Uveitis Masquerade Syndromes

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Article initiated by:

Erin Jennings, Robert H. Janigian, Jr. M.D.

All contributors:

Robert H. Janigian, Jr. M.D., Marissa Larochelle, MD

Assigned editor:

Marissa Larochelle, MD

Review:

Assigned status Update Pending

 by Marissa Larochelle, MD on February 25, 2024.

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Contributing Editors:	add

In 1967 the term “masquerade syndrome” was first used by Theodore to describe a case of conjunctival carcinoma that presented clinically as chronic conjunctivitis. Since that time, this term has been utilized to describe a number of ophthalmologic pathologies that mimic intraocular inflammation. Specifically, the Uveitis Masquerade Syndromes (UMS) include systemic and ocular pathologies that manifest with intraocular infiltrating cells, which are not secondary to an immune-mediated or infectious process. Generally, UMS can be divided into two groups: neoplastic and non-neoplastic. These include a wide range of pathologies, including hematologic malignancies, chronic retinal detachment, intraocular foreign body, and retinal ischemia, amongst others. 

Disease Entity

The relative paucity of cases, in addition to common misdiagnosis and a dearth of published reports on UMS cases, has made it challenging to accurately report epidemiology and clinical characteristics of UMS. However, there have been two large retrospective studies within the literature that reported frequency of masquerading syndromes within large uveitis centers. In 2001 Rothova found that UMS was diagnosed in 5% of patients within a tertiary uveitis clinic (40/828 patients), and furthermore 48% of those UMS cases were found to have intraocular malignancy (19/40 patients). Similarly Grange reported a UMS prevalence of 2.5%, as 21/853 patients reporting to the National Eye Institute with uveitis between 2004 and 2012 were diagnosed with a neoplastic masquerade syndrome.

Disease

While rare, Uveitis Masquerade Syndromes represent an important clinical entity. Awareness of the clinical conditions and presentations that mimic uveitis, and timely diagnosis of the underlying pathology, is essential to preserve visual acuity, and, in cases of neoplastic masqueraders, can be life-saving. Masquerade syndromes can mimic more common ocular inflammatory conditions such as sarcoidosis, toxoplasmosis, syphilis, tuberculosis, intermediate uveitis, acute retinal necrosis, birdshot chorioretinitis and idiopathic retinal vasculitis. Herein we provide an overview of the conditions that can mimic uveitis, with a focus on clinical presentation, incidence, and clinical strategies for appropriate and timely diagnosis. 

Etiology

Neoplastic Masquerade Syndromes 

Intraocular lymphomas

Primary Intraocular Lymphoma (PIL), otherwise known as primary vitreoretinal lymphoma (PVRL) is a subset of Primary CNS Lymphoma (PCNSL) where ocular symptoms represent the initial clinical findings.  PVRL is the most common intraocular lymphoma, and also constitutes the majority of neoplastic uveitic masquerading syndromes, representing 75% of the malignant UMS cases documented in the reports of Grange and Rothova (30/40).

Primary Uveal Lymphoma

Primary Uveal Lymphoma is an exceptionally rare type of intraocular lymphoma involving the choroid, iris, or ciliary body. Typically of B-cell origin, uveal lymphoma is classified as primary when the uvea is the initial or only site of neoplastic infiltration. Much like PVRL, primary uveal lymphoma has a wide range of non-specific symptoms and can masquerade as multiple ocular conditions, including the various uveitides. However this condition differs from vitreo-retinal disease as presentation is often low-grade and non-aggressive, rarely manifesting systemically. 

Leukemia

Leukemia is an umbrella term that describes a group of several hematologic malignancies of white blood cell (WBC) origin, generally arising from either myeloid or lymphocytic cell lines. Ophthalmic manifestation is extremely common, as up to 90% of leukemic patients have reported ocular involvement. Furthermore, ocular manifestation is highly variable, as leukemia can infiltrate almost any ocular tissue. This occurs by direct infiltration of neoplastic cells,  secondary involvement by non-viable or dysplastic cells, or by complication arising from hematologic abnormalities and increased risk of opportunistic infection.  With the advent of innovative and successful treatments, there has been significant improvement in survival rates which have contributed to increased variability of presentation.              

