Differential diagnoses for posterior uveitis include infectious, inflammatory or neoplastic causes. It is best to assume infectious cause in the initial work-up and management of posterior uveitis, as treatment with antibiotic or antiviral therapy often mitigates the disease. And ruling out infectious causes enables safe initiation of immunosuppressive therapy. Herein, we describe the acronym “SSTTEEVE” (sarcoidosis, syphilis, toxoplasmosis, tuberculosis, endogenous endophthalmitis, virus, etc.), which we first proposed in 2013,1 as a potential tool for assessment of some of the most common infectious causes of posterior uveitis.
Sarcoidosis, although not infectious, is a diagnosis that should not be missed. Clinical features of sarcoidosis include vasculitis (traditionally “candle-wax dripping” periphlebitis) and even retinitis mimicking viral retinitis. The diagnosis of sarcoidosis requires high clinical suspicion with the aid of diagnostic indicators including serum profiles (most commonly used) and vitreous sample analysis (less common).2
Current reports suggest that the number of cases of syphilis (Treponema pallidum) is on the rise.3-5 As such, syphilis should be considered high on the differential diagnosis of posterior uveitis and panuveitis.6,7 Specific presentations of ocular syphilis that must be assessed include neuroretinitis, acute syphilitic posterior placoid chorioretinitis (ASPPC), and syphilitic punctate inner retinitis. Nontreponemal (VDRL and RPR) and treponemal (TPPA and FTA-Abs) are useful diagnostic tests for syphilis but should not be used for determining disease severity or response to therapy.
Syphilis with associated neuroretinitis displays inflammation of the prelaminar optic nerve vasculature extending into the retina, and is suggested to be more closely aligned with a disc vasculitis than a retinal vasculopathy.8 Leakage of lipid and protein with exudate accumulation in the peripapillary outer plexiform layer results from the optic nerve vasculitis. Following reabsorption of the serous component of the exudate over subsequent 2-3 week period, a lipid-rich deposit precipitates in the outer plexiform layer of Henle’s layer, which is responsible for the typical macular star appearance, classically associated with cat scratch disease.9
In cases of ASPPC, large, solitary, gray-white or pale-yellowish placoid subretinal lesions with associated central fading and coarsely stippled hyperpigmentation are best seen on fundus autofluorescence (Figure 1). Other key features as seen on fluorescein angiography include early hypofluorescence in the area of the yellowish opacification, which stains late, and a leopard spot pattern of nonfluorescence in the faded regions of lesions.8 Syphilitic posterior uveitis may also present as syphilitic punctate inner retinitis, which has a distinct feature of multiple preretinal/inner retinal white dots and retinal arteriolitis.10
Neurosyphilis may be present in any of the 3 clinical stages of syphilis, particularly in patients with ocular involvement.11 Given the high probability and complications associated with neurosyphilis, a lumbar puncture, followed by a neurosyphilis treatment protocol are recommended for all patients with ocular syphilis.12 A high index of suspicion for neurosyphilis should be present for patients with human immunodeficiency virus (HIV), as they are at a greater risk of developing neurosyphilis.13 It is also important to investigate concomitant HIV infection in all cases of ocular syphilis, due to the increased risk of acquiring and transmitting HIV in these patients.14
Because HIV-positive patients already have cerebrospinal fluid abnormalities, significance of cerebrospinal fluid abnormalities relevant to neurosyphilis may be more challenging to detect.15 Polymerase chain reaction (PCR) analysis of intraocular fluids is particularly useful for patients with collagen vascular disease, advanced age, or HIV infection, where the reliability of serologic testing is limited.16 Treatment for syphilis should be initiated only following a thorough work-up for causes of uveitis and with consideration of the patient’s clinical picture.17
One of the most common causes (30% to 50%) of infectious retinochoroiditis in humans is Toxoplasma gondii.18,19 Clinical features of toxoplasmosis include a lesion of focal necrotizing retinochoroiditis accompanied by vitreous inflammation. The acute lesion often arises from the border of a chorioretinal scar and remains active for up to 16 weeks, and eventually resolves to leave a hyperpigmented scar (Figure 2). Large destructive lesions, punctate inner lesions, and punctate deep lesions may also be seen.
