was true in our case series, although posterior uveitis in all of our patients was very subtle, likely involved the choroid and was only appreciated on fundus autofluorescence (9,10). Disc edema with normal afferent visual function is also seen in papilledema that can be asymmetric; however, none of our patients had symptoms or neuroimaging signs of increased intracranial pressure. Syphilitic disc edema has also been described in the absence of any intraocular inflammation, elevated intracranial pressure, or radiologic evidence of perineuritis; however, fundus autofluorescence was not described in Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Case 2. A. Optical coherence tomography of the peripapillary retinal nerve fiber layer showing marked edema of the right optic disc with more mild swelling in the left. B. 24-2 visual field testing with enlargement of the blind spot in the right eye. C. Postcontrast T1 axial fat sat MR image showing subtle enhancement of the bilateral optic nerve sheaths (arrows). D. Asymmetric disc edema was apparent on fundus photographs (above) and fundus autofluorescence (E, below) showed small punctate foci of hyperautofluorescence bilaterally in the posterior pole. Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 e177 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Case 3. A. Optical coherence tomography of the peripapillary retinal nerve fiber layer showing bilateral optic disc edema. B. 24-2 visual field testing revealed diffuse depression in the right eye with more peripheral loss in the left eye. C. Postcontrast T1 axial fat sat MR image showing enhancement of the right optic nerve sheath (arrow). D. Both optic discs demonstrated temporal pallor and mild elevation. E. Fundus autofluorescence showed hyperautofluorescence in the peripapillary region bilaterally. e178 Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Case 4. A. Optical coherence tomography of the peripapillary retinal nerve fiber layer showing right optic disc edema. B. There was enlargement of the blind spot in the right eye. C. Optical coherence tomography of the macula revealed disruption of the outer retinal architecture with loss of the ellipsoid zone. D. Fundus photographs showing right optic disc edema. E. Fundus autofluorescence demonstrating multiple hyperautofluorescence dots scattered throughout the posterior pole of the right eye. Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 e179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution these patients, thus subtle chorioretinitis could have been missed (11). An ischemic mechanism of optic nerve edema in patients with syphilitic optic neuropathy is also possible if syphilisinduced vasculitis involves posterior ciliary arteries supplying the optic nerve head. In the retina where vessels are more readily imaged using fundus photography and fluorescein angiography, a wide spectrum of retinal vasculitis secondary to syphilis has been described with perivascular inflammatory infiltrates causing arterial narrowing, thrombosis, and occlusion (12–14). Syphilis has been well described to mimic outer retinal disorders, specifically multiple evanescent white dot syndrome (MEWDS) and AZOOR (4,15,16). Both of these conditions are characterized by chorioretinitis and characteristic findings on fundus autofluorescence. Optic nerve head edema can be present in both MEWDS and AZOOR where photopsias is the predominant symptom (17–19). Photopsias were the main presenting symptom in Case 1 and 2 in our series, and in all 3 cases where fundus autofluorescence was performed, abnormal hyperfluorescent spots were seen, most strikingly in Case 4. Although our conclusions are limited by the small number of subjects due to the rarity of syphilitic optic neuropathy, this series demonstrates that outer retinopathy is likely very common in patients with ocular syphilis explaining their frequent complaint of photopsias. Fundus autofluorescence is a very useful test in evaluating patients with suspected syphilitic optic neuropathy and is expected to demonstrate abnormalities consistent with subtle chorioretinitis. Optic perineuritis is also very common on neuro-imaging and is likely explained by the meningeal involvement of the optic nerve sheath by syphilis. CONCLUSIONS Syphilis with ocular involvement is immediately visionthreatening and is associated with long-term ocular and systemic complications. Early recognition is critical as antibiotic treatment is curative. Although patients at high risk for syphilis should all be screened, many would not volunteer pertinent historical details at the first visit. Patients with optic disc edema complaining of photopsia should all be investigated for syphilis. Fundus autofluorescence is a high-yield test in investigating patients with suspected syphilitic optic neuropathy likely signifying a varying degree of chorioretinitis. Mechanisms of optic disc edema in patients with syphilis likely include meningeal involvement of the optic nerve sheath (optic perineuritis), varying degree of posterior uveitis, and posterior ciliary artery vasculitis producing ischemia of the optic nerve head in more severe cases. e180 STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson; b. Acquisition of data: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson; c. Analysis and interpretation of data: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson. Category 2: a. Drafting the article: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson; b. Revising it for intellectual content: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson. Category 3: a. Final approval of the completed article: E. Margolin, T. Jeeva-Patel, A. Kabanosvki, and L. Donaldson. REFERENCES 1. Choudhri Y, Miller J, Sandhu J, Leon A, Aho J. Infectious and congenital syphilis in Canada, 2010-2015. Can Commun Dis Rep. 2018;44:43–48. 2. Peeling R, Mabey D, Kamb M, Chen X, Radolf JD, Benzaken AS. Syphilis. Nat Rev Dis Primers. 2017;3:17073. 3. Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology. 1990;97:1288–1297. 4. Lima BR, Mandelcorn ED, Bakshi N, Nussenblatt RB, Sen HN. Syphilitic outer retinopathy. Ocul Immunol Inflamm. 2014;22:4–8. 5. Dai T, Wu X, Zhou S, Wang Q, Li D. 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Acute idiopathic blind spot enlargement and acute zonal occult outer retinopathy: potential mimics of neuro-ophthalmic disease. J Neuroophthalmol. 2020;40(Suppl 1):S43–S50. Kabanovski et al: J Neuro-Ophthalmol 2022; 42: e173-e180 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.