Ophthalmologic Manifestations of Syphilis
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After a decade of steady decline from 1990 to 2000, syphilis rates in the US have increased in the past few years [1]. The diagnosis of syphilis for an ophthalmologist can be challenging but should be considered in every case of unexplained neuro-ophthalmic findings regardless of sexual history. Serologic testing is low risk and should be considered for this potentially treatable disease.
Disease Entity
Disease
Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Transmission of the disease can occur through small breaks in the skin during sexual contact, or via congenital transmission in utero, either across the placenta or less commonly by contact with an active genital lesion during delivery .[2]
Epidemiology
It is estimated that there are 12 million new cases of syphilis per year, the vast majority of which occur in developing countries. [3]In the United States, the rates of primary and secondary syphilis dropped dramatically between 1990 and 2000[1], but since the year 2000 an increase has been observed in men having sex with men (MSM).[4]
Etiology
Studies in animals have shown that T. pallidum organisms appear in lymph nodes within a few minutes of inoculation and are widely dispersed throughout the body within hours. [5]Ocular manifestations can occur in any stage (primary, secondary, or tertiary). Syphilis has a wide range of targets in the eye, including the conjunctiva, sclera, cornea, lens, uveal tract, retina, retinal vasculature, optic nerve, pupillomotor pathways, and cranial nerves.[1] The likelihood of syphilitic CNS and ocular involvement is increased in HIV co-infection. [4]Ocular syphilis is considered to be neurosyphilis for treatment purposes.
Risk Factors
As syphilis is primarily transmitted sexually, the most important risk factor is sexual contact with an individual carrying the disease. Transmission rates vary widely across studies but are estimated to be about 60%. Syphilis rates are highest among African Americans, and the regions of the US with highest syphilis rates are the South and Northeast.[2]
HIV co-infection has emerged as an important risk factor for syphilitic infection of the eye. In fact, HIV-positive patients may often present with ocular syphilis before the HIV status is known [6]. Additionally, HIV and syphilis tend to cluster in the same groups, particularly MSM. HIV may also modulate immune response to T. pallidum increasing the propensity for progression to neurosyphilis. [6]HIV co-infection makes syphilis more severe and increases the likelihood of syphilitic CNS involvement. Ocular syphilis in HIV patients who are not receiving antiretroviral therapy is more likely to involve both eyes and has more frequent posterior segment involvement. [4]A literature review by Amaratunge et al. identified that all but one patient with isolated anterior uveitis was HIV-positive, giving patients with syphilitic anterior uveitis 14.5 times relative risk to be HIV-positive than HIV-negative. [7]. In summary, any patient diagnosed with syphilis, one may consider testing for HIV as well. Risk factors are similar, and the presence of a genital chancre increases the risk of acquiring and transmitting HIV . [8] Although syphilis can occur in any age, either gender, any race and with any sexual preference, men who have sex with men (MSM) is a major risk factor in the US.