While classic toxoplasmosis retinitis presents with both inner retinal involvement and intense vitritis, punctate outer retinal toxoplasmosis (PORT) is associated with lesions in the deep retinal layers, minimal vitritis, and little spillover of the inflammatory cells into the vitreous cavity.20 On optical coherence tomography (OCT), acute ocular toxoplasmosis may present with retinal thickening and associated macular edema or macular schisis.21 As these lesions heal, significant retinal thinning with excavation of the retinal and subretinal layers including the choriocapillaris may be seen on OCT. These pigmented retinal scars may also serve as a useful indication of previous toxoplasmosis infection.
Papillitis or neuroretinitis are commonly seen in cases of peripapillary toxoplasmosis, another form of toxoplasmosis.22 Toxoplasmosis in immunocompromised patients is more challenging to assess as it may be multifocal and expand into large areas of full-thickness retinal necrosis. Differentiating these lesions from viral retinitis, which is associated with treatment resistance and a poor prognosis, may be challenging due to their similarities in appearance. The clinical presentation of ocular toxoplasmosis may also resemble tuberculosis, sarcoidosis, and Behcet uveitis.23
Tuberculosis is a slowly progressive, chronic, granulomatous infection caused by Mycobacterium tuberculosis.24 For individuals infected, there is a lifetime risk of tuberculosis activation of 5% to 10%, which increases each year of life by 5% for persons living with HIV/AIDS.12 Similar to syphilitic uveitis, tuberculosis can also present as anterior, intermediate, or posterior uveitis.25 Clinical features of ocular tuberculosis in the posterior segment include choroidal tubercles or tuberculomas, subretinal abscess, serpiginous choroiditis, or retinal vasculitis. Choroidal tubercles, suggestive of hematogenous spread of tuberculosis, are small yellow nodules with ill-defined borders that often become pigmented as they heal and scar. Larger solitary tumor-like masses are tuberculomas, which may be accompanied by overlying hemorrhage, exudate, or subretinal fluid, and which may grow vertically or spread diffusely in the choroid.25 Vitritis and sometimes neuroretinitis may also be seen in tuberculosis-related retinal vasculitis. Neovascularization, vitreous hemorrhage, and retinal detachment may result from tuberculosis-periphlebitis with capillary nonperfusion (Figure 3).
Serpiginous-like choroiditis (SLC), tuberculosis-induced hypersensitivity reaction within the choroid or RPE must be considered in patients with classic serpiginous choroiditis (SC) who fail to respond to steroids or immunosuppressive agents.26 In tuberculosis SLC, discrete and noncontiguous multifocal plaque-like choroiditis may be evident. Progression to a contiguous lesion with an active advancing edge similar to SC may also be seen in tuberculosis SLC (Figure 4). The fluorescence pattern associated with tuberculosis choroiditis is similar to that of SC, with early hypofluorescence and later hyperfluorescence or staining of the active border.27
The term “confirmed ocular tuberculosis” is used to describe cases with clinical features and diagnostic evidence of tuberculosis on stain or culture. Given that the evidence of the organism with culture or acid-fast stain is rare, the term “presumed ocular tuberculosis” is most commonly used for cases with a suspected tuberculosis infection. In cases of “presumed tuberculosis,” the patient has clinical features of TB with a positive test for TB (positive skin test, QuantiFERON assay, chest x-ray lesion, or evidence of active extrapulmonary tuberculosis), and no indication for other uveitic entities. This diagnosis is further supported with a positive therapeutic trial of antituberculosis therapy. QuantiFERON assay is a very useful diagnostic test in the diagnosis of tuberculosis-related uveitis.28
Fungi are the most common cause of endogenous endophthalmitis and often associated with Candida albicans.29 Typical features of fungal endophthalmitis include creamy white, well-circumscribed chorioretinal lesions, often in the posterior pole with associated yellow or white fluffy vitreous opacities. Originating from the choroid, these lesions spread through full thickness retina to eventually break through into the vitreous cavity (Figure 5). The classic string-of-pearls configuration is formed by coalesced vitreous fungus balls. Active chorioretinitis lesions develop into chorioretinal scars following treatment. Although not always evident, cicatricial changes may also occur including epiretinal membrane, tractional RD and hypotony from cyclitic membranes.