Metastatic Solid Tumors

Intraocular metastases is the most common type of intraocular malignancy, with an estimated incidence 20,000 cases per year in the United States. Ocular metastases tend to effect the most high vascularized regions of the eye, most notably the uveal tract. This tendency to involve the choroid can thus mimic various ocular inflammatory conditions such as posterior scleritis and granulomatous diseases.

Non-Malignant Masquerade Syndromes

Intraocular Foreign Body

These injuries vary widely in presentation based on the ocular region involved, type of foreign body, momentum of object and associated complications. While occult, penetrating injuries are typically recognizable in a patient with a history of eye trauma, a high index of suspicion and early intervention of IOFB is crucial. Sustained foreign bodies, particularly heavy metals of iron and copper, can lead to rapid retinal degeneration and severe visual loss. Furthermore, missed IOFB can have prolonged and atypical symptom presentation, including chronic anterior or posterior segment inflammation, often mimicking uveitis and further confounding the diagnosis.

Pigment Dispersion Syndrome

Pigment Dispersion Syndrome (PDS) is an ocular disorder in which friction between the posterior surface of the iris and the lens zonules causes a release of pigment and cells into the anterior chamber. Pigmented debris can deposit on the corneal endothelium, trabecular meshwork, iris or lens. PDS can be acute, progressive, or insidious in nature and symptoms of pigment dispersion syndrome often mimic that of acute anterior uveitis.

Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is a rare, heterogeneous, group of inherited retinal dystrophies resulting in progressive photoreceptor and retinal pigment epithelium  (RPE) cell death. The name is a misnomer as retinitis implies inflammation but studies show there is very little inflammation associated with this disease. However, due to its association with a large number of genes, presentation can vary and can often mimic that of uveitis. Common findings in RP include the presence of cystoid macular edema and cells or debris in the vitreous, and hypopigmentation and mottling of the RPE, all of which findings in various forms of uveitis. In patients with this particular combination of clinical findings, misdiagnosis of intermediate uveitis can be made.

Ocular Amyloidosis

Ocular amyloidosis describes a heterogeneous group of diseases in which amyloid, a misfolded insoluble protein, accumulates in the extracellular space and deposits in ocular tissue and adnexa. Deposition of amyloid has been reported in essentially all parts of the eye and orbit, and therefore presentation varies widely. Amyloidosis can be systemic or localized, and acquired or hereditary in nature. Ocular involvement can be the first clinical sign of systemic disease. Involvement has been reported to be onset dependent, with conjunctival and lacrimal involvement in early onset disease and corneal opacities, vitreous opacities and glaucoma in late-onset disease. Amyloid deposition in the trabecular network can cause a secondary glaucoma and can resemble anterior uveitis both clinically and on exam. One should suspect ocular amyloidosis when an anterior uveitis is refractory to corticosteroids, if there is further systemic involvement, or there is a family history of amyloidosis.

Ocular Ischemic Syndrome

Ocular ischemic syndrome (OIS) occurs as a result of chronic ocular hypoperfusion due to stenosis or occlusion of the common or internal carotid arteries. Approximately 2/3 of patients with OIS develop iris neovascularization. Angle involvement and secondary glaucoma occurs in 50% of cases. Of these patients, 20% are found to have inflammatory cells in the aqueous chamber mimicking immune mediated anterior uveitis. Elevated VEGF levels resulting in increased vascular permeability is thought to play a role.

Retinal Detachment

Rhegmatogenous retinal detachments (RRD) have the potential to present as a masquerade in both the acute and chronic form. While rare, this atypical presentation typically consists of proliferative vitreoretinopathy associated with intraocular inflammation, hypotony, and choroidal detachment. In the setting of severe inflammation, identification of retinal breaks can be especially challenging due to posterior synechiae formation. Therefore, one must always consider retinal detachment in the setting of ocular inflammation, particularly in patients that have a contralateral rhegmatogenous pathology, or have negative labs that would indicate immune mediated uveitis.  While RRD is typically associated with low intraocular pressure, Schwartz-Matsuo syndrome is a condition where one sees elevated pressure with cells in the anterior chamber likely representing photoreceptor outer segments and inflammatory cells.