Anatomy
Anterior Segment
Conjunctiva Syphilitic chancres of the lid or conjunctiva in primary syphilis and gummas of the conjunctiva in tertiary syphilis have been described but are rare. Mild conjunctivitis is likely common in secondary syphilis, though often overshadowed by the systemic symptoms of the same time period. A sarcoidosis-like conjunctivitis with granulomas may also occur. In all of these cases, demonstration of the organism is the surest means of diagnosis. [9]
Sclera Though both are rare, isolated episcleritis is more common during the secondary stage and isolated scleritis is more common during the tertiary stage of syphilis (Margo). Syphilitic scleritis may be nodular or diffuse. There are no particular features that would lead one to consider syphilis when encountered with scleritis, so a high level of suspicion is needed to consider this diagnosis .[1]
Cornea Syphilitic keratitis is a unilateral or bilateral inflammation of the corneal stroma that is immune mediated, and neither ulcerative nor suppurative .[8] [2]The inflammatory process can last for years, leading to neovascularization, and leaving behind a scarred cornea with ghost vessels after the inflammation burns out. For these reasons, syphilitic keratitis can severely impair vision. [1]The immunologic mechanism for this is given further credence by the fact that interstitial keratitis is not responsive to penicillin but improves with steroids. [10] Before the advent of antibiotics, most interstitial keratitis was often caused by syphilis, 10% by sexually acquired syphilis and 90% by congenital syphilis [8][1]. Since that time, herpes simplex has replaced syphilis as the most common cause of active interstitial keratitis, while syphilis remains the third most common cause of active interstitial keratitis and the leading cause of inactive interstitial keratitis. [8]
Crystalline Lens The lens can be affected in congenital, secondary, or tertiary syphilis. In most cases, the result is a cataract, [8]most likely due to uveal inflammation .[9]
Posterior Segment
Lee et al. reported that panuveitis is the most common diagnosis in HIV-positive patients, whereas, posterior uveitis is the predominant diagnosis in HIV-negative patients [6]. In a different study, Villanueva reported that out of 20 patients with syphilis 15 had chorioretinitis (posterior uveitis), while three presented with panuveitis, and two with retinal vasculitis [11]. Acute syphilitic posterior uveitis is associated with both central nervous system involvement and HIV co-infection .[12]
Retina Syphilis can present as a necrotizing or non-necrotizing retinitis in the macula, midperiphery and peripheral retina.[1] Patches of retinitis may become confluent and are often associated with a vasculitis and vascular occlusion. Syphilitic retinitis may resemble acute retinal necrosis or progressive outer retinal necrosis, however unlike these mimics syphilitic necrotizing retinitis is only slowly progressive and shows a robust response to intravenous penicillin [1]. Placoid confluent lesions can also occur in syphilis.
Syphilitic necrotizing retinitis was first described by Mendelsohn and Jampol who reported a case of necrotizing retinitis in a young patient who made a full visual recovery with adequate treatment with penicillin .[13] A characteristic feature of syphilitic retinitis is that the lesions heal without disrupting the underlying retinal pigment epithelium .[12]
Retinal detachment: Exudative retinal detachment is an uncommon manifestation of ocular syphilis . Jumper et al. described three cases of exudative retinal detachment and retinal infiltrates associated with syphilis that showed satisfactory response to antibiotic treatment . [14]Visual outcomes were poor (20/400 vision or worse in 5 of 6 eyes) likely due to progression to rhegmatogenous or tractional retinal detachment.[12]
Syphilitic uveitis may also be rarely complicated by tractional and rhegmatogenous retinal detachment (RRD).[15] These cases are commonly complicated by early proliferative vitreoretinopathy, and retinal breaks are typically associated with areas of prior retinitis. Visual outcomes are poor: an analysis of 23 eyes with syphilitic RRD by Shughoury et al. found that 11 of 23 eyes (48%) remained 20/200 or worse despite surgical repair, and only 6 of 23 (26%) attained visual acuity of 20/40 or better.[15]
Retinal blood vessels: Retinal arteries, arterioles, capillaries and veins can all be affected. The range of presentations runs from vascular staining only visible on fluorescein angiography, to vascular tortuosity, perivascular exudation and fibrosis, and obliteration of vessels. Additionally, retinal vasculitis can present as branch retinal vein occlusion .[12][1]
Acute syphilitic posterior placoid chorioretinitis (ASPPC) is a rare manifestation of ocular syphilis that has been described in patients with secondary syphilis. ASPPC lesions are located on the surface of the retina (retinal pigmented epithelium, RPE) at or near the macula. They are placoid, yellowish in color, and have a faded center with stipulation of the adjacent retina. These lesions are the result of inflammation, possibly due to direct invasion of the choriocapillaris by T. pallidum, or by deposition of immune complexes, or perhaps a combination. [12]Differential diagnosis of ASPPC includes acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis, and viral retinitis. Distinguish syphilitic placoids from APMPPE and serpiginous choroiditis by the small, leopard-spot changes in the retinal pigment epithelium seen on intravenous fluorescein angiography after disease resolution. Distinguish from herpetic retinitis by the presence of full-thickness opacified retinal lesions found both in the posterior pole and in the periphery.[16]