B-scan ultrasound is helpful in identifying vitritis or chorioretinal infiltrates in cases where the fundus is obscured by vitreous opacities. It is important to differentiate fungal and bacterial causes of endophthalmitis and systemic status of the patient including blood cultures and workup, and patient risk factors, such as bacterial septicemia from wound infections, endocarditis, liver abscess (particularly Klebsiella, which has a very poor prognosis), are valuable in narrowing down the underlying cause of endophthalmitis.30 An emerging technique for detecting the etiology of endogenous endophthalmitis is the use of PCR for the aqueous and vitreous samples.31
The herpes family of viruses (varicella zoster, herpes simplex, cytomegalovirus [CMV], Epstein-Barr) is predominant in cases of viral retinopathy. A careful anterior segment examination is recommended for all cases of suspected viral panuveitis. Corneal sensation with careful inspection of the iris for subtle transillumination defects may help identify underlying herpetic disease. Polymerase chain reaction is most useful for determining the appropriate treatment and quantifying the viral load.32
Acute retinal necrosis (ARN) is primarily caused by herpes viruses as has been shown in studies using both vitreous culture and PCR. It also most commonly presents in immunocompetent patients.33-35 Acute retinal necrosis initially starts with moderate to severe vitritis eventually progressing (5 days to 10 days without treatment) to involve peripheral well-delineated patches of retinal necrosis. Resolution of the active phase causes the retinitis to recede, resulting in pigmentation and scarring with associated retinal atrophy. The formation of a sharp demarcation line between the affected and normal retina has a high risk for retinal tear and detachment (50% to 75%). The leading cause of ARN is varicella zoster virus (rarely CMV and Epstein-Barr) and these patients are often older.36 Acute retinal necrosis caused by herpes simplex virus (HSV) includes patients with HSV-1 who tend to be older than patients with HSV-2, which usually affects younger patients.37
Bilateral disease (known as BARN) occurs in up to 35% of cases usually within 6 weeks. Recent studies have highlighted the clinical utility of anterior chamber fluid PCR in diagnosing ARN, with a reported positive predictive value approaching 99%.38,39 It is important to note that PCR may not be accessible in community settings and may require referral to an academic institution to obtain this test. In this circumstance, clinical suspicion of ARN may be enough to initiate treatment given how rapidly progressive and destructive it can be.
Progressive outer retinal necrosis (PORN) and CMV should be suspected in immunocompromised individuals. In PORN, varicella zoster is almost exclusively the responsible virus agent.40 Progressive outer retinal necrosis evolves to include multifocal lesions throughout the posterior and peripheral retina with opacification of the deep retinal layers, with or without areas of confluence (Figure 6). Perivenular clearing of retinal opacification is also described. In contrast to ARN, macular lesions are seen in up to 32% of PORN cases. There is often minimal or no intravitreal inflammation as patients are immunocompromised and outer retinal involvement predominates. Progressive outer retinal necrosis progresses more rapidly than ARN and is bilateral in up to 70% of cases.41
Fulminant CMV retinitis presents with large areas of hemorrhage and a white, edematous, or necrotic retina. This is in contrast to granular CMV, where more indolent progression occurs and peripheral lesions with minimal edema, exudate, or hemorrhage are seen (Figure 7). Significant perivascular sheathing highlights the third subtype known as frosted branch angiitis (Figure 8). CMV can be further classified based on the area of involvement: zone 1 (within 1,500 mm of the optic nerve or 3,000 mm of the fovea), zone 2 (extends from zone 1 to the equator), and zone 3 (remaining anterior retina terminating at the ora serrata).41 Differentiating between varicella zoster and CMV is essential prior to initiating treatment, as acyclovir is not advised for CMV due to high rates of resistance.42
The final “E,” for “et cetera,” serves as a reminder for all other infectious possibilities, which will be specific to the patient’s clinical presentation.