Pediatric masqueraders

Retinoblastoma

Retinoblastoma is the most common pediatric intraocular malignancy, with a reported incidence ranging from 1 in 15,000 to 18,000 live births. The diffuse form of the disease can manifest as a devastating uveitic masquerader. While retinoblastoma typically presents with leukocoria and strabismus, the infiltrating subtype typically lacks these common manifestations and can present with a variety of symptoms typical of anterior or posterior uveitis, which often leads to misdiagnosis. In a report by Shields et al that investigated 1507 patients of retinoblastoma, 9% of cases of the diffuse subtype were originally referred with a diagnosis of uveitis.  

Coats Disease

Coats Disease is a rare, idiopathic ocular disorder which is characterized by abnormal retinal vessel development (retinal telangiectasia) with associated exudates and hemorrhage. Coats disease typically occurs in young males in the first or second decade of life, and is typically unilateral in nature (95-100%). Clinical presentation has a wide variance which leads to common misdiagnosis and loss of vision.  Accompanying ocular inflammation can simulate uveitis and therefore in a young patient presenting with atypical uveitis associated with vision loss and retinal vascular findings, it is crucial to incorporate Coats into the overall differential.

Juvenile Xanthogranuloma (JXG)

A rare pediatric systemic condition, with 40-70% of cases being congenital or appearing within the first year of life. This is a dermatologic condition belonging to a class of non-Langerhans cell histiocytosis, with a reported association with neurofibromatosis type 1 (NF-1). JXG is typically benign and self-limiting in nature and with typical cutaneous manifestations, while ocular lesions occur in up to 10% of patients. Common clinical manifestations in ocular patients include iris granulomatous lesions, heterochromia, hyphema, glaucoma and masquerading anterior uveitis.JXG can rarely have posterior segment findings leading to blindness, and should be ruled out in any pediatric case with atypical uveitis unresponsive to therapy, especially when there is an accompanying lid or iris mass or hyphema on examination. 

Medulloepithelioma

A rare, non-hereditary neoplasm of childhood thought to arise from primitive cells of the medullary cavity. The neoplasm most often originates unilaterally in the ciliary body, specifically within the non-pigmented ciliary epithelium. Neoplasms typically appear in patients between 2 and 10 years of age, and presentation includes loss of vision, pain, conjunctival injection and leukocoria. The tumor can “hide” for extended period of time within the ciliary body region, thus creating secondary manifestations that include cataract, glaucoma, and uveitis.Patients are often treated for the secondary problem, allowing for the neoplasm itself to go undiagnosed for significant periods of time, leading to extraocular extension of the tumor adversely affecting the prognosis.

Epidemiology/Risk Factors

Primary Vitreoretinal Lymphoma: Rare disease, with an annual incidence of approximately 1 per 100,000 persons, typically affecting women in their 5th-6th decade of life but some studies show no gender predilection. Immunodeficiency and immunosuppression are risk factors. Incidence is rising possibly because of increased use of immunosuppressive medications and better diagnostic tools. Up to 25% with primary CNS lymphoma will have ocular involvement. Most patients who present exclusively with ocular involvement, even with no CNS symptoms, will develop CNS lymphoma.

Metastatic Solid Tumors: Approximately, 8-10% of patients with metastatic disease have ocular involvement, and in about 30% of cases, intraocular metastasis can be the first sign of systemic tumor dissemination. Incidence is rising because of aging population and greater survival of stage IV patients.

Intraocular Foreign Body: Intraocular foreign bodies (IOFB) are seen in 17-40% of penetrating eye injuries, and account for 18-41% of all open-globe injuries.

Pigment Dispersion Syndrome: Incidence of PDS is approximately 4.8 per 100,000 of the population. The prevalence of PDS in a population screening was 2.45%.

Retinitis Pigmentosa: One of the most common retinal genetic disorders (1 in 4,000); a leading cause of blindness in people under the age of 40.