Uveal tract: Uveitis is the most common ophthalmologic presentation of syphilis .[8] Syphilitic uveitis can occur as soon as 6 weeks after primary infection, and often follows resolution of other signs of secondary syphilis, or alternatively may be the only systemic sign of syphilis. On the other hand, uveitis may appear years after the initial infection during the late latent stage of syphilis. The manifestations vary widely: inflammation may be granulomatous or non-granulomatous; may involve the anterior segment, posterior segment, or both; and may be unilateral or bilateral .[1] The most common manifestations of inflammation secondary to syphilis reported by Barile and Flynn were granulomatous iridocyclitis (46%), non-granulomatous iridocyclitis (25%), panuveitis (13%), posterior uveitis (8%), and keratouveitis (8%) .[17] Additional findings in syphilitic anterior uveitis consist of iris nodules, dilated iris vessels (roseolae of the iris), iris atrophy, posterior synechiae and lens dislocation . Anterior segment inflammation may remain confined or may present with associated vitritis .[1]
Since the advent of penicillin, syphilis is now considered a rare cause of uveitis. Today, syphilis is thought to compromise less than 1% to 2% of all uveitis cases . As it is difficult to determine syphilitic uveitis simply based on clinical presentation, syphilis may be considered in any unexplained ocular inflammation .[1]
Optic disc: Syphilis can affect the optic nerve in one or both eyes. This mainly manifests as perineuritis, anterior or retrobulbar optic neuritis, and papilledema .[18] These manifestations can appear in the optic disc as neuroretinitis, pallor, or a solid inflammatory lesion . [6]There is no clinical feature to prove syphilitic optic neuritis over non-syphilitic causes. However, it is important to distinguish between syphilitic perineuritis and syphilitic optic neuritis due to the asymptomatic course of the former, and the potential for rapid vision loss of the latter. Syphilitic optic neuritis can be further subdivided into anterior optic neuritis, in which the optic nerve head appears inflamed and is often associated with inflammation in the posterior vitreous, and retrobulbar neuritis in which the optic nerve head may appear normal, but a relative afferent pupillary defect (RAPD) and diminished color vision suggest poor optic nerve function .[12]
Pupillomotor pathways
The Argyll Robertson pupil is a classic finding in syphilis. Argyll Robertson pupils are miotic and do not constrict in response to light but do constrict in response to near vision. This phenomenon, termed light-near dissociation, may result from damage to the ciliary nucleus or the to the neuronal connections between the Edinger-Westphal nuclei and the pretectal nuclei . [1]Though most common late in the disease, it can be seen in early neurosyphilis. [1]Although the Argyll Robertson pupil is the most well known pupil finding in syphilis, tonic pupils and Horner syndrome also can occur in syphilis.
Argyll Robertson-like pupillary findings have been described in patients with multiple sclerosis, diabetes mellitus, alcoholism, and encephalitis. However, true Argyll Robertson can be differentiated by pupil size, which when tonically small are characteristic of neurosyphilis .[9]
Visual and ocular motor pathways
Syphilis can invade the blood vessels, meninges, or the very parenchyma of the central nervous system. Generally, early neurosyphilis shows invasion of blood vessels and meninges. [9]Subtle eye movement abnormalities like saccade velocity and the accuracy of smooth pursuit movements may be present .[19] Late neurosyphilis generally manifests as invasion of the parenchyma . Focal gummas along the nerves, superior orbital fissure syndrome, brainstem infarction, or syphilitic aneurysmal compression or hemorrhage tend to be late manifestations. [9]Additionally, the optic nerve can be involved, with manifestations including optic neuritis, papillitis with or without retinal vasculitis, perineuritis, and neuroretinitis.[1] Of note, while late neurosyphilis may present as either general paresis or tabes dorsalis, pupillary abnormalities are more common in tabes .[9]
Arteritis associated with syphilitic invasion can cause strokes that affect vision and eye movement. Homonymous hemianopsia can be caused by middle or posterior cerebral artery infarction, or by syphilitic basilar meningitis or gummas.[9] Alternatively, progressive visual loss secondary to optic atrophy can be seen as a manifestation of tertiary syphilis. [8]Syphilitic invasion can cause infarction of the posterior inferior cerebellar artery, leading to ipsilateral Horner’s syndrome, Wallenberg’s syndrome, or vestibular nystagmus .[9]
Pathophysiology
Syphilis is divided into four overlapping stages:
Primary: incubation period of ten to 90 days with chancres at the site of inoculation, which due to their painless nature are often not noticed. Chancres are indurated but not tender or purulent and resolve in about 4 weeks . [2]These chancres contain spirochetes, and samples for testing may be taken directly from them.