An algorithmic approach to the extensive differential diagnosis of posterior uveitis may serve as a useful tool in the initial stages of diagnosis and work-up for patients. Careful history, examination and use of relevant diagnostic modalities are critical for an accurate diagnosis, while timely treatment is often curative and may greatly reduce risk of long-term complications. For noninfectious causes of uveitis, treatment with immunosuppressive therapy may be safely initiated once some of the most common infectious etiologies (syphilis, toxoplasmosis, tuberculosis, endogenous endophthalmitis, and viral causes) have been ruled out. RP
- Mandelcorn ED. Infectious causes of posterior uveitis. Can J Ophthalmol. 2013;48(1)31-39.
- Yang SJ, Salek S, Rosenbaum JT. Ocular sarcoidosis: new diagnostic modalities and treatment. Curr Opin Pulm Med. 2017;23(5):458-467.
- US Centers for Disease Control and Prevention. Syphilis statistics. Available at https://www.cdc.gov/std/syphilis/stats.htm .
- Torrone EA, Bertolli J, Li J, Sweeney P, Jeffries WL 4th, Ham DC, Peterman TA. Increased HIV and primary and secondary syphilis diagnoses among young men--United States, 2004-2008. J Acquir Immune Defic Syndr. 2011;58(3):328-335.
- Finlayson TJ, Le B, Smith A, et al. HIV risk, prevention, and testing behaviors among men who have sex with men--National HIV Behavioral Surveillance System, 21 U.S. cities, United States, 2008. MMWR Surveill Summ. 2011;60(14):1-34.
- Tamesis R, Foster S. Ocular syphilis. Ophthalmology. 1990;97:1281.
- Woolston SL, Dhanireddy S, Marrazzo J. Ocular syphilis: a clinical review. Curr Infect Dis Rep. 2016;18(11):36.
- Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology. 1990;97:1288-1297.
- Ray S, Gragoudas E. Neuroretinitis. Int Ophthalmol Clin. 2001;41(1):83-102.
- Wickremasinghe S, Ling C, Stawell R, Yeoh J, Hall A, Zamir E. Syphilitic punctate inner retinitis in immunocompetent gay men. Ophthalmology. 2009;116(6):1195-1200.
- Schöfer H. Early and late syphilis. In: G Gross, Tyring SK, eds. Sexually Transmitted Infections and Sexually Transmitted Diseases. Springer-Verlag Berlin Heidelberg; 2011:151-161.
- Dattner B, Thomas EW, De Mello L. Criteria for the management of neurosyphilis. Am J Med. 1951;10(4):463-467.
- Marra CM. Syphilis and human immunodeficiency virus: prevention and politics. Arch Neurol. 2004;61(10):1505-1508.
- Chesson HW, Pinkerton SD, Irwin KL, Rein D, Kassler WJ. New HIV cases attributable to syphilis in the USA: estimates from a simplified transmission model. AIDS. 1999;13(11):1387-1396.
- Amaratunge BC, Camuglia JE, Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients. Clin Exp Ophthalmol. 2010;38(1):68-74.
- Muller M, Ewert I, Hansmann F, et al. Detection of Treponema pallidum in the vitreous by PCR. Br J Ophthalmol. 2007;91:592-595.
- Villanueva AV1, 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.
- Woods AC, Jacobs L, Wood RM, Cook MK. A study of the role of toxoplasmosis in adult chorioretinitis. Am J Ophthalmol. 1954;37(2):163-177.