Juvenile Xanthogranuloma: JXG most commonly develops in infants younger than 2 years of age but has been found in older children. Ocular involvement in 0.3%-10% of patients with cutaneous JXG.

Medulloepithelioma: typically occurs in first decade of life with no gender or race predilection.

General Pathology

• 98% of PVRL cases are non-Hodgkin B cell lymphomas. Cytological specimens show pleomorphic cells with large hyperchromatic nuclei and scanty basophilic cytoplasm.
• Amyloidosis: Fibrillar appearance on electron micrography with amorphous eosinophilic appearance on hematoxylin and eosin staining, and Apple-green birefringence on Congo red histological staining.
• Juvenile xanthogranuloma: foamy histiocytes, lymphocytes, fibroblasts and multinucleated giant cells, including Touton-type giant cells.

Diagnosis

A high index of suspicion is of paramount importance particularly in older patients presenting with their first episode of uveitis and in situations where there is initial response to steroid with subsequent resistance. Any patient with uveitis and a history of carcinoma (particularly breast or lung) or hematologic malignancy should be approached cautiously.

History

Primary vitreoretinal lymphoma: Onset is typically insidious and presentation includes a spectrum of non-specific symptoms, and varies based on the site of intraocular invasion (vitreous, retina, retinal pigment epithelium, or optic nerve). When involving the vitreous, symptoms similar to intermediate uveitis prevail including floaters and blurred vision but may be asymmetric. While rare, awareness of disease characteristics is of utmost importance to ophthalmologists, as the variance in clinical presentation allows for mimicry of anterior, intermediate, and posterior uveitis, along with a variety of other ocular diseases. 

Physical examination

Primary vitreoretinal lymphoma: Vitreous cellular infiltration and anterior cells of variable degree is often the only evidence of disease in this malignancy, and thus a presumptive diagnosis of uveitis is often made with steroids as the treatment of choice. However, steroid use can temporarily quell signs and symptoms, ultimately contributing to delay in diagnosis.  Posterior segment findings include creamy yellow/white subretinal infiltrates similar to sarcoidosis or "white dot syndromes"; retinal infiltrates can mimic retinitis and perivascular infiltrates can resemble frosted branch angiitis or retinal vasculitis.

Primary uveal lymphoma: The dominant clinical feature seen on clinical exam was that of yellow-white choroidal infiltrates, demonstrated in 100% (34/34) eyes examined. 22% of patients of patients studied were initially treated with steroids for a presumed uveitis or similar inflammatory condition. Much like PVRL, many patients respond initially to these steroid treatments, further altering the clinical picture and adding to a delay in diagnosis.

Leukemia: In the anterior segment specifically, direct neoplastic infiltration or secondary responses can induce nonspecific inflammation that can easily mimic that of anterior uveitis. However, there are several overt anterior chamber manifestations that are more indicative of a malignant etiology. Perhaps the most recognizable finding is that of pseudohypopyon, which has been reported in conjunction with ALL, AML, and CML.  These leukemic hypopyons differ in presentation from an inflammatory hypopyon as they can be bilateral, viscous, and are often bloodstained.Other anterior segment findings indicative of leukemia include iris infiltration with associated heterochromia, iris nodules and elevated IOP due to infiltration of the trabecular network. The most common ocular manifestations of leukemia are seen on the retinal exam. Common clinical findings include cotton wool spots and white centered retinal hemorrhages similar to Roth spots, thought to be formed by aggregation of fibrin and white blood cells. Retinal vein tortuosity and dilation is also often present on exams, likely due to hyperviscosity and direct cellular infiltration of the vessel wall can mimic retinal vasculitis. Serous retinal detachment has also been described, which can VKH and posterior scleritis.

Metastatic Solid Tumors: Choroidal involvement is most common manifesting as creamy white or pale yellow choroidal mass associated with subretinal fluid - may be multifocal and bilateral. Iris metastases, in particular, tend to present as a uveitis masquerader. Iris metastases are exceptionally rare, but have been reported in conjunction with primary breast, lung, colonic, prostate, kidney, and gastric adenocarcinomas. Patients with iris metastases typically manifest with eye pain, iridocyclitis, hyphema, or secondary glaucoma.