Secondary: Between four and ten weeks of the initial appearance of the chancre, most patients who do not receive treatment will develop secondary syphilis. The hematogenous dissemination that occurs in this stage can lead to neurologic, ophthalmologic, gastrointestinal, and hepatic disease . [2]The eyes are affected in approximately 10% of cases . The classic description of syphilis includes a diffuse maculopapular rash that includes the palms and soles, and this is in fact the presenting complaint in more than 70% of patients with secondary syphilis. Other symptoms can include fever, generalized non-tender lymphadenopathy, headache, malaise, anorexia, nausea, joint pain, mouth ulcer, and hair loss .[1]
Latent: The latent period exists between the disappearance of the secondary manifestations and either treatment or the development of tertiary syphilis . Early latent describes the time period within a year of initial infection, and late latent the time period after a year since initial infection. Of those patients that are not treated in the latent period, about a third progress to tertiary syphilis.[2]
Gumma: a benign localized granulomatous reaction. Though most frequently found in the skin and mucous membranes, they can involve any part of the body including the choroid and iris. The majority develop within 15 years of the resolution of secondary syphilis but can develop in as little as one year.[2]
Tertiary: Both cardiovascular and neurologic involvement in tertiary syphilis come with substantial risks . Cardiovascular involvement consists of aortitis, aortic aneurysms, aortic valve insufficiency, and narrowing of the coronary ostia. Neurologic involvement includes meningeal, meningovascular, and parenchymatous (tabes dorsalis and general paresis) syphilis .[2]
Jarisch-Herxheimer reaction: When treating syphilis one may consider the effects of the Jarisch-Herxheimer reaction, a systemic reaction to inflammatory lipoproteins from dying T. pallidum organisms . It has been reported to occur in 30 to 70% of patients with early syphilis, 43 to 55% of infants with congenital syphilis, 45% of pregnant patients with syphilis, and 2% of patients with neurosyphilis. The reaction has systemic involvement with fever, headache, pharyngitis, malaise and myalgias. Even leukocytosis with lymphopenia has been reported (Singh). [2]Symptomatic antipyretic and analgesic treatment may be pursued, and use of prednisolone to control symptoms has been described. [20]Reactions do not appear to be modified by pretreatment with antihistamines or initial use of small doses of penicillin .[2] In the case of ocular syphilis, the Jarisch-Herxheimer reaction has been described to cause decreased visual acuity, a swollen optic disc with macular edema and cotton wool spots. On fluorescein angiogram, the investigators found extensive leakage around the right optic disc and areas of non-perfusion in the inferotemporal quadrant.[20]
Diagnosis
Clinical Presentation
Syphilis is called the great imitator because its clinical presentations vary widely and overlap with many other etiologies. For this reason, correct diagnosis of syphilitic infection of the eye requires a high index of suspicion. Additionally, correct diagnosis may be arrived at through recognition of hints in the history and physical exam, including multiple sexual partners, HIV infection, classic physical manifestations of congenital syphilis such as saddle node deformity, painless chancres, or a maculopapular rash that includes the palms and soles.