- McCannel CA, Holland GN, Helm CJ, Cornell PJ, Winston JV, Rimmer TG. UCLA Community-Based Uveitis Study Group. Causes of uveitis in the general practice of ophthalmology. Am J Ophthalmol. 1996;121(1):35-46.
- Doft BH, Gass DM. Punctate outer retinal toxoplasmosis. Arch Ophthalmol. 1985;103(9):1332-1336.
- Ouyang Y, Pleyer U, Shao Q, et al. Evaluation of cystoid change phenotypes in ocular toxoplasmosis using optical coherence tomography. PloS one. 2014;9(2):e86626.
- Holland GN. Ocular toxoplasmosis: a global reassessment. Part II: disease manifestations and management. Am J Ophthalmol. 2004;137(1):1-17.
- Vasconcelos-Santos DV, Dodds EM, Oréfice F. Review for disease of the year: differential diagnosis of ocular toxoplasmosis. Ocul Immunol Inflamm. 2011;19(3):171-179.
- Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep. 1997;46:1-55.
- Gupta V, Shoughy SS, Mahajan S, et al. Clinics of ocular tuberculosis. Ocul Immunol Inflamm. 2015;23(1):14-24.
- Vasconcelos-Santos DV, Rao PK, Davies JB. Clinical Features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol. 2010;128(7):853-858.
- Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A. Presumed tubercular serpiginouslike choroiditis: Clinical presentations and management. Ophthalmology. 2003;110:1744-1749.
- Zanetti S, Bua A, Molicotti P, Maiore I, Pinna A. QuantiFERON-TB gold assay on plasma for confirmation of presumed tuberculosis-related uveitis. Land GA, ed. J Clin Microbiol. 2016;54(8):2175-2177.
- Sridhar J, Flynn HW Jr, Kuriyan AE, Miller D, Albini T. Endogenous fungal endophthalmitis: risk factors, clinical features, and treatment outcomes in mold and yeast infections. J Ophthalmic Inflamm Infect. 2013;3(1):60.
- Sadiq MA, Hassan M, Agarwal A, et al. Endogenous endophthalmitis: diagnosis, management, and prognosis. J Ophthalmic Inflamm Infect. 2015;5(1):32.
- Sugita S, Kamoi K, Ogawa M, Watanabe K, Shimizu N, Mochizuki M. Detection of candida and aspergillus species DNA using broad-range real-time PCR for fungal endophthalmitis. Graefes Arch Clin Exp Ophthalmol. 2012;250(3):391-398.
- Sugita S, Shimizu N, Watanabe K, et al. Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. Br J Ophthalmol. 2008;92(7):928-932.
- Fisher JP, Lewis ML, Blumenkranz M, et al. The acute retinal necrosis syndrome. Part 1: Clinical manifestations. Ophthalmology. 1982;89(12):1309-1316.
- Culbertson WW, Blumenkranz MS, Pepose JS, Stewart JA, Curtin VT. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology. 1986;93(5):559-569.
- Lewis ML, Culbertson WW, Post JD, Miller D, Kokame GT, Dix RD. Herpes simplex virus type 1. A cause of the acute retinal necrosis syndrome. Ophthalmology. 1989;96(6):875-878.
- Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis: features, management, and outcomes. Ophthalmology. 2007;114(4):756-762.
- Cunningham ET Jr. Uveitis in HIV positive patients. Br J Ophthalmol. 2000;84(3):233-235.
- Tran TH, Rozenberg F, Cassoux N, Rao NA, Bodaghi B. Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol. 2003;87(1):79-83.
- Harper TW, Miller D, Schiffman JC, Davis JL. Polymerase chain reaction analysis of aqueous and vitreous specimens in the diagnosis of posterior segment infectious uveitis. Am J Ophthalmol. 2009;147(1):140-147.
- Kuppermann BD, Quiceno JI, Wiley C, et al. Clinical and histopathologic study of varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1994;118(5):589-600.
- Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101(9):1488-1502.
- Tan BH. Cytomegalovirus treatment. Curr Treat Options Infect Dis. 2014;6(3):256-270.