Intraocular Foreign Body: Very careful ocular exam looking for entrance wound. Gonioscopy, scleral indentation (if permissible and safe) may help identify a small IOFB.

Pigment Dispersion Syndrome (PDS): pigment granules can mimic that of inflammatory cells within the anterior chamber, further confusing the diagnosis. However, there are several clinical characteristics that one should be aware of that differentiate this clinical entity from anterior uveitis including the presence of Krukenberg spindles, iris transillumination defects, iris concavity, and pigmentation in the trabecular network.

Retinitis pigmentosa: Vision varies from 20/20 to LP, Mild vitreous cell, attenuated retinal arteries, waxy pallor of optic nerve, varying degree of bone spicules in mid periphery, cystoid macular edema, posterior subcapsular cataract.

Ocular Ischemic Syndrome (OIS): Anterior segment findings include iris neovascularization; cell and flare - although flare is more prominent. Retinal findings include mid peripheral dot/blot hemorrhages, cotton-wool spots, attenuated arteries and dilated veins.

Retinal detachment: Anterior chamber shows cell/flare associated with low IOP particularly if PVR is present. Otherwise varying degree of cell with Schwartz-Matsuo syndrome associated with high IOP. Dilated fundus exam may show shallow retinal detachment with anterior break in patients with Schwartz-Matsuo syndrome.

Retinoblastoma: Pseudohypopyon due to infiltrative neoplastic cells with associated flare and hyphema, secondary glaucoma due to infiltration of the trabecular network, vitreous seeding, iris neovascularization, and serous retinal detachment.

Coats Disease: Telangiectasia most prominently located in the inferior and temporal quadrants extending from equator to ora serrata, decreased visual acuity (<20/200),  xanthocoria, strabismus, and retinal detachment and exudation as the disease progresses.

Juvenile xanthogranuloma: Iris is most commonly affected although can see lesions on lids and conjunctiva, in orbit and rarely in retina/choroid. Unilateral iris lesions can mimic uveitis and appear yellow, vascularized and raised.

Medulloepithelioma: May present with cataracts, lens subluxation, retrolental membrane and iris neovascularization with secondary neovascular glaucoma.  Tumor is in the region of the ciliary body and appears whitish-pink in color. May be associated with uveitis, hyphema, vitreous hemorrhage.

Symptoms

Primary vitreoretinal lymphoma: Onset is often subtle and insidious. While preexisting CNS involvement is common (16-34% of cases), systemic findings are typically absent. Although presentation varies widely between patients, documented clinical observations can aid in a timely diagnosis. Often masquerades as chronic posterior uveitis, causing blurred vision (40-50%), decreased visual acuity (25-30%), floaters (20-25%), bilateral involvement (60-90%), and vitreous cells on exam.

Metastatic Solid Tumors: Pain, visual field defects, and blurred vision are among the most common presenting symptoms. 

Pigment Dispersion Syndrome: PDS can be acute, progressive, or insidious in nature and symptoms of pigment dispersion syndrome often mimic that of acute anterior uveitis, as patients typically present with overlapping symptoms, including blurred vision, redness, ocular pain, photophobia, and tearing. 

Ocular Ischemic Syndrome: Ocular symptoms seen in OIS can be the first sign of severe carotid stenosis, a disease requiring prompt therapy, and therefore should be considered in any patient presenting with refractory uveitis or neovascular glaucoma. OIS typically manifests as gradual visual loss (90% of cases), pain in the effected eye (40%), and varying degrees of visual field loss. 

Retinitis pigmentosa: nyctalopia, prolonged dark adaptation, photopsia, field loss 

Retinal Detachment: Floaters/flashes/ field loss. Pain/photophobia not typical. 

Retinoblastoma: Eye redness, pain, and posterior synechiae are typically absent which can help differentiate this entity from uveitis. 