Syphilitic panuveitis: characterized by superficial retinal precipitates, that are small, creamy-white, and migratory. Differentiate from necrotizing herpetic retinitis by the mildly opacified appearance of SP as opposed to the white appearance of NHR. Another feature of syphilitic retinitis is that the areas of retinal involvement tend to heal with minimal disruption of the retinal pigment epithelium.[21]
Acute syphilitic posterior placoid chorioretinitis (ASPPC): Differential diagnosis includes acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis, and viral retinitis. Distinguish syphilitic placoids from APMPPE and serpiginous choroiditis by the small, leopard-spot changes in the retinal pigment epithelium seen on intravenous fluorescein angiography after disease resolution. Distinguish from herpetic retinitis by the presence of full-thickness opacified retinal lesions found both in the posterior pole and in the periphery . [16]Additionally, a distinctive finding of ASPPC is uniform distribution of outer retinal and inner choroidal inflammation in a discrete oval or circular area of the posterior pole.[21]
Diagnostic tests
Nontreponemal: Classically, VDRL and RPR card test are useful in screening for active disease and antibody quantification. These work by detecting antibodies for mammalian membrane phospholipids like cardiolipin; results are given as a titer level. Because these are sensitive but not specific, positive results may need to be confirmed with treponemal tests .[2]
Treponemal: FTA-ABS (fluorescent treponemal antibody absorption Test), the MHA-TA (microhemagglutination-T. pallidum Test), and the T. pallidum-particle agglutination test detect previous or current infection. Classically, there are performed after non-treponemal tests due to a higher specificity to remove false positives. As treponemal tests are more specific, a positive help rule in the diagnosis. The downside is that these are not qualitative, and cannot distinguish active disease from past infection with syphilis. [2]Syphilis IgG for Treponemal pallidum is often the first test in the reverse algorithm testing for syphilis.
Most authors recommend both treponemal and non-treponemal testing for syphilis in neuro-ophthalmology.
Neurosyphilis: in order to diagnose neurosyphilis, the CSF may be tested . Generally, first with a CSF-VDRL and then a CSF-FTA-ABS if the first test is positive .[8]
Immunoassays: Enzyme immunoassay (EIA) and Chemiluminescence immunoassays (CIA) are more sensitive than RPR. Patients with very early or late infection may be positive by EIA and CIA but negative for RPR. A positive result by EIA or CIA may be confirmed with Treponema Pallidum particle agglutination assay (TP-PA), while a negative treponemal result Is usually sufficient to exclude diagnosis.[21]
Differential diagnosis
Due to the propensity of ocular syphilis to present with a wide variety of manifestations, the differential diagnosis will vary substantially from patient to patient. Generally, one might consider ocular vascular disease, other infectious causes such as ocular herpes, tumors or masses, autoimmune reactions, and trauma.
Management
Antibiotics
Ocular syphilis may be considered a finding of neurosyphilis. Studies have demonstrated that at least 35% of cases of ocular syphilis also have neurosyphilis, based on reactive VLDR of CSF . However a negative CSF study does not necessarily rule out neurosyphilis. Therefore, neurosyphilis protocol may be considered for treatment of all cases of ocular syphilis. Xu et al. found no benefit with co-administration of corticosteroids or immunosuppressants along with antibiotics, though this remains common in practice, and more research is needed to determine whether corticosteroids have a role in patients with severe ocular inflammation or macular edema.[22]
The recommended adult regimen is IV aqueous crystalline penicillin G 18-24 million units per day (either as continuous infusion or 3-4 million units every 4 hours) for 10-14 days. Alternative regimen for adults is procaine penicillin 2.4 million units IM per day and probenecid 500mg PO four times per day, also for 10-14 days.[21]
Steroids
The exception to penicillin use for treatment of manifestations of ocular syphilis is in the case of syphilitic keratitis, which is due to an immune reaction and therefore may be addressed with corticosteroids (Wilhelmus).[23] Orsoni reports successfully treating a patient using dexamethasone 3 times daily.[10]
Prognosis
Though studies addressing this specific question are lacking, Xu reports that factors associated with poor visual prognosis included the time between onset of uveitis and treatment (>12 weeks), longer duration of ocular symptoms (>28 days), presence of macular edema or long-standing optic neuropathy, coinfection with HIV, and poor initial visual acuity. Factors associated with higher success rates included the presence of vasculitis (as detected by fundus fluorescence angiography), anterior uveitis, or neurosyphilis
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Kiss, S., F.M. Damico, and L.H. Young, Ocular manifestations and treatment of syphilis. Semin Ophthalmol, 2005. 20(3): p. 161-7.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Singh AE, Romanowski B. Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev 1999; 12(2):187–209.
- ↑ Hook EW 3rd, Peeling RW. Syphilis control: a continuing challenge. N Engl J Med 2004; 351:122-124.
- ↑ 4.0 4.1 4.2 Gaudio PA. Update on ocular syphilis. Curr Opin Ophthalmol, 2006;17(6), 562-566.
- ↑ Raiziss, G. W., and M. Severac. 1937. Rapidity with which Spirochaeta pallida invades the bloodstream. Arch. Dermatol. Syphilol. 35:1101–1109
- ↑ 6.0 6.1 6.2 6.3 Lee et al. Journal of Ophthalmic Inflammation and Infection (2015) 5:26
- ↑ Amaratunge, B.C., J.E. Camuglia, and A.J. Hall, Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients. Clin Experiment Ophthalmol, 2010. 38(1): p. 68-74.
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Aldave, A.J., J.A. King, and E.T. Cunningham, Jr., Ocular syphilis. Curr Opin Ophthalmol, 2001. 12(6): p. 433-41.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 Margo CE, Hamed LM. Ocular syphilis. Surv Ophthalmol 1992; 37(3):203–20.
- ↑ 10.0 10.1 Orsoni JG, Zavota L, Manzotti F, Gonzales S. Syphilitic interstitial keratitis: treatment with immunosuppressive drug combination therapy. Cornea. 2004 Jul;23(5):530-2.
- ↑ Villanueva AV, Sahouri MJ, Ormerod LD, Puklin JE, Reyes MP. Posterior uveitis in patients with positive serology for Syphilis. Clin Infect Dis. 2000;30(3):479–485. doi:10.1086/313689.
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Dutta Majumder P, Chen EJ, Shah J, Ching Wen Ho D, Biswas J, See Yin L, Gupta V, Pavesio C, Agrawal R. Ocular Syphilis: An Update. Ocul Immunol Inflamm. 2019;27(1):117-125. doi: 10.1080/09273948.2017.1371765.
- ↑ Mendelsohn, AD., Jampol, LM. Syphilitic retinitis. A cause of necrotizing retinitis.Retina. 1984 Fall-Winter;4(4):221-4
- ↑ Jumper JM, Machemer R, Gallemore RP, Jaffe GJ. Exudative retinal detachment and retinitis associated with acquired syphilitic uveitis. Retina. 2000;20(2):190–194.
- ↑ 15.0 15.1 Shughoury A, Carr EW, & Moorthy RS (2023). Rhegmatogenous retinal detachment in syphilitic uveitis: a case series and comprehensive review of the literature. Ocular Immunology and Inflammation, 32(7), 1302–1313. https://doi.org/10.1080/09273948.2023.2238810
- ↑ 16.0 16.1 Chao, J.R., et al., Syphilis: reemergence of an old adversary. Ophthalmology, 2006. 113(11): p. 2074-9.
- ↑ Barile GR, Flynn TE. Syphilis exposure in patients with uveitis. Ophthalmology 1997; 104(10):1605–9.
- ↑ Smith GT. Neurosyphilis with optic neuritis: an update. Postgrad Med J. 2006;82(963):36–39. doi:10.1136/pgmj.2004.020875
- ↑ Rosenhall ULF, Lowhagen G-B, Roupe G: Oculomotor dysfunction in patients with syphilis. Genitourin 63: 83-86, 1989. doi: 10.1136/sti.63.2.83
- ↑ 20.0 20.1 Fathilah J.The Jarisch-Herxheimer Reaction in Ocular Syphilis. Med J Malaysia August 2003; 58(3)
- ↑ 21.0 21.1 21.2 21.3 Davis, J. Ocular syphilis. Current Opinion in Ophthalmology, 2014. 25(6), pp.513-518.
- ↑ Zhang T, Zhu Y, Xu G. Clinical Features and Treatments of Syphilitic Uveitis: A Systematic Review and Meta-Analysis. J Ophthalmol. 2017;2017:6594849. doi:10.1155/2017/6594849
- ↑ Wilhelmus, K. and Jones, D. Adult-Onset Syphilitic Stromal Keratitis. American Journal of Ophthalmology, 2006. 141(2), pp.319-321.[i]