Clinical diagnosis

The clinician must have a high index of suspicion particularly when neoplastic disease is a consideration. Diagnosis has been found to be delayed up to a year after symptom onset in patients with PVRL because of confusion with inflammatory disease. Since steroids are lympholytic, treatment may temporarily quell the disease process delaying proper referral or consideration of vitreous biopsy. In addition, due to the lympholytic nature of steroids, fragile lymphoma cells may lyse resulting in a negative biopsy result and further delaying the diagnosis.

Diagnostic procedures

When neoplastic disease is a consideration, the clinician should have a low threshold to perform diagnostic procedures including vitreous biopsy and/or diagnostic paracentesis. Vitreous biopsy is important in the diagnosis of lymphoma especially when there is no evidence of CNS or CSF involvement. Ideally, one should obtain at least 1 ml of undiluted vitreous. Prior to the procedure, communication with an experienced pathologist is crucial so that the specimen is promptly and properly handled.

Imaging and Laboratory testing

Primary Vitreoretinal Lymphoma

• Optical coherence tomography: subretinal hyper-reflective infiltrates, RPE undulation.
• Fluorescein angiography: hypofluorescent spots similar to "Leopard spots".
• B scan ultrasonography: vitreous debris, elevated subretinal lesions, subretinal fluid.
• Neuroimaging: Since nearly all patients with PVRL will either have preexisting CNS lymphoma or will develop it - all patients need to undergo CNS surveillance.
• Cerebrospinal fluid analysis: nearly one third of patients will have lymphoma cells. If lymphoma cells are confirmed in a patient with ocular involvement, the need for vitreous biopsy is less important.
• Vitreous specimen: cytokine analysis (elevated ratio of IL-10 to IL-6 is supportive evidence for lymphoma); gene rearrangement studies for evidence of monoclonality.

Leukemia

• Paracentesis/biopsy: cytological evaluation of hypopyon, iris nodules or suspicious cells.

Metastatic Solid Tumors

• B scan ultrasonography: Elevated choroidal mass with or without subretinal fluid.
• Paracentesis/biopsy: iris mass/suspicious nodules, cytology.

Intraocular Foreign Body

• B Scan: sensitivity variable based on user
• CT Scan of globe/orbits: 2-3 mm cuts when metallic IOFB is a consideration. Not helpful for non-metallic IOFB.
• MRI: contraindicated when metallic IOFB is a possibility.

Retinitis Pigmentosa

• Electroretinogram (ERG): reduction in a and b-wave amplitudes with or without prolonged implicit time in early disease but nondetectable ERG later.

Ocular Ischemic Syndrome

• Fluorescein angiography: Prolonged retinal arteriovenous time is present in nearly all. Optic disc and vascular staining as well as capillary non-perfusion is also seen.
• Carotid duplex ultrasonography: provides anatomic imaging of carotid arteries and flow parameters to determine the degree of stenosis.

Retinal Detachment

• B scan ultrasonography: subretinal fluid may be shallow

Retinoblastoma

• Ocular imaging can be particularly useful in differentiating uveitis and retinoblastoma, as retinoblastoma will typically display intralesional calcification on ultrasound. However, Shields et al notes that, particularly in cases of the diffuse subtype, calcification may be absent or subtle. Therefore, a thorough history, clinical exam, with or without CT scanning and prompt referral to an ocular tumor specialist should be undertaken in order to make this life-saving diagnosis.

Medulloepithelioma

• B scan ultrasonography and MRI very helpful in diagnosing intraocular mass. Definitive diagnosis requires biopsy with histopathology.

Differential diagnosis

• inflammatory/autoimmune: Intermediate uveitis, multifocal choroiditis, sarcoidosis, Vogt-Koyanagi-Harada disease, retinal vasculitis, birdshot chorioretinitis, serpiginous choroiditis, Acute posterior multifocal placoid pigment epitheliopathy
• infectious: toxoplasmosis, syphilis, tuberculosis, acute retinal necrosis, CMV retinitis
• Neoplastic: metastatic tumors, amelanotic melanoma

Management

Medical and surgical therapy of conditions masquerading as uveitis is beyond the scope of this article.

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